Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of TAK 831 in Healthy Adult Asian Subjects
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Neurocrine Biosciences

Title: Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of 
TAK-831 in Healthy Adult Asian Subjects 
NCT Number: NCT03687684 
Protocol Approve Date: 26-Feb-2019 
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). 

CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of 
TAK-831 in Healthy Adult Asian Subjects
Phase 1 Study of TAK-831 in Healthy Adult Asian Subjects
Study Identifier:
TAK-831-1002
Compound:
TAK-831
Date:
26 February 2019
Version/Amendment 
Number:
Amendment 3
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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CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................16
4.1
Background .............................................................................................................16
4.2
Rationale for the Proposed Study.............................................................................16
4.3
Benefit/Risk Profile .................................................................................................17
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................19
5.1
Hypothesis...............................................................................................................19
5.2
Trial Objectives .......................................................................................................19
5.2.1
Trial Primary Objective......................................................................................19
5.2.2
Trial Secondary Objective..................................................................................19
5.2.3
Trial Exploratory Objective................................................................................19
5.3
Endpoints.................................................................................................................19
5.3.1
Primary Endpoint...............................................................................................19
5.3.2
Secondary Endpoints..........................................................................................19
5.3.3
Exploratory Endpoints .......................................................................................20
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................21
6.1
Trial Design.............................................................................................................21
6.2
Cohort transition/Dose Escalation............................................................................23
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................24
6.3.1
Rationale for Study Population...........................................................................24
6.3.2
Rationale of Trial Design ...................................................................................24
6.3.3
Rationale for Dose .............................................................................................24
6.3.4
Rationale for Endpoints......................................................................................25
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures ................26
6.4
Trial Beginning and End/Completion.......................................................................26
6.4.1
Definition of Beginning of the Trial ...................................................................26
6.4.2
Definition of End of the Trial.............................................................................27
6.4.3
Definition of Trial Discontinuation ....................................................................27
6.4.4
Criteria for Premature Termination or Suspension of the Trial............................27
6.4.5
Criteria for Premature Termination or Suspension of a Study Site......................28
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............29
7.1
Inclusion Criteria .....................................................................................................29
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7.2
Exclusion Criteria ....................................................................................................30
7.3
Excluded Medications Supplements, Dietary Products.............................................32
7.4
Diet, Fluid, Activity.................................................................................................33
7.4.1
Diet and Fluid ....................................................................................................33
7.4.2
Activity..............................................................................................................34
7.5
Documentation of Subject Failure............................................................................34
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................34
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................36
7.8
Subject Replacement................................................................................................36
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................37
8.1
Clinical Study Drug .................................................................................................37
8.1.1
Clinical Study Drug Labeling.............................................................................37
8.1.2
Clinical Study Drug Inventory and Storage ........................................................37
8.1.3
Randomization Code Creation and Storage ........................................................37
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................37
8.1.5
Accountability and Destruction of Sponsor-Supplied Drugs...............................38
9.0
STUDY PROCEDURES...............................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent Procedure..............................................................................39
9.1.2
Inclusion and Exclusion .....................................................................................39
9.1.3
Medical History/Demography ............................................................................39
9.1.4
Concomitant Medications...................................................................................40
9.2
Clinical Procedures and Assessments.......................................................................40
9.2.1
Full Physical Exam ............................................................................................40
9.2.2
Height and Weight .............................................................................................40
9.2.3
BMI ...................................................................................................................40
9.2.4
Vital Signs .........................................................................................................40
9.2.5
12-Lead ECG.....................................................................................................40
9.2.6
Holter ECG........................................................................................................41
9.2.7
Columbia Suicide Severity Rating Scale (C-SSRS)............................................41
9.2.8
Study Drug Administration ................................................................................41
9.2.9
AE Monitoring...................................................................................................41
9.2.10 Laboratory Procedures and Assessments ............................................................42
9.3
Biomarker, PK, PD, and PGx Samples.....................................................................43
9.3.1
PK Measurements..............................................................................................44
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9.3.2
PD Analysis .......................................................................................................45
9.3.3
PGx Measurements ............................................................................................46
9.3.4
Confinement ......................................................................................................46
10.0
ADVERSE EVENTS ....................................................................................................48
10.1
Definitions and Elements of AEs .............................................................................48
10.1.1 SAEs..................................................................................................................50
10.2
AE Procedures.........................................................................................................51
10.2.1 Assigning Severity/Intensity of AEs...................................................................51
10.2.2 Assigning Causality of AEs................................................................................51
10.2.3 Assigning Causality of AEs to Study Procedures................................................51
10.2.4 Start Date...........................................................................................................52
10.2.5 End Date............................................................................................................52
10.2.6 Pattern of Adverse Event (Frequency)................................................................52
10.2.7 Action Taken with Study Treatment...................................................................52
10.2.8 Outcome ............................................................................................................52
10.2.9 Collection and Reporting of AEs, SAEs, and Abnormal LFTs............................53
10.2.10
Safety Reporting to Investigators, IRBs and Regulatory Authorities.............54
11.0
STATISTICAL METHODS..........................................................................................55
11.1
Statistical and Analytical Plans ................................................................................55
11.1.1 Analysis Sets......................................................................................................55
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................55
11.1.3 PK Analysis .......................................................................................................55
11.1.4 PD Analysis .......................................................................................................56
11.1.5 Safety Analysis ..................................................................................................56
11.2
Determination of Sample Size..................................................................................57
11.3
Interim Analysis and Criteria for Early Termination ................................................58
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
12.1
Study-Site Monitoring Visits ...................................................................................59
12.2
Protocol Deviations..................................................................................................59
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................60
13.1
IRB Approval ..........................................................................................................60
13.2
Subject Information, Informed Consent, and Subject Authorization .........................60
13.3
Subject Confidentiality ............................................................................................61
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................62
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13.4.1 Publication and Disclosure.................................................................................62
13.4.2 Clinical Trial Registration..................................................................................62
13.5
Clinical Trial Results Disclosure..............................................................................62
13.6
Insurance and Compensation for Injury....................................................................62
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................63
14.1
Administrative Information......................................................................................63
14.1.1 Study Contact Information .................................................................................63
14.1.2 Investigator Agreement......................................................................................63
14.1.3 Study-Related Responsibilities...........................................................................63
14.1.4 List of Abbreviations .........................................................................................63
15.0
DATA HANDLING AND RECORDKEEPING............................................................65
15.1
eCRFs......................................................................................................................65
15.2
Record Retention .....................................................................................................66
16.0
REFERENCES..............................................................................................................67
17.0
APPENDICES...............................................................................................................68
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Cohorts..........................................................................................22
Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects............................25
Table 7.a
Excluded Medications, Supplements, Dietary Products ......................................33
Table 9.a
Primary Specimen Collections ...........................................................................44
Table 9.b
Blood Sample Collection for PK Analysis..........................................................45
Table 9.c
Blood Sample Collection for PD Analysis..........................................................45
Table 10.a
Takeda Medically Significant AE List................................................................51
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................11
Figure 6.a
Study Schematic ................................................................................................22
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................68
Appendix B
Pregnancy and Contraception.............................................................................69
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Appendix C
Acceptable Time Window for Study Procedure..................................................71
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals
Compound:
TAK-831
Study Identifier: TAK-831-1002
Phase: 1
Title of Study: Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of TAK 831 in Healthy Adult Asian Subjects
Trial Design:
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) of TAK-831 in healthy adult Asian subjects.
This study will include up to 5 cohorts of healthy adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered under a 3 sequential dose escalation design, and the safety, 
PK and PD will be assessed. Eight healthy adult Japanese subjects will be randomized in dosing orders of A 
(100 mg→300 mg), B (100 mg→placebo), and C (placebo→300 mg) at a 4:2:2 ratio. A single dose of TAK-831 or 
placebo will be administered on Day 1 and Day 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
Cohort 2 will include 8 healthy adult Japanese subjects. Of these subjects, 6 will be randomly assigned to the TAK-831 
group and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed by their 
multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with subjects followed for 
approximately 72 hours of assessments for safety, PK and PD. Treatment for multiple doses will start with a 
once-daily regimen on Day 4, which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at 
least 48 hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 to 5 will be optional, in which a single dose will be administered followed by multiple doses, and Cohorts 3 
and 4 may be studied based on emerging data from Cohorts 1 and 2.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 and 5 will include 8 healthy adult Japanese 
subjects. Of these subjects in the respective cohorts, 6 will be randomly assigned to the TAK-831 group and 2 to the 
placebo group. A single dose of TAK-831 or placebo will be administered, followed by their multiple doses. A single 
dose of TAK-831 or placebo will be administered on Day 1 with subjects followed for approximately 72 hours of 
assessments for safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, which 
will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 hours after the last 
TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before discharge.
Trial Primary Objective:
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Secondary Objectives:
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Target: Healthy adult Asian subjects
Planned Number of Subjects:
Cohort 1: 8 subjects
Cohorts 2 to 5: 8 subjects per cohort
Planned Number of Sites:
1 site
Dose Levels:
<Cohort 1>
Single dose at 100 mg on Day 1 (Part 1) and 300 mg on 
Day 9 (Part 2) (fasted)
<Cohort 2>
Single dose at 600 mg on Day 1. Multiple doses 
Route of Administration:
Oral
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(once-daily) at 600 mg on Days 4 to 17 (fasted)
<Cohort 3>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
<Cohort 4>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
<Cohort 5>
Single dose at 50 mg on Day 1. Multiple doses 
(once-daily) at 50 mg on Days 4 to 17 (fasted)
Duration of Treatment:
<Cohort 1>
Part 1: Single dose on Day 1
Part 2: Single dose on Day 9
<Cohorts 2 to 5>
Single dose on Day 1 and once-daily multiple doses on 
Days 4 to 17, for 14 days, in each Cohort
Planned Trial Duration:
<Cohort 1>
Screening period: Day -28 to -1
Treatment period: Days 1 to 12
Follow-up period: Day 23
<Cohorts 2 to 5>
Screening period: Day -28 to -1
Treatment period: Days 1 to 19
Follow-up period: Day 31
Inclusion Criteria:
Subject eligibility will be determined according to the following criteria.
1.
The subject must understand the study procedures and agree to participate by providing written informed consent 
(for Chinese subjects, an interpreter should be present as necessary).
2.
The subject must be willing and able to comply with all study procedures and restrictions.
3.
The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, inclusive, at the 
Screening.
4.
The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the Screening.
5.
The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing products (e.g., 
nicotine patch) for at least 6 months prior to the Screening.
6.
Chinese subjects are defined as subjects who were born in mainland China, and their biological parents and 
grandparents must all have been of Chinese origin (for Cohort 3 only).
7.
Chinese subjects who have lived out of China for more than 5 years must not have significantly modified their 
diets since leaving China (for Cohort 3 only).
8.
The subject must be judged to be in good health by the investigator or sub-investigator, based on clinical 
evaluations including laboratory tests, medical history, full physical examination, 12-lead electrocardiogram, 
and vital sign measurements performed at the Screening. and prior to the first dose of study drug.
9.
The subject must meet the birth control requirements.
Exclusion Criteria:
The subject must be excluded from participating in the study if the subject meet any of the followings.
1.
The subject has a history of clinically significant endocrine, gastrointestinal (including motility disorder and 
intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, or 
genitourinary, or presents with major neurological (including stroke and chronic seizures) abnormalities or 
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diseases.
2.
The subject has participated in another investigational trial within 4 weeks before the pretrial visit (Screening). 
The 4-week window will be derived from the date of the last trial procedure and/or adverse events related to the 
trial procedure in the previous trial to the Screening Visit of the current trial.
3.
The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the sponsor.
4.
The subject has a history of cancer (malignancy).
5.
The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy) or has had 
an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.
6.
The subject has a positive alcohol or drug or immunological screen.
7.
The subject is of childbearing potential or lactating.
8.
The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 8 weeks prior to 
the first dose of study drug.
9.
The subject with any gastrointestinal surgery that could impact upon the absorption of study drug.
10.
The subject has a known hypersensitivity to any component of the formulation of TAK-831 or related 
compounds.
11.
The subject is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before administration of the initial 
dose of trial drug, throughout the trial (including washout intervals between trial periods), until the Follow-up 
Visit.
12.
The subject has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce] per day).
13.
The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
14.
The subject has a history of drug abuse.
15.
The subject has a (QT interval with Fridericia’s correction method) QTcF >450 ms (males) or >470 ms (females) 
or PR outside the range of 120 to 220 ms at the Screening Visit or Check-in.
Main Criteria for Evaluation and Analyses:
Primary Endpoint
Safety: Adverse event, laboratory tests, vital signs, weight, 12-lead electrocardiogram
Secondary Endpoints
Pharmacokinetics: The following parameters will be calculated.
Cmax (Cohort 1, Day 1 of Cohorts 2 to 5)
Cmax,ss (Day 17 of Cohorts 2 to 5)
tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 5)
AUClast (Cohort 1, Day 1 of Cohorts 2 to 5)
AUC∞(Cohort 1, Day 1 of Cohorts 2 to 5)
AUCτ (Days 1 and 17 of Cohorts 2 to 5)
Statistical Considerations:
Pharmacokinetics:
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and treatment 
period for Cohorts 2, 4 and 5 as well as Cohort 3.
Concentrations of TAK-831 in plasma and cerebrospinal fluid will be summarized by each scheduled sampling time 
using summary statistics. Individual plasma concentration data versus time of TAK-831 will be presented. Plasma PK 
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parameters, including dose-normalized Cmax and AUC, will be summarized by dose and day using summary statistics. 
Accumulation of TAK-831 from Day 1 to Day 17 will be assessed by summarizing the ratio of Cmax and AUC at 
Days 1 and 17 by dose. Dose linearity in plasma PK parameters (Cmax and AUC) will be assessed graphically for those 
parameters at Days 1 and 9 for Cohort 1 and Day 1 for Cohorts 2 to 5. Additional analyses on dose linearity will be 
included if appropriate.
Pharmacodynamics:
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and each 
scheduled sampling time for Cohorts 2, 4 and 5 as well as Cohort 3. Concentrations of D-serine, L-serine and the ratio 
of D-serine to total serine in plasma and concentrations of D-serine, L-serine and the ratio of D-serine to total serine in 
cerebrospinal fluid (if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of D-serine to total serine in 
plasma, and change and percent change from baseline will be summarized by day using summary statistics. The 
potential relationship between TAK-831 exposure and biomarker response will be explored graphically. Additional 
statistical or PK-PD analyses will be included if appropriate.
Safety:
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for Cohorts 2, 4 and 5, and 
for Cohort 3.
A treatment-emergent adverse event (TEAE) refers to an adverse event that occurs after the start of study treatment. 
The frequency of all TEAEs, drug-related TEAEs , all TEAEs by intensity, drug-related TEAEs by intensity, TEAEs 
leading to study drug discontinuation, and serious TEAEs will be summarized. TEAEs will be coded using Medical 
Dictionary for Regulatory Activities Terminology (MedDRA) and summarized by system organ class (SOC) and 
preferred term (PT).
For continuous values of laboratory findings, vital signs and other safety parameters, summary statistics will be 
provieded for observed values and change from baseline at each evaluation time point. Pre- and post-dose shift tables 
will be prepared for categorical variables.
Sample Size Justification:
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size required to assess the 
safety, tolerability, PK and PD of each cohort. This is not based on any statistical rationale.
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2.0
STUDY SCHEMATIC
Figure 2.a shows the schematic of the trial design.
Figure 2.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
Sequence of 
administration
Part 1
Washout 
interval
Part 2
Day 1 to 4
Day 5 to 8
Day 9 to 12
A
TAK-831 100 mg
Washout
TAK-831 300 mg
B
TAK-831 100 mg
Placebo
C
Placebo
TAK-831 300 mg
<Cohorts 2 to 5>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening (c)
Hospitalization (c)
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion.
(c)
After Cohort 3, Screening will be on Days -28 to -3, hospitalization will be on Day -2 and an examination at 
hospitalization will be on Day -1.
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3.0
SCHEDULE OF STUDY PROCEDURES
<Cohort 1>
Screening period
Treatment period
Early
Termina
tion
Follow-up 
visit
Screening Hospitali
zation
Part 1
Washout interval
Part 2
Day
-28 to -2
-1
1
2
3
4
5 to 7
8
9
10
11
12
23 (±2)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics, medical history
X
Prior medications
X
Physical examination
X
X
X
X
X
X
X
X (l)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X (l)
Weight, height, BMI (b)
X
X
X
X
X
X
X (l)
12-lead electrocardiogram (ECG) (c)
X
X
X
X
X
X
X
X
X (l)
Laboratory tests (d)
X
X
X
X
X
X
X (l)
Immunological test, alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
X
C-SSRS (f)
X
X
X
X
X
X
Sample collection for pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X(k)
Blood sample collection for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
X
X
Urine sample (for future tests) (j)
X
X
X
X
Study drug administration
X
X
Adverse events
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Concomitant medications
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Hospitalization
X
X-----------------------------------X
X
X-----------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36, 48 and 72 hours postdose on Day 1, on Day 8, predose on Day 9, and 1, 4, 12, 24, 36, 48 and 72 hours 
postdose on Day 9.
(b)
Height will be measured at Screening only. Weight will be measured at Screening visit, Day -1, 72 hours postdose on Day 1, Day 8, 72 hours postdose on Day 9.
(c)
12-lead ECG will be measured at Screening, Day -1, predose, 2 and 72 hours postdose on Day 1, Day 8, predose on Day 9, 2 and 72 hours postdose on Day 9.
(d)
Laboratory tests will be performed at Screening, on Day -1, 72 hours postdose on Day 1, on Day 8, and at 72 hours postdose on Day 9.
(e)
FSH will be measured in postmenopause women only.
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(f)
C-SSRS will be investigate at Screening, Day -1, Day 4, Day 8, and Day 12.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 9, and 0.5, 1. 1.5, 2, 4, 8, 12, 24, 36, 48, 
and 72 hours postdose on Day 9.
(i)
Samples for PD assessment will be collected on Day -1 (at 20, 16, 12 hours predose on Day 1), predose, 1, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose, 1, 4, 8, 
12, 24, 36, 48, and 72 hours postdose on Day 9.
(j)
Urine samples will be collected on Day -1, 24 hours postdose on Day 1, and 24 hours postdose on Day 9.
(k)
Samples for PK assessment at discontinuation will be collected if it is possible.
(l)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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<Cohorts 2 to 5>
Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening
(n)
Hospitalization
(n)
Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics, medical 
history
X
Prior medications
X
Physical examination
X
X
X
X
X
X (m)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (m)
Weight, height, BMI (b)
X
X
X
X
X (m)
12-lead 
electrocardiogram 
(ECG) (c)
X
X
X
X
X
X
X
X
X (m)
Holter ECG (c)
X
Laboratory tests (d)
X
X
X
X
X
X (m)
Immunological test, 
alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
C-SSRS (f)
X
X
X
X
Sample collection for 
pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection 
for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X (l)
Blood sample collection 
for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
Cerebrospinal fluid 
sample collection for 
pharmacodynamic (PD) 
assessment (j)
X
X
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Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening
(n)
Hospitalization
(n)
Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Urine sample (for future 
tests) (k)
X
X
X
X
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Concomitant 
medications
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Hospitalization
X
X-------------------------------------------------------------------------------------------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36 and 48 hours postdose on Day 1, predose on Days 4 to 16, predose on Day 17, and 1, 4, 12, 24, and 
48 hours postdose on Day 17.
(b)
Height will be measured at Screening only. Weight will be measured at Screening, on Day -1, and 48 hours postdose on Day 17.
(c)
12-lead ECG will be measured at Screening, Day -1, presdose and 2 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose, 2 and 48 hours postdose on Day 
17.
Holter ECG will be measured from -23 hours predose to 24 hours post dose on Day 1 (after Cohort 3). Data will be extracted at -23, -22, -20, -16 and -12 predose, predose and 
1, 2, 4, 8, 12 and 24 hours postdose on Day 1.
(d)
Laboratory tests will be performed at Screening, Day -1, predose on Day 11, and at 48 hours postdose on Day 17.
(e)
FSH will be measured in postmenopause women only.
(f)
C-SSRS will be investigate at Screening Visit, Day -1, and Day 19.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose on 
Day 14, predose, 0.25, 0.5, 1. 1.5, 2, 4, 8, 12, 16, and 24 hours postdose on Day 17.
(i)
Samples for PD assessment will be collected at 20, 16, and 12 hours predose on Day 1, predose, 1, 4, 8, 12, and 24 hours postdose on Day 1, predose on Day 11, predose on Day 
14, predose, 1, 4, 8, 12, and 24 hours postdose on Day 17.
(j)
Samples for PD assessment will be collected on Day -1 and 24 hours postdose on Day 17 (if it is performed). Samples will be also used to measure concentration of TAK-831 
cerebrospinal fluid. 
(k)
Urine samples will be collected on Day -1, at 24 hours postdose on Day 1, and 24 hours postdose on Day 17.
(l)
Samples for PK assessment at discontinuation will be collected if it is possible.
(m)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
(n)
After Cohort 3, Screening will be on Days -28 to -3, hospitalization will be on Day -2 and an examination at hospitalization will be on Day -1.
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4.0
INTRODUCTION
4.1
Background
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and
behaves. Schizophrenia usually develops at late adolescence or early adulthood and manifests in 
maximum 1% of the population. For those who have relatives of first degree with schizophrenia, 
the incidence rate is higher by 10% (the concordance rate for schizophrenia in identical twins is 
40% to 65%) [1][2][3]. Symptoms of schizophrenia can be subdivided into 3 broad classes: 
positive, negative, and cognitive symptoms [4]. Positive symptoms include hallucinations, 
delusions, and disordered thought and speech, and can be summarized as psychosis. Negative 
symptoms include reduced emotion, reduced ability to experience pleasure (anhedonia), lack of 
motivation, and reduced social interaction. Finally, cognitive symptoms include poor information 
processing, impaired ability to focus on objectives, and abnormalities of working memory and 
learning [4]. Currently available antipsychotics are broadly effective for the treatment of positive
symptoms. However, the negative symptoms and cognitive impairment of schizophrenia are the 
known particular aspects that cause dysfunction, for which no therapy has been approved. There 
still are significant unmet medical needs.
Hypofunction of N-methyl-D-aspartic acid (NMDA) receptor is considered a potential mechanism 
in the pathophysiology of schizophrenia, which could be mitigated with increased D-serine levels 
in the brain [5]. D-amino acid oxidase (DAAO) contributes to the metabolism of D-serine in the 
brain and is highly expressed in the cerebellum. Changes in the D-serine levels or D-serine to total 
serine ratios have been reported in the plasma of patients with schizophrenia both naive and under 
drug treatment [6]-[9]. In addition, serine racemase (the D serine generating enzyme) and the 
NMDA NR2A subunit are among the risk genes identified from the recent large scale 
genome-wide association study analysis, indicating the biological relevance to schizophrenia of 
the genetic pathway in which DAAO resides [10]. Therefore, inhibition of DAAO is considered to 
be a promising target in treatment of schizophrenia.
TAK-831 is a highly selective and potent inhibitor of DAAO. TAK-831 increased D-serine levels 
in the cerebellum of normal mice and showed efficacy in a mouse model of Friedreich ataxia 
(FRDA) mouse models. It also demonstrated a positive effect on cognition and social interaction in 
rodent cognition and behavioral models.
As stated above, TAK-831 is expected to provide a therapeutic effect on FRDA and cognitive 
impairment as well as negative symptoms associated with schizophrenia.
4.2
Rationale for the Proposed Study
TAK-831 is currently under development for the treatment of FRDA and cognitive impairment as 
well as negative symptoms of schizophrenia. Three overseas phase 1 studies in healthy adults 
(single and multiple dose study [TAK-831-1001], positron emission tomography [PET] study to 
determine DAAO brain enzyme occupancy [TAK-831-1003], and a study to evaluate the food 
effect [TAK-831-1004]) have been conducted so far, in which TAK-831 was well-tolerated.
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In addition, two phase 1 studies in healthy adults (study with single and multiple doses at high dose 
level [TAK-831-1005] and relative bioavailability and food effect study [TAK-831-1006]) are
being conducted or planned. Two phase 2 studies in patients with schizophrenia (small-scale 
crossover study to examine the cerebellar functions [TAK-831-2001], and a study to evaluate the 
efficacy and safety for negative symptoms of schizophrenia [TAK-831-2002]) are also underway. 
Besides, a phase 2 proof-of-concept (POC) study in patients with schizophrenia is being planned in 
China. Based on the result of these phase 2 studies, a phase 3 global study (long-term study) has 
been planned.
In parallel with these development plans, TAK-831 is also being developed in Japan for the 
treatment of cognitive impairment and negative symptoms associated with schizophrenia. In 
respect of FRDA, a genetic disease, since there has been no confirmed report as of June 2018 that 
clearly indicates the existence of Japanese patients, no development plan has been made for FRDA 
in Japan.
Enrollment of Japanese patients into the phase 3 global study and the phase 2 POC study in China 
has been considered. This study was planned to examine the safety and pharmacokinetic (PK) of 
TAK-831 in Japanese as well as to evaluate the safety and PK in Asian healthy subjects for the 
aforementioned studies.
4.3
Benefit/Risk Profile
Because this study will be conducted in healthy adults, there is no benefit to subjects.
The following risk mitigation measures will be implemented in this study. These measures are 
based on what is known about the mechanism of action of TAK-831, nonclinical data, and the 
phase 1 studies (4 studies, including preliminary data of TAK-831-1005). Procedures may be 
added during the study as necessary based on evaluation of any additional clinical or nonclinical 
data.
The safety of TAK-831 has been studied in a prior single dose (up to 750 mg in suspension and 
100 mg T1 tablet formulation) and multiple dose (up to 400 mg once daily [QD] in suspension) 
study in healthy Western subjects (TAK-831-1001), a single dose (up to 500 mg in suspension) 
PET study to investigate DAAO occupancy in the brain (TAK-831-1003) and a single dose food 
effect (400 mg T2 tablet formulation) study (TAK-831-1004). These studies have not resulted in a 
safety signal that would prevent additional studies. Additionally, TAK-831 given as single and 14 
days multiple doses (up to 1200 mg in suspension and 600 mg T2 tablet formulation) is currently 
being studied in healthy adult subjects (TAK-831-1005). TAK-831 has been safe and well 
tolerated to date (provisional data as of end-April 2018).

Acute hypersensitivity/anaphylactic reactions to new chemical entities are always a possible 
risk in any clinical study. Appropriate procedures should be used to manage such possible 
risks.

Study procedure-specific risks include issues relating to blood collection for safety 
assessment/PK and pharmacodynamics (PD) monitoring (venipuncture may cause bruising), 
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and the placement of ECG pads (which may cause some local redness and/or 
erythema/itching).

In case of serious adverse events (SAE), the investigator has discretion to use his/her clinical 
judgment as to whether to allow a subject to proceed in the study or whether to unblind the 
subject in order to determine his/her treatment allocation.

The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered to monitor 
emergent suicidality.
The Investigator's Brochure should be referred for more detailed safety of TAK-831.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed on the basis of the following hypothesis.

TAK-831 given as single or multiple doses shows no safety issue and is well tolerated.

The PK of TAK-831 given as single or multiple doses to Asian subjects is equivalent to that in 
Western subjects.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult 
Asian subjects.
5.2.2
Trial Secondary Objective
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
5.2.3
Trial Exploratory Objective
To assess the effect of TAK-831 on the concentrations of D-serine and L-serine in plasma (and 
concentrations of D-serine and L-serine in cerebrospinal fluid as necessary) after TAK-831 
administration to healthy Asian subjects.
5.3
Endpoints
5.3.1
Primary Endpoint
Safety: Adverse events (AEs), laboratory tests, vital signs, weight, 12-lead electrocardiogram
(ECG)
5.3.2
Secondary Endpoints
PK: The following parameters will be calculated.

Cmax (Cohort 1, Day 1 of Cohorts 2 to 5)

Cmax,ss (Day 17 of Cohorts 2 to 5)

tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 5)

AUClast (Cohort 1, Day 1 of Cohorts 2 to 5)

AUC∞(Cohort 1, Day 1 of Cohorts 2 to 5)

AUCτ (Days 1 and 17 of Cohorts 2 to 5)
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5.3.3
Exploratory Endpoints

PK: Rac (Cmax) and Rac(AUC) on Days 1 and 17 (Cohorts 2 to 5), t1/2z, CL/F, Vz/F

Concentration of TAK-831 cerebrospinal fluid (if collected cerebrospinal fluid samples for 
PD)

PD: Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (Days -1 and 18) (may be assessed in Cohort 2 or thereafter based on PD in plasma)
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, PK and 
PD of TAK-831 in healthy adult Asian subjects. This study will include up to 5 cohorts of healthy 
adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered at each dose level under a 3-sequential 
dose escalation design. Eight healthy adult Japanese subjects will be randomized to the sequence 
of administration A, B, and C at a 4:2:2 ratio. A single dose of TAK-831 or placebo will be 
administered on Days 1 and 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
In Cohort 2, a single dose of study drug will be administered to healthy adult Japanese subjects, 
followed by multiple doses. Of these subjects, 6 will be randomly assigned to the TAK-831 group 
and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed 
by their multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with 
subjects followed for approximately 72 hours of assessments for safety, PK and PD. Treatment for 
multiple doses will start with a once-daily regimen on Day 4, which will continue to Day 17 (for 
14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo 
dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 to 5 will be optional, in which a single dose of study drug will be administered followed 
by multiple doses, and Cohorts 3 and 4 may be studied based on emerging data from Cohorts 1 and 
2.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 and 5 will include 8 healthy 
adult Japanese subjects. Of these subjects in the respective cohorts, 6 will be randomly assigned to 
the TAK-831 group and 2 to the placebo group. A single dose of TAK-831 or placebo will be 
administered, followed by their multiple doses. A single dose of TAK-831 or placebo will be 
administered on Day 1 with subjects followed for approximately 72 hours of assessments for 
safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, 
which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 
hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before 
discharge.
Table 6.a shows the summary of cohorts, and Figure 6.a shows the schematic of the trial design.
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Table 6.a
Summary of Cohorts
Cohort
Subject
Dose
Remarks
1
Japanese
8 subjects
Part 1:
100 mg (4×25 mg T3 tablet formulation)
Fasted, single dose
Wash out period between part 1 and 2 will be 
8 days.
Part 2:
300 mg (1×300 mg T3 tablet formulation)
Fasted, single dose
2
Japanese
8 subjects
600 mg (2×300 mg T3 tablet formulation)
Fasted, single dose + multiple dose (once 
daily)
3
Chinese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 3 may be run if emerging data from 
Cohorts 1 and 2 suggest ethnic-related 
differences in the tolerability and/or PK 
profile. Dose level will be determined based 
on the results from Cohorts 1 and 2.
4
Japanese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 4 may be run based on the emerging 
data from Cohorts 1 and 2 in Asian subjects.
5
Japanese
8 subjects
50 mg (2×25 mg T3 tablet formulation)
Fasted, single dose + multiple dose (once 
daily)
TBD: To be decided
Figure 6.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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<Cohorts 2 to 5>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening (c)
Hospitalization (c)
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion.
(c)
After Cohort 3, Screening will be on Days -28 to -3, hospitalization will be on Day -2 and an examination at 
hospitalization will be on Day -1.
6.2
Cohort transition/Dose Escalation
In Cohort 1, TAK-831 100 mg or placebo will be administered on Day 1 (Part 1) followed by 
confirmation of the safety and tolerability (AEs, physical examination, vital signs, weight, 
laboratory tests and 12-lead ECG) up to 72 hours postdose, and then TAK-831 300 mg or placebo 
will be administered on Day 9 (Part 2) followed by confirmation of the safety, tolerability and PK 
up to 72 hours postdose.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohort 1 in a blinded manner and discuss with the sponsor (including the 
medical expert if necessary) as to whether the subsequent cohort should be run.
In Cohort 2, TAK-831 600 mg or placebo will be administered on Day 1, followed by 
confirmation of the safety and tolerability up to 72 hours postdose. Then, multiple doses of 
TAK-831 600 mg or placebo will be administered on Days 4 to 17. The data on safety and 
tolerability up to 48 hours postdose and PK up to 24 hours postdose will be examined.
The dose in Cohort 2 will be adjusted based on the safety and tolerability as well as PK and PD in 
Cohort 1.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohorts 1 and 2 in a blinded manner and discuss with the sponsor 
(including the medical expert if necessary) as to whether Cohorts 3 and 4 should be run.
If Cohorts 3 and 4 are conducted, TAK-831 or placebo will be administered on Day 1, followed by 
confirmation of the safety and tolerability up to 72 hours postdose. Then, multiple doses of 
TAK-831 or placebo will be administered on Days 4 to 17. In Cohorts 3 and 4, the dose will be 
adjusted within 600 mg based on data from prior cohorts. If the dose is escalated, the dose 
escalation will be discontinued according to the following discontinuation criteria.
Discontinuation criteria for dose escalation:

Exposures in any cohort exceed those observed at the highest dose tested in monkey (Cmax of 
3680 ng/mL, AUC24 of 35700 hr*ng/mL)
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
One or more subjects in any single cohort or across more than 1 cohort experience an SAE or 2 
severe or clinically significant AEs occur that are considered related to study drug

One or more subjects in any single cohort or across more than 1 cohort experience severe 
psychiatric symptoms, including (any level of) treatment-emergent suicidal ideation* that are 
considered related to study drug.
*Treatment-emergent suicidality compared to baseline, as measured by changes in suicidal 
ideation or behavior category on the C-SSRS during treatment from the maximum suicidal 
ideation/behavior category at baseline, or any suicidal ideation/behavior during treatment if there 
was none at baseline.
In Cohort 5, TAK-831 50 mg or placebo will be administered on Day 1, and multiple dose of 
TAK-831 50 mg or placebo will be administered on Days 4 to 17.
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale for Study Population
The subject of this study is Japanese or Chinese with a purpose to support the future conduct of 
studies in Asian subjects. The study will be conducted in healthy adult subjects without any 
disease including circulatory or cerebrovascular diseases to appropriately assess the safety and 
tolerability as well as PK and PD of TAK-831.
6.3.2
Rationale of Trial Design
With a purpose to assess the safety and tolerability as well as the PK and PD profiles of TAK-831 
when administered to Asian subject for the first time, this study employed a design with both 
single and multiple doses.
6.3.3
Rationale for Dose
To this date, the highest dose of TAK-831 tested in healthy Western subjects is 1200 mg 
(suspension formulation) once daily in the study TAK-831-1005. Based on the preliminary results, 
there were no significant adverse effects reported at this dose level, and as shown in Table 6.b, the 
mean steady-state exposure was Cmax of 3015 ng/mL and AUC24 of 10501 h*ng/mL. The dose 
regimen of 600 mg given once daily (T2 tablet formulation) was also well tolerated and safe in 
healthy Western subjects. As for the mean steady-state exposures, Cmax was 1494 ng/mL and 
AUC24 was 5090 h*ng/mL. This exposure at 600 mg was similar to that of monkeys at 
100 mg/kg/day, the no-observed-adverse-effect-level (NOAEL).
In the study TAK-831-1005, the PK and PD of TAK-831 given as multiple doses at 100 and 
600 mg (per day) to non-Japanese subjects was examined. The dose of 300 mg will be further 
examined in the study.
Based on the above, the doses of 100, 300 and 600 mg were selected for this study in consideration 
to the safety in humans as well as the comparability of PK and PD between non-Japanese and 
Japanese subjects.
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In addition, the doses used in a relative bioavailability between T2 and T3 tablets and food effect 
study (TAK-831-1006), which is planned overseas, are decided as 50 and 600 mg after the start of 
this study. Data of PK on T3 tablet 50 and 600 mg used in this study will be available from 
TAK-831-1006 study. Therefore, the dose of 50 mg was selected additionally considering the 
comparison of PK and PD between non-Japanese and Japanese with lower dose of T3 tablet.
In the 13-week repeat dose toxicity study in monkeys that are considered the more sensitive 
species than rats, adverse effects (vomiting, diarrhea, and loose stool) were noted at 
600 mg/kg/day. The NOAEL was 100 mg/kg/day for both sexes.
TAK-831 has been administered at doses up to 1200 mg to non-Japanese, and no SAE has been 
reported with exposures exceeding the NOAEL. Besides, the adverse effects (vomiting, diarrhea, 
and loose stool) noted at a dose of 600 mg/kg/day in the 13-week repeat dose toxicity study in 
monkeys will be easily monitored in clinical trials.
Therefore, it is considered possible to administer doses exceeding the NOAEL exposure by 
carefully examining the safety and PK in each Cohort in this study. However, We have no 
information on toxicity at the level exceeding the exposure at 600 mg/kg/day in the 13-week 
repeated dose toxicity study in monkeys. Dose escalation will be stopped if exposures exceed that 
at 600 mg/kg/day in monkeys.
Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects
Animal species-Study
Dose
(mg/kg/day or mg)
Cmax
(ng/mL)
AUC24
(h*ng/mL)
Monkey 13-week (Day 91)
100 mg/kg/day (NOAEL)
1340 (male)
1270 (female)
7490 (male)
9190 (female)
600 (300 BID) mg/kg/day
4650 (male)
2710 (female)
45500 (male)
25900 (female)
Human MRD (Day 16)
1200 mg QD (suspension 
formulation)
3015
10501
Human MRD (Day 16)
600 mg QD (T2 tablet 
formulation)
1494
5090
BID, twice daily; MRD, multiple repeated dose; NOAEL, no-observed-adverse-effect-level; QD, once daily
6.3.4
Rationale for Endpoints
6.3.4.1
Safety Endpoint
The safety endpoints in this study were defined to determine the safety and tolerability following a 
single dose and multiple dose of TAK-831. These are standard endpoints in the Phase 1 studies in 
healthy subjects.
Since TAK-831 involves effects on the central nervous system, the C-SSRS will be administered 
to assess the influence on suicidal ideation or suicidal behavior.
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6.3.4.2
Pharmacokinetic Endpoint
Concentrations of TAK-831 in plasma will be examined to assess the PK of TAK-831 given as a 
single dose or multiple doses to healthy adult Asian subjects, and then the following PK 
parameters will be calculated.

PK parameters: Cmax, Cmax,ss (Cohorts 2 to 5), tmax, AUClast, AUC∞, AUCτ (Cohorts 2 to 5), 
Rac(Cmax) (Cohorts 2 to 5), Rac(AUC) (Cohorts 2 to 5), t1/2, CL/F, Vz/F
Concentration of TAK-831 cerebrospinal fluid will be examined as needed.
6.3.4.3
Pharmacodynamic Endpoint
Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, AUEC24, 
Emax and time to Emax following TAK-831 doses will be examined to assess the PD of TAK-831 in 
healthy adult Asian subjects. Concentrations of D-serine, L-serine and the ratio of D-serine to total 
serine in cerebrospinal fluid may be assessed as necessary.
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures
The objective of this section is to specify the sequence of procedures in the cases where the timing 
of each procedure overlaps.

Safety evaluation will be conducted within the predetermined allowance window as far as 
possible.

Blood samples for PK assessment will be collected at time points as close to the specified time
as possible.

Other procedures must be completed at time points as close to the specified or planned hours as 
possible irrespective of before or after the specified times.

If the timing of blood sampling and ECG or vital signs measurement overlap, blood sampling 
should be prioritized. ECG or vital signs measurement may be performed within an acceptable 
time window (Appendix C).

The priority may be changed upon agreement between the investigator and the sponsor based 
on discussion.

Any test and procedure necessary to immediately assess safety concerns at the time of AEs 
must be prioritized over other regular predetermined procedures.

The safety of subjects in the follow-up period may be confirmed by telephone unless abnormal, 
clinically significant findings are observed upon discharge.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The entire study will start when the first subject signs the informed consent form to participate in 
this study.
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6.4.2
Definition of End of the Trial
The study will end when the last subject completes the last planned visit or follow-up visit (or last 
communication [may be via telephone] relating to the planned visit) or is withdrawn from the 
study or lost to follow up (the status that the subject cannot be reached by the investigator).
6.4.3
Definition of Trial Discontinuation
The study may be discontinued for reasons other than safety such as the followings:

A finding (eg, PK, pharmacodynamics, efficacy, biologic targets) from the other nonclinical or
clinical studies results with the study drug in the study discontinuation for non-safety related
reasons.

Data from drugs classified in the same class as the study drug, or methodologies used in this 
study become available and results in the study being stopped for a non-safety related reason.

Study discontinuation due to non-scientific and non-safety-related reasons, such as slow
enrollment.
Discontinuation of the clinical study for safety reasons:

The study is prematurely terminated because other clinical or non-clinical trials where 
TAK-831 or other drugs of the same class are administered have confirmed unexpected safety 
concerns based on the methodology used in this study
6.4.4
Criteria for Premature Termination or Suspension of the Trial
6.4.4.1
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 met that
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the compound, such that the
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.
6.4.4.2
Procedures for Premature Termination or Suspension of the Trial
In the event that the Sponsor, an institutional review board (IRB), or a regulatory authority elects
to terminate or suspend the study, a study-specific procedure for early termination or suspension
will be provided by the Sponsor; the procedure will be followed by the applicable study sites 
during the course of termination or study suspension.
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6.4.5
Criteria for Premature Termination or Suspension of a Study Site
6.4.5.1
Criteria for Premature Termination or Suspension of a Study Site
A study 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 is permitted by the contractual agreement.
6.4.5.2
Procedure for Premature Termination or Suspension in a Study Site
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend of the
study site, a study-specific procedure for early termination or suspension will be provided by the
Sponsor; the procedure will be followed by the applicable study sites during the course of 
termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria.
1. The subject must understand the study procedures and agree to participate by providing written 
informed consent (for Chinese subjects, an interpreter should be present as necessary).
2. The subject must be willing and able to comply with all study procedures and restrictions.
3. The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, 
inclusive, at the Screening.
4. The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the 
Screening.
5. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing 
products (e.g., nicotine patch) for at least 6 months prior to the Screening.
6. Chinese subjects are defined as subjects who were born in mainland China, and their biological 
parents and grandparents must all have been of Chinese origin (for Cohort 3 only).
7. Chinese subjects who have lived out of China for more than 5 years must not have significantly 
modified their diets since leaving China (for Cohort 3 only).
8. The subject must be judged to be in good health by the investigator or sub-investigator, based 
on clinical evaluations including laboratory tests, medical history, full physical examination, 
12-lead electrocardiogram, and vital sign measurements performed at the Screening. and prior 
to the first dose of study drug.
9. The subject must meet the following birth control requirements:
•
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicidal cream or jelly, from the first dose of study drug until 
95 days (5 half-lives plus 90 days) after the last dose of study drug. No restrictions will be
required for a vasectomized male subject provided the subject is at least 1 year post 
bilateral vasectomy procedure prior to the first dose of study drug. A male subject whose 
vasectomy procedure was performed less than 1 year prior to the first dose of study drug 
must follow the same restrictions as a nonvasectomized man. Appropriate documentation 
of surgical procedure should be provided.
•
Is a male subject who agrees to not donate sperm from the first dose of study drug until 95 
days (5 half-lives plus 90 days) after the last dose of study drug.
•
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a)
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years or ≥6 months of spontaneous amenorrhea in females aged >45 years with 
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serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate 
documentation of follicle-stimulating hormone levels should be required.
b)
Hysterectomy and/or bilateral oophorectomy with appropriate documentation of 
surgical procedure.
c)
Had a tubal ligation with appropriate documentation of surgical procedure.
d)
Congenital conditions such as uterine aplasia etc.
[Rationale for the inclusion criteria]
Inclusion criteria 1, 2, 5, 8 and 9:
These are standard criteria for clinical pharmacology studies in healthy adult subjects and defined 
in consideration to the safety of subjects.
Inclusion Criterion 3:
This is a standard criterion for clinical pharmacology studies in healthy adult subjects for sex. This 
is a standard criterion for clinical pharmacology studies in healthy adult subjects for age.
Inclusion Criterion 4:
This is the range of normal weight in the diagnosis criteria for obesity and obesity disease [11]
proposed by the Japan Society for the Study of Obesity.
Inclusion Criterion 6:
This is set to appropriately assess the safety and PK in Chinese.
Inclusion Criterion 7:
This is set to eliminate the influence by dietary habits on the PK.
7.2
Exclusion Criteria
The subject will be excluded from participating in the study if the subject meet any of the 
followings.
1. The subject has a history of clinically significant endocrine, gastrointestinal (including 
motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, or genitourinary, or presents with major neurological 
(including stroke and chronic seizures) abnormalities or diseases.
2. The subject has participated in another investigational trial within 4 weeks before the pretrial 
visit (Screening). The 4-week window will be derived from the date of the last trial procedure 
and/or adverse events related to the trial procedure in the previous trial to the Screening Visit 
of the current trial.
3. The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) 
of the sponsor.
4. The subject has a history of cancer (malignancy).
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5. The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerability to prescription or 
nonprescription drugs or food.
6. The subject has a positive alcohol or drug or immunological screen.
7. The subject is of childbearing potential or lactating.
8. The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 
8 weeks prior to the first dose of study drug.
9. The subject with any gastrointestinal surgery that could impact upon the absorption of study 
drug.
10. The subject has a known hypersensitivity to any component of the formulation of TAK-831 or 
related compounds.
11. The subject is unable to refrain from or anticipates the use of any medication, including 
prescription and nonprescription drugs or herbal remedies, beginning approximately 7 days 
before administration of the initial dose of trial drug, throughout the trial (including washout 
intervals between trial periods), until the Follow-up Visit.
12. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on 
average (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).
13. The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
14. The subject has a history of drug abuse.
15. The subject has a (QT interval with Fridericia’s correction method) QTcF >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec at the Screening Visit or 
Check-in.
[Rationale for the exclusion criteria]
Exclusion Criteria 1, 15:
This is set to eliminate the influence on safety evaluation for TAK-831.
Exclusion Criterion 2:
This is a minimum duration in which the previous clinical trial is considered to have no influence 
in reference to “General Considerations for Clinical Trials” [12] in order to ensure the safety of 
subjects.
Exclusion Criteria 3, 4, 6, 7, 12, 13, 14:
These are standard criteria for clinical pharmacology studies and defined in consideration to the 
safety of subjects.
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Exclusion Criterion 5:
This is defined in consideration to the safety of subjects.
Exclusion Criteria 8, 9, 11:
This is defined in consideration to the safety of subjects. This is also defined for potential influence 
on PK and PD assessment.
Exclusion Criterion 10:
This is set to exclude subjects who have a known hypersensitivity to any component of the 
formulation of TAK-831 or related compounds in consideration of the safety of subjects.
7.3
Excluded Medications Supplements, Dietary Products
Table 7.a shows excluded medications, supplements, and dietary products.
Use of the drugs listed on Table 7.a (prescribed drugs and over-the-counter [OTC] drugs), 
vitamins, supplements, and dietary products will be excluded from a specified time point to until 
discharge given the effect on the safety and PK. Use of prohibited concomitant drugs will be
allowed when the investigator or sub-investigator deems it necessary to use any of the concomitant
drugs for reasons including treatment of an AE.
Subjects must be instructed not to take any medications including OTC products, without first
consulting with the investigator or sub-investigator.
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Table 7.a
Excluded Medications, Supplements, Dietary Products
From 28 days before admission (Day -1)
to the last discharge
7 days before admission (Day -1)
to the last discharge
72 hours before admission (Day -1)
to the last discharge
• Prescription drugs
• Supplements (St. John's wort, ginseng, 
kava kava, ginkgoes, chinese herbal 
medicine, and melatonin)
• OTC drugs (including aspirin or 
aspirin-containing drugs) (a)
• Vitamins
• Caffeine or xanthine containing 
products
• Vaccination/vaccine (b)
• Beverages containing grapefruit 
(fruit juice, flesh), star fruits (fruit 
juice, flesh), citrus aurantiums 
(high acidity), orange (seville 
oranges), or marmalade
• Apple, orange or pineapple juice
• Brassicaceae vegetables (kale, 
cress, collard greens, kohlrabi, 
brussels sprouts, and mustard).
• Meat cocked over the charcoal
• Nicotine-containing products
• CYP 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1 and 2A6 inhibitors/inducers 
OTC drugs (c)
• Alcohol containing products
CYP: cytochrome P-450, OTC drugs: over-the-counter drugs
Note: Excludes the drug needs to be administered to treat an AE and if the investigator or sub-investigator considers 
necessary to use the drug
(a)
Use of paracetamol (≤1 g/daily) will be allowed.
(b)
Includes H1N1 and other influenza vaccines, however, not limited to these medications.
(c)
Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Diet and fluid (except water) must be ingested at least10 hours before clinical laboratory tests.
On the day before clinical laboratory tests, evening meal must be ingested by 21:00.
During hospitalization, pre-specified diets must be ingested, and other diets will be prohibited. 
After discharge, excessive drinking and eating must be avoided until completion of follow-up 
period.
Subjects will be instructed to fast for at least 10 hours before study drug administration.
Subjects in Cohort 2 to 5 will be instructed to fast for an additional 4 hours on Days 1, 4 and 17 and 
2 hours for all other study drug administration days.
If a blood draw/any examinations coincides with a meal, a blood draw/any examinations will take 
precedence followed by the study procedure and then the meal.
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Subjects should be prohibited from drinking any liquid from 1 hour before to 1 hours after study 
drug administration, with the exception of water (150 mL) taken with the study drug.
7.4.2
Activity
Smoking is prohibited during the study.
Excessive exercise is prohibited during the study.
Blood donation is prohibited for at least 12 weeks (84 days) from completion of the last test.
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 or sub-investigator should
communicate that medical institution about the subject’s participation in the study.
7.5
Documentation of Subject Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a
subject discontinues the study before the first study drug administration, the investigator or
sub-investigator should complete the electronic case report form (eCRF).
The primary reason for subject failure is to be recorded in the eCRF using the following categories:

Death

AE

Screening failure (failed inclusion criteria or did meet exclusion criteria) <specify the reasons>

Protocol deviation

Lost to follow up

Withdrawal by subject <specify the reasons>

Study terminated by the Sponsor

Pregnancy

Sample size sufficient

Other <specify the reasons>
Any subject identification number, once assigned to a subject, should not be reused if the assigned
subject discontinues the study prior to the first study drug administration. Nevertheless, if a reserve 
subject is enrolled in the other 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 the subject who is withdrawn from the
study before the first study drug administration in Period 1, refer to Section 7.5.
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1. Death
The subject died on study.
Note: If the subject dies on study, the event will be considered as a serious adverse event 
(SAE). Refer to Section 10.2.9.3 for 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.
The study drug will be immediately discontinued if a condition meets any following criteria 
during the treatment, and appropriate follow-up will be performed (clinical laboratory tests 
will be repeatedly performed until the clinical laboratory test profiles have normalized or 
returned to baseline, refer to Section 9.2.10.1):
•
Liver Function Test (LFT) Abnormalities
-
ALT or AST >8×the upper limit of normal (ULN), or
-
ALT or AST >5×ULN and persists for more than 2 weeks, or
-
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (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%)
•
Prolonged QT/QTcF intervals
If at least one remarkable prolonged QT interval was observed on 12-lead ECG (eg, 
absolute value of QTcF intervals >500 msec or an increase >60 msec from baseline), and 
the investigator or sub-investigator considered inappropriate to continue the study.
3. Protocol deviation
The discovery after the start of the first study drug administration 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. Pregnancy
If a subject was found to be pregnant.
Note: Participation in the study is immediately discontinued for any pregnancy. Refer to 
Appendix B for the procedures.
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6. Voluntary withdrawal
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).
7. Study terminated by the Sponsor
The Sponsor terminates the study.
8. 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
The Part 1 in Cohort 1 and Cohorts 2 to 5 can have a few reserve subjects considered eligible for 
participation in the study based on screening test. If a subject has not received the study drug as 
scheduled during the study owing to any reason occurring before the study drug administration, a 
reserve subject will be allowed to participate in the study.
If a subject withdraws from the study after initiation of the study drug, the subject will not be 
replaced with a reserve subject.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
[Drug product]
Code name: TAK-831
Dosage form and strength:
TAK-831 tablet is a yellowish-red film-coated tablet containing 25 or 300 mg of TAK-831.
TAK-831 placebo tablet contains no TAK-831 and has same appearance as TAK-831 tablet.
8.1.1
Clinical Study Drug Labeling
Study drug labeling will show name of the study drug, quantity and storage condition of the study 
drug, manufacture number, expiration date, protocol number, name and address of the Sponsor, 
and statement the drug is for clinical trial use only.
8.1.2
Clinical Study Drug Inventory and Storage
TAK-831 is stored at a room temperature (1°C to 30°C).
Study drug must be kept in an appropriate, limited-access, secure place until it is used, or returned
to the Sponsor or its designee. Study drug must be stored under the conditions specified on the
label, and remain in the original container until dispensed.
8.1.3
Randomization Code Creation and Storage
The personnel responsible for randomization (the Sponsor's designee) will prepare the
randomization table/schedule prior to the start of the study. All randomization information will be 
stored in a secured area, accessible only by authorized personnel.
8.1.4
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 will be 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.
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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 eCRF.
If the investigator or sub-investigator breaks the blinding of the study drug, 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 (except cases where the 
investigator or sub-investigator is not informed of unblinding information [unblinding for 
open-label analysis for the Sponsor]).
8.1.5
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 managing 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.
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 Number
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
In Cohorts 1-2 and Cohort 5, and Cohorts 3 and 4 (if added), the subjects will be assigned in the 
order of medication identification number by Cohort according to the randomization code. The 
medication identification number will be a 4-digit number, starting with the following number:
Cohort 1: 1001, Cohort 2: 2001, Cohort 3: 3001, Cohort 4: 4001, Cohort 5: 5001
The assigned medication identification number will be used to identify the samples for PK by the 
study site and the only number to identity a subject during blood sampling for PK. The number will 
be always shown on the sample vials, which are sent to the laboratory to evaluate the PK. The 
laboratory will report the results using this number. The number will be used for only the purpose 
described in this section and cannot be replaced with the 7-digit subject identification number, 
which is assigned at the time of informed consent procedure and used in all other procedures 
during the clinical study period to identify a subject. In case of subject replacement, the study drug 
with a medication identification number for the withdrawn subject will be used by the replacing 
subject.
9.1.2
Inclusion and Exclusion
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, height, weight, caffeine 
use, alcohol use, and smoking status of the subject.
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Medical history to be obtained will include determining whether the subject has any clinically 
significant conditions or diseases that resolved within 1 year prior to the signing of informed 
consent. Ongoing conditions will be considered concurrent medical conditions. Medication history 
information to be obtained will include 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. 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 drugs, 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 is calculated using the formula provided below.
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.
9.2.4
Vital Signs
Vital signs will include body temperature (axilla measurement), sitting blood pressure (systolic 
and diastolic, after resting more than 5 minutes), and pulse (beats per minute).
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.
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The investigator or sub-investigator (or a qualified observer at the investigational site) will 
interpret the ECG using one 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.
9.2.6
Holter ECG
After Cohort 3, continuous (Holter) ECG will be measured from -23 hours predose to 24 hours 
postdose on Day 1 as needed. Procedures regarding Holter ECG will be provided in the separately 
created manual.
ECG obtained from 24 hours Holter measurement will not be analyzed as safety endpoints.
9.2.7
Columbia Suicide Severity Rating Scale (C-SSRS)
C-SSRS will be performed at the study procedures-specified time point. The investigator or 
sub-investigator will evaluate suicide risks based on the information obtained from C-SSRS. For 
any suicidal ideation and suicidal behavior will be documented as an adverse event.
9.2.8
Study Drug Administration
In Cohort 1, a single dose of TAK-831 T3 tablet 25 mg×4 tablets or placebo will be orally 
administered on Day 1 (Part 1), and a single dose of TAK-831 T3 tablet 300 mg×1 tablet or 
placebo will be orally administered on Day 9 (Part 2).
In Cohort 2, a single dose of TAK-831 T3 tablet 300 mg×2 tablets or placebo will be orally 
administered on Day 1, followed by multiple doses of TAK-831 T3 tablet 300 mg×2 tablets (once 
daily) or placebo on Days 4-17.
In Cohort 5, a single dose of TAK-831 T3 tablet 25 mg×2 or placebo will be orally administered 
on Day 1, followed by multiple doses of TAK-831 T3 tablet 25 mg×2 (once daily) or placebo on 
Days 4 to 17.
The study drug will be orally administered with 150 mL of water at a fasted state (fasted at least 10 
hours before administration).
In Cohorts 3 and 4, the dose of the study drug will be determined based on the data obtained from 
Cohorts 1 and 2.
9.2.9
AE Monitoring
AE monitoring will begin after the signing of informed consent. A complete description of AE
collections and procedures is provided in Section 10.2.
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9.2.10
Laboratory Procedures and Assessments
Laboratory samples will be taken following a minimum 10 hour overnight fast on the days 
stipulated in the Schedule of Study Procedures (Section 3.0). Refer to Appendix C for the amount 
of blood samples.
The investigator or sub-investigator will take responsibility for evaluation of the clinical 
laboratory test results and storage. The investigator will maintain a copy of the reference ranges for 
the laboratory used.
9.2.10.1 Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Red blood cell count
White blood cell count and differential leukocytes 
(lymphocytes, neutrophils, eosinophils, basophils, and 
monocytes)
Hemoglobin
Hematocrit
Platelet count
PT
APTT
Chemistry
Chemistry evaluations will consist of the following chemistry tests:
Albumin
Creatinine
ALP
Glucose
ALT
Sodium
AST
Calcium
γ-GTP
Creatine kinase
Total bilirubin
Potassium
Direct bilirubin
Chloride
Total protein
Urea nitrogen
Urinalysis
Urinalysis will consist of the following tests:
pH
Specific gravity
Qualitative (protein, glucose, occult blood, and nitrite)
Urinary sediment (erythrocytes, leukocytes, and cylinder) 
(a)
(a)
Will be performed for any abnormal urinalysis parameter.
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Other
Immunological tests
HIV antibody and antigen tests, hepatitis tests (HBs antigen and HCV antibody)
Alcohol tests (urinalysis or breath test)
Urinary drug tests
FSH (postmenopausal female subjects only)
HIV: human immunodeficiency virus, HBs: hepatitis B surface antigen, HCV: hepatitis C virus, FSH: 
follicle-stimulating hormone
Note: The investigator or sub-investigator will report the results of immunology, urine drug tests, and alcohol tests
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.
If subjects experience an ALT or AST of >3×ULN (except the tests at Screening), follow-up 
laboratory tests (at a minimum, serum alkaline phosphatase [ALP], ALT, AST, total bilirubin, 
gamma-glutamyl transferase [γ-GTP], 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 10.2.9.4 for the discontinuation or withdrawal criteria of a subject 
and the appropriate guidance on reporting abnormal LFTs as SAEs, respectively.
9.2.10.2 Urine sample for Future Tests
Urine samples for future tests will be collected according to the Schedule of Study Procedures 
(Section 3.0).
If acute renal failure is suspected, urinary biomarkers such as KIM-1, NGAL, and cystatin C may 
be measured using the collected sample.
The result of future urine test will not be analyzed as safety endpoints.
9.3
Biomarker, PK, PD, and PGx Samples
Samples for PK, PD, and PGx will be collected according to the schedule of study procedures 
(Section 3.0). Separated procedures describe the details of sampling, handling, and transferring to 
central laboratory. The actual sampling time for PK and PD analyses will be documented in the 
subject’s source documents and eCRF.
Table 9.a shows primary specimen collections.
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Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of
Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
PK Analysis
Mandatory
Plasma sample for PD
Blood
Plasma
PD analysis
Mandatory
Cerebrospinal fluid sample for PD Cerebrospinal fluid Cerebrospinal fluid
PK Analysis
PD analysis
Optional
Blood sample for DNA PGx
Blood
DNA
PGx analysis
Optional
9.3.1
PK Measurements
The following PK parameters will be calculated from plasma concentrations of TAK-831, unless 
otherwise specified.
Mark/Term
Definition
Plasma
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
Area under the plasma concentration-time curve from time 0 to time of infinity
AUCτ
Area under the plasma concentration-time curve during a dosing interval
Cmax
Maximum observed plasma concentration (measured value)
Cmax, ss
Maximum observed steady-state plasma concentration during a dosing interval (measured value)
tmax
Time of first occurrence of Cmax
t1/2z
Terminal disposition phase half-life
λz
Terminal disposition phase rate constant
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration
CL/F
Apparent clearance after extravascular administration
Rac(Cmax)
Accumulation ratio based on Cmax
Rac(AUC)
Accumulation ratio based on AUC
9.3.1.1
Plasma for PK Measurements
Blood samples for plasma TAK-831 concentration will be collected (Table 9.b). The sampling 
schedule may change based on emerging data but the number of samples will not exceed the 
number of planned samples.
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Table 9.b
Blood Sample Collection for PK Analysis
Dose Levels:
Date of 
administration
Sampling time
Single dose
1
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
9
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
1
Predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, and 48 hours postdose
4, 11, 14
Predose
17
Predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 16, and 24 hours postdose
9.3.1.2
Cerebrospinal fluid samples for PK Measurements
Concentration of TAK-831 cerebrospinal fluid will be measured using cerebrospinal fluid samples 
collected for PD measurements (Section 9.3.2.2).
9.3.2
PD Analysis
The following PD parameters will be calculated from plasma concentrations of D-serine and 
L-serine, unless otherwise specified
Mark/Term
Definition
Plasma
AUEC24
Area under the effect-time curve from time 0 to 24 hours postdose
Emax
Maximum effect
time to Emax
Time to reach maximum PD effect
9.3.2.1
Plasma Samples for PD Analysis
Blood samples will be collected to measure plasma D-serine and L-serine concentrations (Table 
9.c). The sampling schedule may change based on emerging data but the number of samples will 
not exceed the number of planned samples.
Table 9.c
Blood Sample Collection for PD Analysis
Dose Levels:
Specimen
Date of 
administration
Sampling time
Single dose
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, 24, 36, 48 and 
72 hours postdose
9
Predose, 1, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, and 24 hours 
postdose
11, 14
Predose
17
Predose, 1, 4, 8, 12, and 24 hours postdose
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9.3.2.2
Cerebrospinal fluid samples for PD Analysis
Cerebrospinal fluid will be collected to measure D-serine and L-serine concentrations (3.0 mL per 
scheduled time). The cerebrospinal fluid sampling schedule may change based on emerging data 
but the number of samples will not exceed the number of planned samples. Cerebrospinal fluid 
samples for PD analysis will be also used to measure concentration of TAK-831 cerebrospinal 
fluid. After Cohort 2, collection of cerebrospinal fluid in the next Cohorts will be determined based 
on the results of plasma D-serine and L-serine concentrations obtained from the previous Cohorts.
9.3.3
PGx Measurements
9.3.3.1
Blood Sample for DNA PGx Measurements
When sampling of whole blood for pharmacogenomic analysis occurs, the subject must sign 
informed consent/be consented separately for PGx sampling, storage and analysis. PGx 
measurement is a part of the study, but participation of a subject is optional.
One 6-mL of whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected 
prior to the single dosing on Day 1 from each consenting subject in the study.
The samples will be stored for no longer than 15 years after completion of the TAK-831 study 
and/or until the drug development of TAK-831 is no longer actively pursued. No samples will be 
stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification by the Sponsor. “Stored samples” are defined as samples that are coded (the samples 
are stripped of all personal identifying information but a key links the samples to the clinical data 
collected from the sample donor) and are used in the analysis of the study drug or related drug.
The sampling of whole blood for PGx and genotyping analysis is mandatory. Every subject must 
sign informed consent separately for PGx sampling. DNA samples will be used to evaluate drug 
metabolic enzyme and transporter polymorphisms.
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of some of this gene in drug response, which may lead to additional 
exploratory research with the samples for PGx measurements.
9.3.4
Confinement
Cohort 1:
Subjects will be hospitalized from Day -1 to Day 4 and Day 8 to Day 12 and will be discharged 
after the investigator or sub-investigator confirm no clinically significant health problems based 
on the examination and tests on Days 4 and 12.
Cohorts 2:
Subjects will be hospitalized from Day -1 to Day 19 and will be discharged after the investigator or 
sub-investigator confirm no clinically significant health problems based on the examination and 
tests on Day 19.
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Cohorts 3 to 5:
Subjects will be hospitalized from Day -2 to Day 19 and will be discharged after the investigator or 
sub-investigator confirm no clinically significant health problems based on the examination and 
tests on Day 19.
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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 clinical study; it does not necessarily have to have a 
causal relationship with the the treatment (including the study drug) 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 treatment (including the study drug) or study 
procedures.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing 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 may be considered as 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 for an abnormal value are not considered as 
an intervention. In addition, repeated or additional non-invasive tests for verification and 
evaluation of abnormality or monitoring purpose will not be considered as an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a
concurrent medical history conditions and should NOT be recorded as an AE. The
observations or evaluations of first examination at baseline (eg, laboratory test, ECG, X-ray, 
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etc) should NOT be recorded as AEs unless related to a study procedure. However, if the 
subject experiences a worsening or complication of such a concurrent medical history 
condition, the worsening or complication should be recorded appropriately as an AE 
(worsening or complication occurs after informed consent is signed). 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. 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 pre-existing chronic 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. 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 drug or after any change in study drug, the worsening or complication should be
recorded as a new AE. The investigator or sub-investigator should ensure that the event term 
reported captures the change in adverse event (eg, “worsening of…”).
Changes in severity of AEs:

If a subject experiences a change in the severity of an AE that is not associated with a change in 
study drug, 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 the signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
earlier (eg, as an emergency) due to a worsening of a 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 study 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 sub-investigator to decide whether a dose is 
to be considered as overdose, in consultation with the Sponsor.
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in 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 (ADRS)
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Malignant hypertension
Convulsive seizures (includes convulsion and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (includes interstitial pneumonia)
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Confirmed or suspected endotoxin shock
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
Severity/Intensity of AEs will be classified or defined as follows:
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 causality 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 disease, 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 the underlying disease, complications, 
concomitant medications and concurrent treatments.
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.
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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 or sub-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 drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable - a study drug was stopped for a reason other than the particular AE; eg, the 
clinical study has been terminated, the subject died, dosing with study drug had not yet started 
or dosing with study drug 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/signs/symptoms have almost disappeared; the abnormal laboratory values improved, 
but have 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 values on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
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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 and continue until the follow-up visit or phone call.
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 the study drug must be monitored until the 
symptoms have resolved and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Nonserious AEs that begin prior to 
the first exposure to the study drug, regardless of related or unrelated to the study procedure, need 
not be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug 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 Adverse Event (Frequency)

Severity/Intensity.

The Investigator’s or sub-investigator’s opinion of the causal relationship between the event 
and administration of study drug(s). (Related/Not related)

Action taken with the study drug

Outcome of the event.

Seriousness.

Timing of occurrence (after administration of the study drug)
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 within 1 
business day of the first onset or notification of the SAE, along with any relevant information. The 
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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 drug(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 the follow-up SAE form or provide other written 
documentation immediately to the Sponsor. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory values, discharge summary, postmortem results) in the institution should be 
submitted to the Sponsor, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.
10.2.9.4 Reporting of Abnormal LFTs
If a subject experiences 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 will contact the monitor for discussion 
and investigation of the relevant subject details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease, medical history/ongoing disease. Follow-up 
laboratory tests as described in Section 9.2.10 must also be performed.
10.2.10
Safety Reporting to Investigators, IRBs and Regulatory Authorities
The Sponsor will report all suspected unexpected serious adverse reactions (SUSARs) and any 
other applicable SAEs to regulatory authorities, investigators, IRBs and the head of the study site. 
Relative to the first awareness of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The Sponsor 
will also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of the study drug or that would be sufficient to consider changes in 
the study drug administration or in the overall conduct of the trial. The study 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 unblinding of subject’s 
treatment assignment. 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, 3 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.
The Sponsor will verify the validity of the definitions of the analysis sets and the rules for handling
data in consultation with a medical expert, as needed, prior to unblinding the study drug 
assignment. The Sponsor will address all remaining uncertainties not specified at planning, and 
will finalize the SAP prior to unblinding of subject’s treatment assignment.
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, and who 
were appropriately evaluable for at least 1 PK parameter.
11.1.1.3 PD Analysis Set
The PD Analysis Set will consist of subjects who received at least one dose of study drug, and who 
were appropriately evaluable for at least 1 PD parameter.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the Safety Analysis 
Set.
11.1.3
PK Analysis
Endpoints and its analytical method
[Endpoints]
Secondary endpoints: Cmax (Cohort 1, Day 1 in Cohorts 2 to 5), Cmax,ss (Day 17 in Cohorts 2 to 5), 
tmax (Cohort 1, Days 1 and 17 in Cohort 2 to 5), AUClast (Cohort 1, Day 1 in Cohorts 2 to 5), AUC∞
(Cohort 1, Day 1 in Cohorts 2 to 5), AUCτ (Days 1 and 17 in Cohorts 2 to 5)
Exploratory endpoints: Rac(Cmax) and Rac(AUC) (Cohort 2 to 5) on Days 1 and 17, t1/2z, CL/F, Vz/F, 
concentration of TAK-831 cerebrospinal fluid (Cohort 2 to 5)
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[Analytical method]
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and treatment period for Cohorts 2, 4 and 5 as well as Cohort 3.
Concentrations of TAK-831 in plasma and cerebrospinal fluid will be summarized by each 
scheduled sampling time using summary statistics. Individual plasma concentration data versus 
time of TAK-831 will be presented. Plasma PK parameters, including dose-normalized Cmax and 
AUC, will be summarized by dose and day using summary statistics. Accumulation of TAK-831 
from Day 1 to Day 17 will be assessed by summarizing the ratio of Cmax and AUC at Days 1 and 17 
by dose. Dose linearity in plasma PK parameters (Cmax and AUC) will be assessed graphically for 
those parameters at Day 1 and Day 9 for Cohort 1 and Day 1 for Cohorts 2 to 5. Additional 
analyses on dose linearity will be included if appropriate.
11.1.4
PD Analysis
Endpoints and its analytical method
[Endpoints]

Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (on Days -1 and 18) (if available)
[Analytical method]
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and each scheduled sampling time for Cohorts 2, 4 and 5 as well as Cohort 3.
Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in plasma and 
concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal fluid 
(if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of 
D-serine to total serine in plasma, and change and percent the change from baseline will be 
summarized by day using summary statistics. The potential relationship between TAK-831 
exposure and biomarker response will be explored graphically. Additional statistical or PK-PD 
analyses will be included if appropriate.
11.1.5
Safety Analysis
Endpoints and its analytical method
[Endpoints]
AEs, laboratory findings, vital signs, weight, 12-lead ECG
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[Analytical method]
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for 
Cohorts 2, 4 and 5, and for Cohort 3.
11.1.5.1 AEs
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset occurs on or 
after the start of study drug.
The followings will be analyzed for TEAEs. TEAEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT).

Frequency of all TEAEs

Frequency of drug-related TEAEs

Frequency of all TEAEs by intensity

Frequency of drug-related TEAEs by intensity

Frequency of TEAEs leading to study drug discontinuation

Frequency of serious TEAEs
11.1.5.2 Clinical Laboratory Evaluation
Summary statistics will be provided for observed values and change from baseline at each 
evaluation time point. Pre- and post-dose shift tables will be prepared for categorical variables.
11.1.5.3 Vital Signs
Summary statistics will be provided for the observed values at each evaluation time point and 
changes from baseline.
11.1.5.4 Other Safety Parameters
The ECG parameters will be summarized as follows. Summary statistics will be calculated for 
observed values and change from baseline at each evaluation time point. Pre- and post-dose shift 
tables will be prepared for categorical variables. The analysis methods for other endpoints will be 
specified in detail in the SAP.
11.2
Determination of Sample Size
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size 
required to assess the safety, tolerability, and PK of each cohort. This is not based on any statistical 
rationale.
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11.3
Interim Analysis and Criteria for Early Termination
In order to support a development plan of TAK-831, an interim analysis of the safety and 
tolerability following a single dose and multiple dose of TAK-831 may be conducted after the 
completion of Cohort 4. Details will be provided in SAP. It should be noted that continuation or 
discontinuation of this study will not be judged by the interim analysis.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its
designee (Contract Research Organization) and by the IRB.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, and 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 study site of the deviation
or changes 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 study 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 study site also may be subject to quality assurance audits by the Sponsor or designees. In this
circumstance, the Sponsor-designated auditor will contact the study 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], and the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory authority, the Sponsor should be notified immediately. The investigator and the head of
the institution 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 Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline for GCP. The
investigator will conduct the study according to applicable local or regional regulatory 
requirements in accordance with the “Responsibilities of the Investigator” that are listed in
Appendix A.
13.1
IRB Approval
The IRB must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or the designee will require documentation noting all names and titles of the 
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 the 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 
written informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements, if applicable, and other documents required by all applicable laws and regulations, 
must be submitted to the IRB for approval. The IRB’s written approval of the protocol and subject 
written informed consent must be obtained and submitted to the Sponsor or the 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, written informed consent 
form) reviewed; and state the approval date. The Sponsor will notify the study site that the Sponsor 
has confirmed the adequacy of the study site regulatory documentation. Until the study site
receives a notification, no protocol activities, including screening, may occur.
The study site must adhere to all requirements stipulated by its respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the written 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 the Sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The written informed consent form describes the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
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The informed consent form will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care.
The investigator is responsible for the preparation, content, and IRB approval of the written 
informed consent form. The written informed consent form must be approved by both the IRB and 
the Sponsor prior to use.
The informed consent form must be described 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 or she will participate 
in the clinical 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 by 
the investigator or sub-investigator to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator or sub-investigator must also sign and date the informed 
consent form 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 will 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.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify the Sponsor of consent 
withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this 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.
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, and PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
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including 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 the facility name, investigator’s city, state (for Americas
investigators), country, and recruiting status will be registered and available for public viewing.
13.5
Clinical Trial Results Disclosure
Takeda will post the results of the clinical study on ClinicalTrials.gov or publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.6
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study subjects. 
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator or sub-investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.2
Investigator Agreement
A separate agreement will be provided to the study site.
14.1.3
Study-Related Responsibilities
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.4
List of Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUEC
area under the effect-time curve
BMI
body mass index
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
DAAO
D-amino acid oxidase
DNA
deoxyribonucleic acid
Emax
maximum effect
FDA
Food and Drug Administration
FRDA
Friedreich ataxia
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
γ-GTP
gamma-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation of Technical Requrements for Pharmaceuticals for Human 
Use
INR
international normalized ratio
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
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Term
Definition
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
PET
positron emission tomography
PMDA
Pharmaceuticals and Medical Devices Agency
PT
prothrombin time
POC
proof-of-concept
Rac
accumulation ratio
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
tmax
time of first occrurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply the study sites with access to eCRFs. The Sponsor will 
provide training opportunities for the site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the Sponsor 
(or the designee) and will be answered by the study site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs.
The following data will not be recorded in the eCRFs.

PGx analysis results

Clinical laboratory test results

Drug concentration measurement results

PD measurement results

Holter ECG measurement date, time and results

Future urinalysis measurement results
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 or sub-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 study site during periodic visits 
by the Sponsor or its designee. 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 
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form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the Sponsor.
15.2
Record Retention
The investigator or the head of the study site agree to keep the records stipulated in Section 15.1
and those documents that include (but not limited to) the study-specific documents, the
identification log of all participating subjects, medical records, all original signed and dated
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its
designees.
The investigator and the head of the study site are required to retain 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 study 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 study 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]
Sham PC, Gottesman, II, MacLean CJ, Kendler KS. Schizophrenia: sex and familial 
morbidity. Psychiatry Res 1994;52(2):125-34.
[2]
Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, et al. 
Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen 
Psychiatry 1999;56(2):162-8.
[3]
Erlenmeyer-Kimling L, Squires-Wheeler E, Adamo UH, Bassett AS, Cornblatt BA, 
Kestenbaum CJ, et al. The New York High-Risk Project. Psychoses and cluster A 
personality disorders in offspring of schizophrenic parents at 23 years of follow-up. Arch 
Gen Psychiatry 1995;52(10):857-65.
[4]
van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
[5]
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor 
antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm 
shift in medication development. Psychopharmacology (Berl) 2003;169(3-4):215-33.
[6]
Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, et al. Plasma 
levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 
2012;142(1-3):83-7.
[7]
Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, et al. Changes in plasma 
glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical 
symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). 
Prog Neuropsychopharmacol Biol Psychiatry 2008;32(8):1905-12.
[8]
Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. 
Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of 
the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen 
Psychiatry 2003;60(6):572-6.
[9]
Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to 
total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog 
Neuropsychopharmacol Biol Psychiatry 2005;29(5):767-9.
[10] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights 
from 108 schizophrenia-associated genetic loci. Nature 2014;511(7510):421-7.
[11] Japan Sciety for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity, 2011 Oct; additional edition.
[12] General Considerations for Clinical Trials (Notification No. 380 of the Evaluation and 
Licensing Division, PMSB dated April 21, 1998).
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CONFIDENTIAL
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 study site in advance to get them accepted.
3. Prepare a written informed consent form 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 study 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 study site and the Sponsor 
in writing.
11. Determine the need of emergency key code unblinding 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 study site of the end of the study in writing.
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Appendix B
Pregnancy and Contraception
Male Subjects and Their Female Partners
From the signing of informed consent, throughout the duration of the study, and for 95 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 or subjects should refrain from having sexual 
intercourse from 1 month prior to the first study drug administration throughout the study period 
and until 35 days after the last study drug administration. 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.
Female Subjects and Their Male Partners
Female subjects of childbearing potential* will be excluded from this study.
* 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 device (IUD)
Hormonal contraceptives
Male condoms with a spermicide
Copper T PLUS condom
Progesterone T PLUS condom
Combined pill
Subjects will be provided with information on acceptable methods of contraception for 95 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 95 days after their last dose of study drug.
Pregnancy
If any subject is found to be pregnant during the study, the subject should immediately discontinue 
the study drug and be withdrawn from the study. In addition, if any pregnancies in the partner of a 
male subject, during the study or for 95 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.
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If the female subject or 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 she or his 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).
All female subjects and the female partners of male subjects who became pregnant will be 
followed to final outcome, using the pregnancy form, with the consent of the female subjects or 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
<Cohort 1>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Study treatment period 
(Part 1)
Day 1 72 hours postdose
Day 4 from awakening
to discharge
Washout period
Day 8
Not applicable
Study treatment period 
(Part 2)
Day 9 72 hours postdose
Day 12 from
awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 and 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 2 and 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Urinary drug tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Washout period
Day 8
Not applicable
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period (Part 1)
Day 1 predose
Not applicable
Blood samples for PK
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
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Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 1 hour postdose
Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 24 hours postdose
Within ± 2 hours
Treatment period (Part 2)
Day 9 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, and FSH
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<Cohorts 2 to 5>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Days 5-10 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Days 12-13 predose
From awakening to 
immediately prior to 
dose
Day 14 predose
From awakening to 
immediately prior to 
dose
Days 15-16 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 1, 4, 12, 24, and 48 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 48 hours postdose
Day 19 from
awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 2 and 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
Holter ECG (b)
(if performed)
Hospitalization
Day 1 -23, -22, -20, -16 and -12 hours 
predose
Within ± 15 minutes
Treatment period
(Single dose part)
Day 1 predose
Within ± 15 minutes
predose
Day 1 1, 2, 4, 8, 12 and 24 hours 
postdose
Within ± 15 minutes
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period
(Single dose part)
Day 1 predose
Not applicable
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CONFIDENTIAL
Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PK
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.25, 0.5, 1, 1.5 and 2 hours 
postdose
Within ± 5 minutes
Day 1 4, 8, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
Within 15 minutes 
predose
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 0.25, 0.5, 1, 1.5, and 2 hours 
postdose
Within ± 5 minutes
Day 17 4, 8, 12, 16 and 24 hours 
postdose
Within ± 15 minutes
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, and 24 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 1 hour postdose
Within ± 15 minutes
Day 17 4, 8, 12, and 24 hours postdose Within ± 15 minutes
Cerebrospinal fluid 
samples for PD
(If performed)
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 3 hours
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 24 hours postdose
Within ± 2 hours
Treatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, FSH, and urinary drug tests
(b)
After Cohort 3, Holter ECG will be performed as needed.
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Total blood sampling volumes for an individual subject is shown below:
<Cohort 1>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total Volume
(mL)
Screening
Day -1
Days 1-4
Day 8
Days 9-12
Clinical Laboratory 
Tests
20
1
1
1
1
1
100
Blood samples for PK
4
-
-
12
-
12
96
Blood samples for PD
6
-
3
9
-
9
126
Samples for PGx 
Measurements
6
-
-
1
-
-
6
Total Blood Sampling Volume
328
-: No blood collection
<Cohorts 2 to 5>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total 
Volume
(mL)
Screening Day -1 Day 1 Day 2
Day 3
Day 4 Day 11 Day 14
Days
17-18 Day 19
Clinical Laboratory 
Tests
20
1
1
-
-
-
-
1
-
-
1
80
Blood samples for PK
4
-
-
9
2
1
1
1
1
11
-
104
Blood samples for PD
6
-
3
5
1
-
-
1
1
6
-
102
Samples for PGx 
Measurements
6
-
-
1
-
-
-
-
-
-
-
6
Total Blood Sampling Volume
292
-: No blood collection
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CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of 
TAK-831 in Healthy Adult Asian Subjects
Phase 1 Study of TAK-831 in Healthy Adult Asian Subjects
Study Identifier:
TAK-831-1002
Compound:
TAK-831
Date:
28 November 2018
Version/Amendment 
Number:
Amendment 2
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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CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................11
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.2
Rationale for the Proposed Study.............................................................................15
4.3
Benefit/Risk Profile .................................................................................................16
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................18
5.1
Hypothesis...............................................................................................................18
5.2
Trial Objectives .......................................................................................................18
5.2.1
Trial Primary Objective......................................................................................18
5.2.2
Trial Secondary Objective..................................................................................18
5.2.3
Trial Exploratory Objective................................................................................18
5.3
Endpoints.................................................................................................................18
5.3.1
Primary Endpoint...............................................................................................18
5.3.2
Secondary Endpoints..........................................................................................18
5.3.3
Exploratory Endpoints .......................................................................................19
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................20
6.1
Trial Design.............................................................................................................20
6.2
Cohort transition/Dose Escalation............................................................................22
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................22
6.3.1
Rationale for Study Population...........................................................................22
6.3.2
Rationale of Trial Design ...................................................................................23
6.3.3
Rationale for Dose .............................................................................................23
6.3.4
Rationale for Endpoints......................................................................................24
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures ................24
6.4
Trial Beginning and End/Completion.......................................................................25
6.4.1
Definition of Beginning of the Trial ...................................................................25
6.4.2
Definition of End of the Trial.............................................................................25
6.4.3
Definition of Trial Discontinuation ....................................................................25
6.4.4
Criteria for Premature Termination or Suspension of the Trial............................26
6.4.5
Criteria for Premature Termination or Suspension of a Study Site......................26
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27
7.1
Inclusion Criteria .....................................................................................................27
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7.2
Exclusion Criteria ....................................................................................................28
7.3
Excluded Medications Supplements, Dietary Products.............................................30
7.4
Diet, Fluid, Activity.................................................................................................31
7.4.1
Diet and Fluid ....................................................................................................31
7.4.2
Activity..............................................................................................................32
7.5
Documentation of Subject Failure............................................................................32
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................34
7.8
Subject Replacement................................................................................................34
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................35
8.1
Clinical Study Drug .................................................................................................35
8.1.1
Clinical Study Drug Labeling.............................................................................35
8.1.2
Clinical Study Drug Inventory and Storage ........................................................35
8.1.3
Randomization Code Creation and Storage ........................................................35
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................35
8.1.5
Accountability and Destruction of Sponsor-Supplied Drugs...............................36
9.0
STUDY PROCEDURES...............................................................................................37
9.1
Administrative Procedures.......................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.2
Inclusion and Exclusion .....................................................................................37
9.1.3
Medical History/Demography ............................................................................37
9.1.4
Concomitant Medications...................................................................................38
9.2
Clinical Procedures and Assessments.......................................................................38
9.2.1
Full Physical Exam ............................................................................................38
9.2.2
Height and Weight .............................................................................................38
9.2.3
BMI ...................................................................................................................38
9.2.4
Vital Signs .........................................................................................................38
9.2.5
12-Lead ECG.....................................................................................................38
9.2.6
Columbia Suicide Severity Rating Scale (C-SSRS)............................................39
9.2.7
Study Drug Administration ................................................................................39
9.2.8
AE Monitoring...................................................................................................39
9.2.9
Laboratory Procedures and Assessments ............................................................39
9.3
Biomarker, PK, PD, and PGx Samples.....................................................................41
9.3.1
PK Measurements..............................................................................................41
9.3.2
PD Analysis .......................................................................................................42
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9.3.3
PGx Measurements ............................................................................................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................................................48
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.............51
11.0
STATISTICAL METHODS..........................................................................................52
11.1
Statistical and Analytical Plans ................................................................................52
11.1.1 Analysis Sets......................................................................................................52
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................52
11.1.3 PK Analysis .......................................................................................................52
11.1.4 PD Analysis .......................................................................................................53
11.1.5 Safety Analysis ..................................................................................................53
11.2
Determination of Sample Size..................................................................................54
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................55
12.1
Study-Site Monitoring Visits ...................................................................................55
12.2
Protocol Deviations..................................................................................................55
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................55
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................56
13.1
IRB Approval ..........................................................................................................56
13.2
Subject Information, Informed Consent, and Subject Authorization .........................56
13.3
Subject Confidentiality ............................................................................................57
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................58
13.4.1 Publication and Disclosure.................................................................................58
13.4.2 Clinical Trial Registration..................................................................................58
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13.5
Clinical Trial Results Disclosure..............................................................................58
13.6
Insurance and Compensation for Injury....................................................................58
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................59
14.1
Administrative Information......................................................................................59
14.1.1 Study Contact Information .................................................................................59
14.1.2 Investigator Agreement......................................................................................59
14.1.3 Study-Related Responsibilities...........................................................................59
14.1.4 List of Abbreviations .........................................................................................59
15.0
DATA HANDLING AND RECORDKEEPING............................................................61
15.1
eCRFs......................................................................................................................61
15.2
Record Retention .....................................................................................................62
16.0
REFERENCES..............................................................................................................63
17.0
APPENDICES...............................................................................................................64
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Cohorts..........................................................................................21
Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects............................24
Table 7.a
Excluded Medications, Supplements, Dietary Products ......................................31
Table 9.a
Primary Specimen Collections ...........................................................................41
Table 9.b
Blood Sample Collection for PK Analysis..........................................................42
Table 9.c
Blood Sample Collection for PD Analysis..........................................................43
Table 10.a
Takeda Medically Significant AE List................................................................48
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................10
Figure 6.a
Study Schematic ................................................................................................21
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................64
Appendix B
Pregnancy and Contraception.............................................................................65
Appendix C
Acceptable Time Window for Study Procedure..................................................67
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals
Compound:
TAK-831
Study Identifier: TAK-831-1002
Phase: 1
Title of Study: Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of TAK 831 in Healthy Adult Asian Subjects
Trial Design:
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) of TAK-831 in healthy adult Asian subjects.
This study will include up to 4 cohorts of healthy adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered under a 3 sequential dose escalation design, and the safety, 
PK and PD will be assessed. Eight healthy adult Japanese subjects will be randomized in dosing orders of A 
(100 mg→300 mg), B (100 mg→placebo), and C (placebo→300 mg) at a 4:2:2 ratio. A single dose of TAK-831 or 
placebo will be administered on Day 1 and Day 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
Cohort 2 will include 8 healthy adult Japanese subjects. Of these subjects, 6 will be randomly assigned to the TAK-831 
group and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed by their 
multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with subjects followed for 
approximately 72 hours of assessments for safety, PK and PD. Treatment for multiple doses will start with a 
once-daily regimen on Day 4, which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at 
least 48 hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 and 4 will be optional, in which a single dose will be administered followed by multiple doses, and may be 
studied based on emerging data from the prior cohorts.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 will include 8 healthy adult Japanese subjects. Of 
these subjects in the respective cohorts, 6 will be randomly assigned to the TAK-831 group and 2 to the placebo group. 
A single dose of TAK-831 or placebo will be administered, followed by their multiple doses. A single dose of 
TAK-831 or placebo will be administered on Day 1 with subjects followed for approximately 72 hours of assessments 
for safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, which will continue 
to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo dose 
on Day 17 for safety, PK, and PD assessments before discharge.
Trial Primary Objective:
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Secondary Objectives:
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Target: Healthy adult Asian subjects
Planned Number of Subjects:
Cohort 1: 8 subjects
Cohorts 2 to 4: 8 subjects per cohort
Planned Number of Sites:
1 site
Dose Levels:
<Cohort 1>
Single dose at 100 mg on Day 1 (Part 1) and 300 mg on 
Day 9 (Part 2) (fasted)
<Cohort 2>
Single dose at 600 mg on Day 1. Multiple doses 
Route of Administration:
Oral
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(once-daily) at 600 mg on Days 4 to 17 (fasted)
<Cohort 3>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
<Cohort 4>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
Duration of Treatment:
<Cohort 1>
Part 1: Single dose on Day 1
Part 2: Single dose on Day 9
<Cohorts 2 to 4>
Single dose on Day 1 and once-daily multiple doses on 
Days 4 to 17, for 14 days, in each Cohort
Planned Trial Duration:
<Cohort 1>
Screening period: Day -28 to -1
Treatment period: Days 1 to 12
Follow-up period: Day 23
<Cohorts 2 to 4>
Screening period: Day -28 to -1
Treatment period: Days 1 to 19
Follow-up period: Day 31
Inclusion Criteria:
Subject eligibility will be determined according to the following criteria.
1.
The subject must understand the study procedures and agree to participate by providing written informed consent 
(for Chinese subjects, an interpreter should be present as necessary).
2.
The subject must be willing and able to comply with all study procedures and restrictions.
3.
The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, inclusive, at the 
Screening.
4.
The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the Screening.
5.
The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing products (e.g., 
nicotine patch) for at least 6 months prior to the Screening.
6.
Chinese subjects are defined as subjects who were born in mainland China, and their biological parents and 
grandparents must all have been of Chinese origin (for Cohort 3 only).
7.
Chinese subjects who have lived out of China for more than 5 years must not have significantly modified their 
diets since leaving China (for Cohort 3 only).
8.
The subject must be judged to be in good health by the investigator or sub-investigator, based on clinical 
evaluations including laboratory tests, medical history, full physical examination, 12-lead electrocardiogram, 
and vital sign measurements performed at the Screening. and prior to the first dose of study drug.
9.
The subject must meet the birth control requirements.
Exclusion Criteria:
The subject must be excluded from participating in the study if the subject meet any of the followings.
1.
The subject has a history of clinically significant endocrine, gastrointestinal (including motility disorder and 
intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, or 
genitourinary, or presents with major neurological (including stroke and chronic seizures) abnormalities or 
diseases.
2.
The subject has participated in another investigational trial within 4 weeks before the pretrial visit (Screening). 
The 4-week window will be derived from the date of the last trial procedure and/or adverse events related to the 
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trial procedure in the previous trial to the Screening Visit of the current trial.
3.
The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the sponsor.
4.
The subject has a history of cancer (malignancy).
5.
The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy) or has had 
an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.
6.
The subject has a positive alcohol or drug or immunological screen.
7.
The subject is of childbearing potential or lactating.
8.
The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 8 weeks prior to 
the first dose of study drug.
9.
The subject with any gastrointestinal surgery that could impact upon the absorption of study drug.
10.
The subject has a known hypersensitivity to any component of the formulation of TAK-831 or related 
compounds.
11.
The subject is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before administration of the initial 
dose of trial drug, throughout the trial (including washout intervals between trial periods), until the Follow-up 
Visit.
12.
The subject has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 
ounce] per day).
13.
The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
14.
The subject has a history of drug abuse.
15.
The subject has a (QT interval with Fridericia’s correction method) QTcF >450 ms (males) or >470 ms (females) 
or PR outside the range of 120 to 220 ms at the Screening Visit or Check-in.
Main Criteria for Evaluation and Analyses:
Primary Endpoint
Safety: Adverse event, laboratory tests, vital signs, weight, 12-lead electrocardiogram
Secondary Endpoints
Pharmacokinetics: The following parameters will be calculated.
Cmax (Cohort 1, Day 1 of Cohorts 2 to 4)
Cmax,ss (Day 17 of Cohorts 2 to 4)
tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 4)
AUClast (Cohort 1, Day 1 of Cohorts 2 to 4)
AUC∞(Cohort 1, Day 1 of Cohorts 2 to 4)
AUCτ (Days 1 and 17 of Cohorts 2 to 4)
Statistical Considerations:
Pharmacokinetics:
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and treatment 
period for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of TAK-831 in plasma will be summarized by each scheduled sampling time using summary statistics. 
Individual plasma concentration data versus time will be presented. Plasma PK parameters, including 
dose-normalized Cmax and AUC, will be summarized by dose and day using summary statistics. Accumulation of 
TAK-831 from Day 1 to Day 17 will be assessed by summarizing the ratio of Cmax and AUC at Days 1 and 17 by dose. 
Dose linearity in plasma PK parameters (Cmax and AUC) will be assessed graphically for those parameters at Days 1 
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and 9 for Cohort 1 and Day 1 for Cohorts 2 to 4. Additional analyses on dose linearity will be included if appropriate.
Pharmacodynamics:
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and each 
scheduled sampling time for Cohorts 2 and 4, as well as Cohort 3. Concentrations of D-serine, L-serine and the ratio of 
D-serine to total serine in plasma and concentrations of D-serine, L-serine and the ratio of D-serine to total serine in 
cerebrospinal fluid (if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of D-serine to total serine in 
plasma, and change and percent change from baseline will be summarized by day using summary statistics. The 
potential relationship between TAK-831 exposure and biomarker response will be explored graphically. Additional 
statistical or PK-PD analyses will be included if appropriate.
Safety:
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for Cohorts 2 and 4, and for 
Cohort 3.
A treatment-emergent adverse event (TEAE) refers to an adverse event that occurs after the start of study treatment. 
The frequency of all TEAEs, drug-related TEAEs , all TEAEs by intensity, drug-related TEAEs by intensity, TEAEs 
leading to study drug discontinuation, and serious TEAEs will be summarized. TEAEs will be coded using Medical 
Dictionary for Regulatory Activities Terminology (MedDRA) and summarized by system organ class (SOC) and 
preferred term (PT).
For continuous values of laboratory findings, vital signs and other safety parameters, summary statistics will be 
provieded for observed values and change from baseline at each evaluation time point. Pre- and post-dose shift tables 
will be prepared for categorical variables.
Sample Size Justification:
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size required to assess the 
safety, tolerability, PK and PD of each cohort. This is not based on any statistical rationale.
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2.0
STUDY SCHEMATIC
Figure 2.a shows the schematic of the trial design.
Figure 2.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
Sequence of 
administration
Part 1
Washout 
interval
Part 2
Day 1 to 4
Day 5 to 8
Day 9 to 12
A
TAK-831 100 mg
Washout
TAK-831 300 mg
B
TAK-831 100 mg
Placebo
C
Placebo
TAK-831 300 mg
<Cohorts 2 to 4>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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3.0
SCHEDULE OF STUDY PROCEDURES
<Cohort 1>
Screening period
Treatment period
Early
Termina
tion
Follow-up 
visit
Screening Hospitali
zation
Part 1
Washout interval
Part 2
Day
-28 to -2
-1
1
2
3
4
5 to 7
8
9
10
11
12
23 (±2)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics, medical history
X
Prior medications
X
Physical examination
X
X
X
X
X
X
X
X (l)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X (l)
Weight, height, BMI (b)
X
X
X
X
X
X
X (l)
12-lead electrocardiogram (ECG) (c)
X
X
X
X
X
X
X
X
X (l)
Laboratory tests (d)
X
X
X
X
X
X
X (l)
Immunological test, alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
X
C-SSRS (f)
X
X
X
X
X
X
Sample collection for pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X(k)
Blood sample collection for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
X
X
Urine sample (for future tests) (j)
X
X
X
X
Study drug administration
X
X
Adverse events
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Concomitant medications
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Hospitalization
X
X-----------------------------------X
X
X-----------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36, 48 and 72 hours postdose on Day 1, on Day 8, predose on Day 9, and 1, 4, 12, 24, 36, 48 and 72 hours 
postdose on Day 9.
(b)
Height will be measured at Screening only. Weight will be measured at Screening visit, Day -1, 72 hours postdose on Day 1, Day 8, 72 hours postdose on Day 9.
(c)
12-lead ECG will be measured at Screening, Day -1, predose, 2 and 72 hours postdose on Day 1, Day 8, predose on Day 9, 2 and 72 hours postdose on Day 9.
(d)
Laboratory tests will be performed at Screening, on Day -1, 72 hours postdose on Day 1, on Day 8, and at 72 hours postdose on Day 9.
(e)
FSH will be measured in postmenopause women only.
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(f)
C-SSRS will be investigate at Screening, Day -1, Day 4, Day 8, and Day 12.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 9, and 0.5, 1. 1.5, 2, 4, 8, 12, 24, 36, 48, 
and 72 hours postdose on Day 9.
(i)
Samples for PD assessment will be collected on Day -1 (at 20, 16, 12 hours predose on Day 1), predose, 1, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose, 1, 4, 8, 
12, 24, 36, 48, and 72 hours postdose on Day 9.
(j)
Urine samples will be collected on Day -1, 24 hours postdose on Day 1, and 24 hours postdose on Day 9.
(k)
Samples for PK assessment at discontinuation will be collected if it is possible.
(l)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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<Cohorts 2 to 4>
Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening Hospitalization Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics, medical 
history
X
Prior medications
X
Physical examination
X
X
X
X
X
X (m)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (m)
Weight, height, BMI (b)
X
X
X
X
X (m)
12-lead 
electrocardiogram 
(ECG) (c)
X
X
X
X
X
X
X
X
X (m)
Laboratory tests (d)
X
X
X
X
X
X (m)
Immunological test, 
alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
C-SSRS (f)
X
X
X
X
Sample collection for 
pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection 
for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X (l)
Blood sample collection 
for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
Cerebrospinal fluid 
sample collection for 
pharmacodynamic (PD) 
assessment (j)
X
X
Urine sample (for future 
tests) (k)
X
X
X
X
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Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening Hospitalization Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Concomitant 
medications
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Hospitalization
X
X-------------------------------------------------------------------------------------------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36 and 48 hours postdose on Day 1, predose on Days 4 to 16, predose on Day 17, and 1, 4, 12, 24, and 
48 hours postdose on Day 17.
(b)
Height will be measured at Screening only. Weight will be measured at Screening, on Day -1, and 48 hours postdose on Day 17.
(c)
12-lead ECG will be measured at Screening, Day -1,presdose and 2 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose, 2 and 48 hours postdose on Day 17.
(d)
Laboratory tests will be performed at Screening, Day -1, predose on Day 11, and at 48 hours postdose on Day 17.
(e)
FSH will be measured in postmenopause women only.
(f)
C-SSRS will be investigate at Screening Visit, Day -1, and Day 19.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose on 
Day 14, predose, 0.25, 0.5, 1. 1.5, 2, 4, 8, 12, 16, and 24 hours postdose on Day 17.
(i)
Samples for PD assessment will be collected at 20, 16, and 12 hours predose on Day 1, predose, 1, 4, 8, 12, and 24 hours postdose on Day 1, predose on Day 11, predose on Day 
14, predose, 1, 4, 8, 12, and 24 hours postdose on Day 17.
(j)
Samples for PD assessment will be collected on Day -1 and 24 hours postdose on Day 17 (if it is performed).
(k)
Urine samples will be collected on Day -1, at 24 hours postdose on Day 1, and 24 hours postdose on Day 17.
(l)
Samples for PK assessment at discontinuation will be collected if it is possible.
(m)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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4.0
INTRODUCTION
4.1
Background
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and
behaves. Schizophrenia usually develops at late adolescence or early adulthood and manifests in 
maximum 1% of the population. For those who have relatives of first degree with schizophrenia, 
the incidence rate is higher by 10% (the concordance rate for schizophrenia in identical twins is 
40% to 65%) [1][2][3]. Symptoms of schizophrenia can be subdivided into 3 broad classes: 
positive, negative, and cognitive symptoms [4]. Positive symptoms include hallucinations, 
delusions, and disordered thought and speech, and can be summarized as psychosis. Negative 
symptoms include reduced emotion, reduced ability to experience pleasure (anhedonia), lack of 
motivation, and reduced social interaction. Finally, cognitive symptoms include poor information 
processing, impaired ability to focus on objectives, and abnormalities of working memory and 
learning [4]. Currently available antipsychotics are broadly effective for the treatment of positive
symptoms. However, the negative symptoms and cognitive impairment of schizophrenia are the 
known particular aspects that cause dysfunction, for which no therapy has been approved. There 
still are significant unmet medical needs.
Hypofunction of N-methyl-D-aspartic acid (NMDA) receptor is considered a potential mechanism 
in the pathophysiology of schizophrenia, which could be mitigated with increased D-serine levels 
in the brain [5]. D-amino acid oxidase (DAAO) contributes to the metabolism of D-serine in the 
brain and is highly expressed in the cerebellum. Changes in the D-serine levels or D-serine to total 
serine ratios have been reported in the plasma of patients with schizophrenia both naive and under 
drug treatment [6]-[9]. In addition, serine racemase (the D serine generating enzyme) and the 
NMDA NR2A subunit are among the risk genes identified from the recent large scale 
genome-wide association study analysis, indicating the biological relevance to schizophrenia of 
the genetic pathway in which DAAO resides [10]. Therefore, inhibition of DAAO is considered to 
be a promising target in treatment of schizophrenia.
TAK-831 is a highly selective and potent inhibitor of DAAO. TAK-831 increased D-serine levels 
in the cerebellum of normal mice and showed efficacy in a mouse model of Friedreich ataxia 
(FRDA) mouse models. It also demonstrated a positive effect on cognition and social interaction in 
rodent cognition and behavioral models.
As stated above, TAK-831 is expected to provide a therapeutic effect on FRDA and cognitive 
impairment as well as negative symptoms associated with schizophrenia.
4.2
Rationale for the Proposed Study
TAK-831 is currently under development for the treatment of FRDA and cognitive impairment as 
well as negative symptoms of schizophrenia. Three overseas phase 1 studies in healthy adults 
(single and multiple dose study [TAK-831-1001], positron emission tomography [PET] study to 
determine DAAO brain enzyme occupancy [TAK-831-1003], and a study to evaluate the food 
effect [TAK-831-1004]) have been conducted so far, in which TAK-831 was well-tolerated.
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In addition, two phase 1 studies in healthy adults (study with single and multiple doses at high dose 
level [TAK-831-1005] and bioequivalence study [TAK-831-1006]) are being conducted or 
planned. Two phase 2 studies in patients with schizophrenia (small-scale crossover study to 
examine the cerebellar functions [TAK-831-2001], and a study to evaluate the efficacy and safety 
for negative symptoms of schizophrenia [TAK-831-2002]) are also underway. Besides, a phase 2 
proof-of-concept (POC) study in patients with schizophrenia is being planned in China. Based on 
the result of these phase 2 studies, a phase 3 global study (long-term study) has been planned.
In parallel with these development plans, TAK-831 is also being developed in Japan for the 
treatment of cognitive impairment and negative symptoms associated with schizophrenia. In 
respect of FRDA, a genetic disease, since there has been no confirmed report as of June 2018 that 
clearly indicates the existence of Japanese patients, no development plan has been made for FRDA 
in Japan.
Enrollment of Japanese patients into the phase 3 global study and the phase 2 POC study in China 
has been considered. This study was planned to examine the safety and pharmacokinetic (PK) of 
TAK-831 in Japanese as well as to evaluate the safety and PK in Asian healthy subjects for the 
aforementioned studies.
4.3
Benefit/Risk Profile
Because this study will be conducted in healthy adults, there is no benefit to subjects.
The following risk mitigation measures will be implemented in this study. These measures are 
based on what is known about the mechanism of action of TAK-831, nonclinical data, and the 
phase 1 studies (4 studies, including preliminary data of TAK-831-1005). Procedures may be 
added during the study as necessary based on evaluation of any additional clinical or nonclinical 
data.
The safety of TAK-831 has been studied in a prior single dose (up to 750 mg in suspension and 
100 mg T1 tablet formulation) and multiple dose (up to 400 mg once daily [QD] in suspension) 
study in healthy Western subjects (TAK-831-1001), a single dose (up to 500 mg in suspension) 
PET study to investigate DAAO occupancy in the brain (TAK-831-1003) and a single dose food 
effect (400 mg T2 tablet formulation) study (TAK-831-1004). These studies have not resulted in a 
safety signal that would prevent additional studies. Additionally, TAK-831 given as single and 14 
days multiple doses (up to 1200 mg in suspension and 600 mg T2 tablet formulation) is currently 
being studied in healthy adult subjects (TAK-831-1005). TAK-831 has been safe and well 
tolerated to date (provisional data as of end-April 2018).

Acute hypersensitivity/anaphylactic reactions to new chemical entities are always a possible 
risk in any clinical study. Appropriate procedures should be used to manage such possible 
risks.

Study procedure-specific risks include issues relating to blood collection for safety 
assessment/PK and pharmacodynamics (PD) monitoring (venipuncture may cause bruising), 
and the placement of ECG pads (which may cause some local redness and/or 
erythema/itching).
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
In case of serious adverse events (SAE), the investigator has discretion to use his/her clinical 
judgment as to whether to allow a subject to proceed in the study or whether to unblind the 
subject in order to determine his/her treatment allocation.

The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered to monitor 
emergent suicidality.
The Investigator's Brochure should be referred for more detailed safety of TAK-831.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed on the basis of the following hypothesis.

TAK-831 given as single or multiple doses shows no safety issue and is well tolerated.

The PK of TAK-831 given as single or multiple doses to Asian subjects is equivalent to that in 
Western subjects.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult 
Asian subjects.
5.2.2
Trial Secondary Objective
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
5.2.3
Trial Exploratory Objective
To assess the effect of TAK-831 on the concentrations of D-serine and L-serine in plasma (and 
concentrations of D-serine and L-serine in cerebrospinal fluid as necessary) after TAK-831 
administration to healthy Asian subjects.
5.3
Endpoints
5.3.1
Primary Endpoint
Safety: Adverse events (AEs), laboratory tests, vital signs, weight, 12-lead electrocardiogram
(ECG)
5.3.2
Secondary Endpoints
PK: The following parameters will be calculated.

Cmax (Cohort 1, Day 1 of Cohorts 2 to 4)

Cmax,ss (Day 17 of Cohorts 2 to 4)

tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 4)

AUClast (Cohort 1, Day 1 of Cohorts 2 to 4)

AUC∞(Cohort 1, Day 1 of Cohorts 2 to 4)

AUCτ (Days 1 and 17 of Cohorts 2 to 4)
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5.3.3
Exploratory Endpoints

PK: Rac (Cmax) and Rac(AUC) on Days 1 and 17 (Cohorts 2 to 4), t1/2z, CL/F, Vz/F

PD: Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (Days -1 and 18) (may be assessed in Cohort 2 or thereafter based on PD in plasma)
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, PK and 
PD of TAK-831 in healthy adult Asian subjects. This study will include up to 4 cohorts of healthy 
adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered at each dose level under a 3-sequential 
dose escalation design. Eight healthy adult Japanese subjects will be randomized to the sequence 
of administration A, B, and C at a 4:2:2 ratio. A single dose of TAK-831 or placebo will be 
administered on Days 1 and 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
In Cohort 2, a single dose of study drug will be administered to healthy adult Japanese subjects, 
followed by multiple doses. Of these subjects, 6 will be randomly assigned to the TAK-831 group 
and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed 
by their multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with 
subjects followed for approximately 72 hours of assessments for safety, PK and PD. Treatment for 
multiple doses will start with a once-daily regimen on Day 4, which will continue to Day 17 (for 
14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo 
dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 and 4 will be optional, in which a single dose of study drug will be administered 
followed by multiple doses, and may be studied based on emerging data from Cohorts 1 and 2.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 will include 8 healthy adult 
Japanese subjects. Of these subjects in the respective cohorts, 6 will be randomly assigned to the 
TAK-831 group and 2 to the placebo group. A single dose of TAK-831 or placebo will be 
administered, followed by their multiple doses. A single dose of TAK-831 or placebo will be 
administered on Day 1 with subjects followed for approximately 72 hours of assessments for 
safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, 
which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 
hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before 
discharge.
Table 6.a shows the summary of cohorts, and Figure 6.a shows the schematic of the trial design.
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Table 6.a
Summary of Cohorts
Cohort
Subject
Dose
Remarks
1
Japanese
8 subjects
Part 1:
100 mg (4×25 mg T3 tablet formulation)
Fasted, single dose
Wash out period between part 1 and 2 will be 
8 days.
Part 2:
300 mg (1×300 mg T3 tablet formulation)
Fasted, single dose
2
Japanese
8 subjects
600 mg (2×300 mg T3 tablet formulation)
Fasted, single dose + multiple dose (once 
daily)
3
Chinese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 3 may be run if emerging data from 
Cohorts 1 and 2 suggest ethnic-related 
differences in the tolerability and/or PK 
profile. Dose level will be determined based 
on the results from Cohorts 1 and 2.
4
Japanese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 4 may be run based on the emerging 
data from Cohorts 1 and 2 in Asian subjects.
TBD: To be decided
Figure 6.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
<Cohorts 2 to 4>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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6.2
Cohort transition/Dose Escalation
In Cohort 1, TAK-831 100 mg or placebo will be administered on Day 1 (Part 1) followed by 
confirmation of the safety and tolerability (AEs, physical examination, vital signs, weight, 
laboratory tests and 12-lead ECG) up to 72 hours postdose, and then TAK-831 300 mg or placebo 
will be administered on Day 9 (Part 2) followed by confirmation of the safety, tolerability and PK 
up to 72 hours postdose.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohort 1 in a blinded manner and discuss with the sponsor (including the 
medical expert if necessary) as to whether the subsequent cohort should be run.
In Cohort 2, TAK-831 600 mg or placebo will be administered on Day 1, followed by 
confirmation of the safety and tolerability up to 72 hours postdose. Then, multiple doses of 
TAK-831 600 mg or placebo will be administered on Days 4 to 17. The data on safety and 
tolerability up to 48 hours postdose and PK up to 24 hours postdose will be examined.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohorts 1 and 2 in a blinded manner and discuss with the sponsor 
(including the medical expert if necessary) as to whether Cohorts 3 and 4 should be run.
In Cohort 2 and onwards, the dose will be escalated but the dose escalation will be discontinued 
according to the following discontinuation criteria. The dose in Cohort 2 will be adjusted based on 
the safety and tolerability as well as PK and PD in Cohort 1.
Discontinuation criteria for dose escalation:

Exposures in any cohort exceed those observed at the highest dose tested in monkey (Cmax of 
3680 ng/mL, AUC24 of 35700 hr*ng/mL)

One or more subjects in any single cohort or across more than 1 cohort experience an SAE or 2 
severe or clinically significant AEs occur that are considered related to study drug

One or more subjects in any single cohort or across more than 1 cohort experience severe 
psychiatric symptoms, including (any level of) treatment-emergent suicidal ideation* that are 
considered related to study drug.
*Treatment-emergent suicidality compared to baseline, as measured by changes in suicidal 
ideation or behavior category on the C-SSRS during treatment from the maximum suicidal 
ideation/behavior category at baseline, or any suicidal ideation/behavior during treatment if there 
was none at baseline
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale for Study Population
The subject of this study is Japanese or Chinese with a purpose to support the future conduct of 
studies in Asian subjects. The study will be conducted in healthy adult subjects without any 
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disease including circulatory or cerebrovascular diseases to appropriately assess the safety and 
tolerability as well as PK and PD of TAK-831.
6.3.2
Rationale of Trial Design
With a purpose to assess the safety and tolerability as well as the PK and PD profiles of TAK-831 
when administered to Asian subject for the first time, this study employed a design with both 
single and multiple doses.
6.3.3
Rationale for Dose
To this date, the highest dose of TAK-831 tested in healthy Western subjects is 1200 mg 
(suspension formulation) once daily in the study TAK-831-1005. Based on the preliminary results, 
there were no significant adverse effects reported at this dose level, and as shown in Table 6.b, the 
mean steady-state exposure was Cmax of 3015 ng/mL and AUC24 of 10501 h*ng/mL. The dose 
regimen of 600 mg given once daily (T2 tablet formulation) was also well tolerated and safe in 
healthy Western subjects. As for the mean steady-state exposures, Cmax was 1494 ng/mL and 
AUC24 was 5090 h*ng/mL. This exposure at 600 mg was similar to that of monkeys at 
100 mg/kg/day, the no-observed-adverse-effect-level (NOAEL).
In the study TAK-831-1005, the PK and PD of TAK-831 given as multiple doses at 100 and 
600 mg (per day) to non-Japanese subjects was examined. The dose of 300 mg will be further 
examined in the study.
Based on the above, the doses of 100, 300 and 600 mg were selected for this study in consideration 
to the safety in humans as well as the comparability of PK and PD between non-Japanese and 
Japanese subjects.
In the 13-week repeat dose toxicity study in monkeys that are considered the more sensitive 
species than rats, adverse effects (vomiting, diarrhea, and loose stool) were noted at 
600 mg/kg/day. The NOAEL was 100 mg/kg/day for both sexes.
TAK-831 has been administered at doses up to 1200 mg to non-Japanese, and no SAE has been 
reported with exposures exceeding the NOAEL. Besides, the adverse effects (vomiting, diarrhea, 
and loose stool) noted at a dose of 600 mg/kg/day in the 13-week repeat dose toxicity study in 
monkeys will be easily monitored in clinical trials.
Therefore, it is considered possible to administer doses exceeding the NOAEL exposure by 
carefully examining the safety and PK in each Cohort in this study. However, We have no 
information on toxicity at the level exceeding the exposure at 600 mg/kg/day in the 13-week 
repeated dose toxicity study in monkeys. Dose escalation will be stopped if exposures exceed that 
at 600 mg/kg/day in monkeys.
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Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects
Animal species-Study
Dose
(mg/kg/day or mg)
Cmax
(ng/mL)
AUC24
(h*ng/mL)
Monkey 13-week (Day 91)
100 mg/kg/day (NOAEL)
1340 (male)
1270 (female)
7490 (male)
9190 (female)
600 (300 BID) mg/kg/day
4650 (male)
2710 (female)
45500 (male)
25900 (female)
Human MRD (Day 16)
1200 mg QD (suspension 
formulation)
3015
10501
Human MRD (Day 16)
600 mg QD (T2 tablet 
formulation)
1494
5090
BID, twice daily; MRD, multiple repeated dose; NOAEL, no-observed-adverse-effect-level; QD, once daily
6.3.4
Rationale for Endpoints
6.3.4.1
Safety Endpoint
The safety endpoints in this study were defined to determine the safety and tolerability following a 
single dose and multiple dose of TAK-831. These are standard endpoints in the Phase 1 studies in 
healthy subjects.
Since TAK-831 involves effects on the central nervous system, the C-SSRS will be administered 
to assess the influence on suicidal ideation or suicidal behavior.
6.3.4.2
Pharmacokinetic Endpoint
Concentrations of TAK-831 in plasma will be examined to assess the PK of TAK-831 given as a 
single dose or multiple doses to healthy adult Asian subjects, and then the following PK 
parameters will be calculated.

PK parameters: Cmax, Cmax,ss (Cohorts 2 to 4), tmax, AUClast, AUC∞, AUCτ (Cohorts 2 to 4), 
Rac(Cmax) (Cohorts 2 to 4), Rac(AUC) (Cohorts 2 to 4), t1/2, CL/F, Vz/F
6.3.4.3
Pharmacodynamic Endpoint
Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, AUEC24, 
Emax and time to Emax following TAK-831 doses will be examined to assess the PD of TAK-831 in 
healthy adult Asian subjects. Concentrations of D-serine, L-serine and the ratio of D-serine to total
serine in cerebrospinal fluid may be assessed as necessary.
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures
The objective of this section is to specify the sequence of procedures in the cases where the timing 
of each procedure overlaps.
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
Safety evaluation will be conducted within the predetermined allowance window as far as 
possible.

Blood samples for PK assessment will be collected at time points as close to the specified time
as possible.

Other procedures must be completed at time points as close to the specified or planned hours as 
possible irrespective of before or after the specified times.

If the timing of blood sampling and ECG or vital signs measurement overlap, blood sampling 
should be prioritized. ECG or vital signs measurement may be performed within an acceptable 
time window (Appendix C).

The priority may be changed upon agreement between the investigator and the sponsor based 
on discussion.

Any test and procedure necessary to immediately assess safety concerns at the time of AEs 
must be prioritized over other regular predetermined procedures.

The safety of subjects in the follow-up period may be confirmed by telephone unless abnormal, 
clinically significant findings are observed upon discharge.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The entire study will start when the first subject signs the informed consent form to participate in 
this study.
6.4.2
Definition of End of the Trial
The study will end when the last subject completes the last planned visit or follow-up visit (or last 
communication [may be via telephone] relating to the planned visit) or is withdrawn from the 
study or lost to follow up (the status that the subject cannot be reached by the investigator).
6.4.3
Definition of Trial Discontinuation
The study may be discontinued for reasons other than safety such as the followings:

A finding (eg, PK, pharmacodynamics, efficacy, biologic targets) from the other nonclinical or
clinical studies results with the study drug in the study discontinuation for non-safety related
reasons.

Data from drugs classified in the same class as the study drug, or methodologies used in this 
study become available and results in the study being stopped for a non-safety related reason.

Study discontinuation due to non-scientific and non-safety-related reasons, such as slow
enrollment.
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Discontinuation of the clinical study for safety reasons:

The study is prematurely terminated because other clinical or non-clinical trials where 
TAK-831 or other drugs of the same class are administered have confirmed unexpected safety 
concerns based on the methodology used in this study
6.4.4
Criteria for Premature Termination or Suspension of the Trial
6.4.4.1
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 met that
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the compound, such that the
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.
6.4.4.2
Procedures for Premature Termination or Suspension of the Trial
In the event that the Sponsor, an institutional review board (IRB), or a regulatory authority elects
to terminate or suspend the study, a study-specific procedure for early termination or suspension
will be provided by the Sponsor; the procedure will be followed by the applicable study sites 
during the course of termination or study suspension.
6.4.5
Criteria for Premature Termination or Suspension of a Study Site
6.4.5.1
Criteria for Premature Termination or Suspension of a Study Site
A study 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 is permitted by the contractual agreement.
6.4.5.2
Procedure for Premature Termination or Suspension in a Study Site
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend of the
study site, a study-specific procedure for early termination or suspension will be provided by the
Sponsor; the procedure will be followed by the applicable study sites during the course of 
termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria.
1. The subject must understand the study procedures and agree to participate by providing written 
informed consent (for Chinese subjects, an interpreter should be present as necessary).
2. The subject must be willing and able to comply with all study procedures and restrictions.
3. The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, 
inclusive, at the Screening.
4. The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the 
Screening.
5. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing 
products (e.g., nicotine patch) for at least 6 months prior to the Screening.
6. Chinese subjects are defined as subjects who were born in mainland China, and their biological 
parents and grandparents must all have been of Chinese origin (for Cohort 3 only).
7. Chinese subjects who have lived out of China for more than 5 years must not have significantly 
modified their diets since leaving China (for Cohort 3 only).
8. The subject must be judged to be in good health by the investigator or sub-investigator, based 
on clinical evaluations including laboratory tests, medical history, full physical examination, 
12-lead electrocardiogram, and vital sign measurements performed at the Screening. and prior 
to the first dose of study drug.
9. The subject must meet the following birth control requirements:
•
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicidal cream or jelly, from the first dose of study drug until 
95 days (5 half-lives plus 90 days) after the last dose of study drug. No restrictions will be
required for a vasectomized male subject provided the subject is at least 1 year post 
bilateral vasectomy procedure prior to the first dose of study drug. A male subject whose 
vasectomy procedure was performed less than 1 year prior to the first dose of study drug 
must follow the same restrictions as a nonvasectomized man. Appropriate documentation 
of surgical procedure should be provided.
•
Is a male subject who agrees to not donate sperm from the first dose of study drug until 95 
days (5 half-lives plus 90 days) after the last dose of study drug.
•
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a)
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years or ≥6 months of spontaneous amenorrhea in females aged >45 years with 
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serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate 
documentation of follicle-stimulating hormone levels should be required.
b)
Hysterectomy and/or bilateral oophorectomy with appropriate documentation of 
surgical procedure.
c)
Had a tubal ligation with appropriate documentation of surgical procedure.
d)
Congenital conditions such as uterine aplasia etc.
[Rationale for the inclusion criteria]
Inclusion criteria 1, 2, 5, 8 and 9:
These are standard criteria for clinical pharmacology studies in healthy adult subjects and defined 
in consideration to the safety of subjects.
Inclusion Criterion 3:
This is a standard criterion for clinical pharmacology studies in healthy adult subjects for sex. This 
is a standard criterion for clinical pharmacology studies in healthy adult subjects for age.
Inclusion Criterion 4:
This is the range of normal weight in the diagnosis criteria for obesity and obesity disease [11]
proposed by the Japan Society for the Study of Obesity.
Inclusion Criterion 6:
This is set to appropriately assess the safety and PK in Chinese.
Inclusion Criterion 7:
This is set to eliminate the influence by dietary habits on the PK.
7.2
Exclusion Criteria
The subject will be excluded from participating in the study if the subject meet any of the 
followings.
1. The subject has a history of clinically significant endocrine, gastrointestinal (including 
motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, or genitourinary, or presents with major neurological 
(including stroke and chronic seizures) abnormalities or diseases.
2. The subject has participated in another investigational trial within 4 weeks before the pretrial 
visit (Screening). The 4-week window will be derived from the date of the last trial procedure 
and/or adverse events related to the trial procedure in the previous trial to the Screening Visit 
of the current trial.
3. The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) 
of the sponsor.
4. The subject has a history of cancer (malignancy).
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5. The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerability to prescription or 
nonprescription drugs or food.
6. The subject has a positive alcohol or drug or immunological screen.
7. The subject is of childbearing potential or lactating.
8. The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 
8 weeks prior to the first dose of study drug.
9. The subject with any gastrointestinal surgery that could impact upon the absorption of study 
drug.
10. The subject has a known hypersensitivity to any component of the formulation of TAK-831 or 
related compounds.
11. The subject is unable to refrain from or anticipates the use of any medication, including 
prescription and nonprescription drugs or herbal remedies, beginning approximately 7 days 
before administration of the initial dose of trial drug, throughout the trial (including washout 
intervals between trial periods), until the Follow-up Visit.
12. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on 
average (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).
13. The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
14. The subject has a history of drug abuse.
15. The subject has a (QT interval with Fridericia’s correction method) QTcF >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec at the Screening Visit or 
Check-in.
[Rationale for the exclusion criteria]
Exclusion Criteria 1, 15:
This is set to eliminate the influence on safety evaluation for TAK-831.
Exclusion Criterion 2:
This is a minimum duration in which the previous clinical trial is considered to have no influence 
in reference to “General Considerations for Clinical Trials” [12] in order to ensure the safety of 
subjects.
Exclusion Criteria 3, 4, 6, 7, 12, 13, 14:
These are standard criteria for clinical pharmacology studies and defined in consideration to the 
safety of subjects.
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Exclusion Criterion 5:
This is defined in consideration to the safety of subjects.
Exclusion Criteria 8, 9, 11:
This is defined in consideration to the safety of subjects. This is also defined for potential influence 
on PK and PD assessment.
Exclusion Criterion 10:
This is set to exclude subjects who have a known hypersensitivity to any component of the 
formulation of TAK-831 or related compounds in consideration of the safety of subjects.
7.3
Excluded Medications Supplements, Dietary Products
Table 7.a shows excluded medications, supplements, and dietary products.
Use of the drugs listed on Table 7.a (prescribed drugs and over-the-counter [OTC] drugs), 
vitamins, supplements, and dietary products will be excluded from a specified time point to until 
discharge given the effect on the safety and PK. Use of prohibited concomitant drugs will be
allowed when the investigator or sub-investigator deems it necessary to use any of the concomitant
drugs for reasons including treatment of an AE.
Subjects must be instructed not to take any medications including OTC products, without first
consulting with the investigator or sub-investigator.
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Table 7.a
Excluded Medications, Supplements, Dietary Products
From 28 days before admission (Day -1)
to the last discharge
7 days before admission (Day -1)
to the last discharge
72 hours before admission (Day -1)
to the last discharge
• Prescription drugs
• Supplements (St. John's wort, ginseng, 
kava kava, ginkgoes, chinese herbal 
medicine, and melatonin)
• OTC drugs (including aspirin or 
aspirin-containing drugs) (a)
• Vitamins
• Caffeine or xanthine containing 
products
• Vaccination/vaccine (b)
• Beverages containing grapefruit 
(fruit juice, flesh), star fruits (fruit 
juice, flesh), citrus aurantiums 
(high acidity), orange (seville 
oranges), or marmalade
• Apple, orange or pineapple juice
• Brassicaceae vegetables (kale, 
cress, collard greens, kohlrabi, 
brussels sprouts, and mustard).
• Meat cocked over the charcoal
• Nicotine-containing products
• CYP 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1 and 2A6 inhibitors/inducers 
OTC drugs (c)
• Alcohol containing products
CYP: cytochrome P-450, OTC drugs: over-the-counter drugs
Note: Excludes the drug needs to be administered to treat an AE and if the investigator or sub-investigator considers 
necessary to use the drug
(a)
Use of paracetamol (≤1 g/daily) will be allowed.
(b)
Includes H1N1 and other influenza vaccines, however, not limited to these medications.
(c)
Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Diet and fluid (except water) must be ingested at least10 hours before clinical laboratory tests.
On the day before clinical laboratory tests, evening meal must be ingested by 21:00.
During hospitalization, pre-specified diets must be ingested, and other diets will be prohibited. 
After discharge, excessive drinking and eating must be avoided until completion of follow-up 
period.
Subjects will be instructed to fast for at least 10 hours before study drug administration.
Subjects in Cohort 2-4 will be instructed to fast for an additional 4 hours on Days 1, 4 and 17 and 
2 hours for all other study drug administration days.
If a blood draw/any examinations coincides with a meal, a blood draw/any examinations will take 
precedence followed by the study procedure and then the meal.
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Subjects should be prohibited from drinking any liquid from 1 hour before to 1 hours after study 
drug administration, with the exception of water (150 mL) taken with the study drug.
7.4.2
Activity
Smoking is prohibited during the study.
Excessive exercise is prohibited during the study.
Blood donation is prohibited for at least 12 weeks (84 days) from completion of the last test.
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 or sub-investigator should
communicate that medical institution about the subject’s participation in the study.
7.5
Documentation of Subject Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a
subject discontinues the study before the first study drug administration, the investigator or
sub-investigator should complete the electronic case report form (eCRF).
The primary reason for subject failure is to be recorded in the eCRF using the following categories:

Death

AE

Screening failure (failed inclusion criteria or did meet exclusion criteria) <specify the reasons>

Protocol deviation

Lost to follow up

Withdrawal by subject <specify the reasons>

Study terminated by the Sponsor

Pregnancy

Sample size sufficient

Other <specify the reasons>
Any subject identification number, once assigned to a subject, should not be reused if the assigned
subject discontinues the study prior to the first study drug administration. Nevertheless, if a reserve 
subject is enrolled in the other 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 the subject who is withdrawn from the
study before the first study drug administration in Period 1, refer to Section 7.5.
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1. Death
The subject died on study.
Note: If the subject dies on study, the event will be considered as a serious adverse event 
(SAE). Refer to Section 10.2.9.3 for 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.
The study drug will be immediately discontinued if a condition meets any following criteria 
during the treatment, and appropriate follow-up will be performed (clinical laboratory tests 
will be repeatedly performed until the clinical laboratory test profiles have normalized or 
returned to baseline, refer to Section 9.2.9.1):
•
Liver Function Test (LFT) Abnormalities
-
ALT or AST >8×the upper limit of normal (ULN), or
-
ALT or AST >5×ULN and persists for more than 2 weeks, or
-
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (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%)
•
Prolonged QT/QTcF intervals
If at least one remarkable prolonged QT interval was observed on 12-lead ECG (eg, 
absolute value of QTcF intervals >500 msec or an increase >60 msec from baseline), and 
the investigator or sub-investigator considered inappropriate to continue the study.
3. Protocol deviation
The discovery after the start of the first study drug administration 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. Pregnancy
If a subject was found to be pregnant.
Note: Participation in the study is immediately discontinued for any pregnancy. Refer to 
Appendix B for the procedures.
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6. Voluntary withdrawal
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).
7. Study terminated by the Sponsor
The Sponsor terminates the study.
8. 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
The Part 1 in Cohort 1 and Cohorts 2-4 can have a few reserve subjects considered eligible for 
participation in the study based on screening test. If a subject has not received the study drug as 
scheduled during the study owing to any reason occurring before the study drug administration, a 
reserve subject will be allowed to participate in the study.
If a subject withdraws from the study after initiation of the study drug, the subject will not be 
replaced with a reserve subject.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
[Drug product]
Code name: TAK-831
Dosage form and strength:
TAK-831 tablet is a yellowish-red film-coated tablet containing 25 or 300 mg of TAK-831.
TAK-831 placebo tablet contains no TAK-831 and has same appearance as TAK-831 tablet.
8.1.1
Clinical Study Drug Labeling
Study drug labeling will show name of the study drug, quantity and storage condition of the study 
drug, manufacture number, expiration date, protocol number, name and address of the Sponsor, 
and statement the drug is for clinical trial use only.
8.1.2
Clinical Study Drug Inventory and Storage
TAK-831 is stored at a room temperature (1°C to 30°C).
Study drug must be kept in an appropriate, limited-access, secure place until it is used, or returned
to the Sponsor or its designee. Study drug must be stored under the conditions specified on the
label, and remain in the original container until dispensed.
8.1.3
Randomization Code Creation and Storage
The personnel responsible for randomization (the Sponsor's designee) will prepare the
randomization table/schedule prior to the start of the study. All randomization information will be 
stored in a secured area, accessible only by authorized personnel.
8.1.4
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 will be 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.
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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 eCRF.
If the investigator or sub-investigator breaks the blinding of the study drug, 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 (except cases where the 
investigator or sub-investigator is not informed of unblinding information [unblinding for 
open-label analysis for the Sponsor]).
8.1.5
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 managing 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.
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 Number
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
In Cohorts 1-2 and Cohorts 3-4 (if added), the subjects will be assigned in the order of medication 
identification number by Cohort according to the randomization code. The medication 
identification number will be a 4-digit number, starting with the following number:
Cohort 1: 1001, Cohort 2: 2001, Cohort 3: 3001, Cohort 4: 4001
The assigned medication identification number will be used to identify the samples for PK by the 
study site and the only number to identity a subject during blood sampling for PK. The number will 
be always shown on the sample vials, which are sent to the laboratory to evaluate the PK. The 
laboratory will report the results using this number. The number will be used for only the purpose 
described in this section and cannot be replaced with the 7-digit subject identification number, 
which is assigned at the time of informed consent procedure and used in all other procedures 
during the clinical study period to identify a subject. In case of subject replacement, the study drug 
with a medication identification number for the withdrawn subject will be used by the replacing 
subject.
9.1.2
Inclusion and Exclusion
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, height, weight, caffeine 
use, alcohol use, and smoking status of the subject.
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Medical history to be obtained will include determining whether the subject has any clinically 
significant conditions or diseases that resolved within 1 year prior to the signing of informed 
consent. Ongoing conditions will be considered concurrent medical conditions. Medication history 
information to be obtained will include 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. 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 drugs, 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 is calculated using the formula provided below.
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.
9.2.4
Vital Signs
Vital signs will include body temperature (axilla measurement), sitting blood pressure (systolic 
and diastolic, after resting more than 5 minutes), and pulse (beats per minute).
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.
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The investigator or sub-investigator (or a qualified observer at the investigational site) will 
interpret the ECG using one 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.
9.2.6
Columbia Suicide Severity Rating Scale (C-SSRS)
C-SSRS will be performed at the study procedures-specified time point. The investigator or 
sub-investigator will evaluate suicide risks based on the information obtained from C-SSRS. For 
any suicidal ideation and suicidal behavior will be documented as an adverse event.
9.2.7
Study Drug Administration
In Cohort 1, a single dose of TAK-831 T3 tablet 25 mg×4 tablets or placebo will be orally 
administered on Day 1 (Part 1), and a single dose of TAK-831 T3 tablet 300 mg×1 tablet or 
placebo will be orally administered on Day 9 (Part 2).
In Cohort 2, a single dose of TAK-831 T3 tablet 300 mg×2 tablets or placebo will be orally 
administered on Day 1, followed by multiple doses of TAK-831 T3 tablet 300 mg×2 tablets (once 
daily) or placebo on Days 4-17.
The study drug will be orally administered with 150 mL of water at a fasted state (fasted at least 10 
hours before administration).
In Cohorts 3 and 4, the dose of the study drug will be determined based on the data obtained from 
Cohorts 1 and 2.
9.2.8
AE Monitoring
AE monitoring will begin after the signing of informed consent. A complete description of AE
collections and procedures is provided in Section 10.2.
9.2.9
Laboratory Procedures and Assessments
Laboratory samples will be taken following a minimum 10 hour overnight fast on the days 
stipulated in the Schedule of Study Procedures (Section 3.0). Refer to Appendix C for the amount 
of blood samples.
The investigator or sub-investigator will take responsibility for evaluation of the clinical 
laboratory test results and storage. The investigator will maintain a copy of the reference ranges for 
the laboratory used.
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
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Red blood cell count
White blood cell count and differential leukocytes 
(lymphocytes, neutrophils, eosinophils, basophils, and 
monocytes)
Hemoglobin
Hematocrit
Platelet count
Chemistry
Chemistry evaluations will consist of the following chemistry tests:
Albumin
Creatinine
ALP
Glucose
ALT
Sodium
AST
Calcium
γ-GTP
Creatine kinase
Total bilirubin
Potassium
Direct bilirubin
Chloride
Total protein
PT
Urea nitrogen
APTT
Urinalysis
Urinalysis will consist of the following tests:
pH
Specific gravity
Qualitative (protein, glucose, occult blood, and nitrite)
Urinary sediment (erythrocytes, leukocytes, and cylinder) 
(a)
(a)
Will be performed for any abnormal urinalysis parameter.
Other
Immunological tests
HIV antibody and antigen tests, hepatitis tests (HBs antigen and HCV antibody)
Alcohol tests (urinalysis or breath test)
Urinary drug tests
FSH (postmenopausal female subjects only)
HIV: human immunodeficiency virus, HBs: hepatitis B surface antigen, HCV: hepatitis C virus, FSH: 
follicle-stimulating hormone
Note: The investigator or sub-investigator will report the results of immunology, urine drug tests, and alcohol tests
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.
If subjects experience an ALT or AST of >3×ULN (except the tests at Screening), follow-up 
laboratory tests (at a minimum, serum alkaline phosphatase [ALP], ALT, AST, total bilirubin, 
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gamma-glutamyl transferase [γ-GTP], 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 10.2.9.4 for the discontinuation or withdrawal criteria of a subject 
and the appropriate guidance on reporting abnormal LFTs as SAEs, respectively.
9.2.9.2
Urine sample for Future Tests
Urine samples for future tests will be collected according to the Schedule of Study Procedures 
(Section 3.0).
If acute renal failure is suspected, urinary biomarkers such as KIM-1, NGAL, and cystatin C may 
be measured using the collected sample.
9.3
Biomarker, PK, PD, and PGx Samples
Samples for PK, PD, and PGx will be collected according to the schedule of study procedures 
(Section 3.0). Separated procedures describe the details of sampling, handling, and transferring to 
central laboratory. The actual sampling time for PK and PD analyses will be documented in the 
subject’s source documents and eCRF.
Table 9.a shows primary specimen collections.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of
Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
PK Analysis
Mandatory
Plasma sample for PD
Blood
Plasma
PD analysis
Mandatory
Cerebrospinal fluid sample for PD Cerebrospinal fluid Cerebrospinal fluid
PD analysis
Optional
Blood sample for DNA PGx
Blood
DNA
PGx analysis
Optional
9.3.1
PK Measurements
The following PK parameters will be calculated from plasma concentrations of TAK-831, unless 
otherwise specified.
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Mark/Term
Definition
Plasma
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
Area under the plasma concentration-time curve from time 0 to time of infinity
AUCτ
Area under the plasma concentration-time curve during a dosing interval
Cmax
Maximum observed plasma concentration (measured value)
Cmax, ss
Maximum observed steady-state plasma concentration during a dosing interval (measured value)
tmax
Time of first occurrence of Cmax
t1/2z
Terminal disposition phase half-life
λz
Terminal disposition phase rate constant
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration
CL/F
Apparent clearance after extravascular administration
Rac(Cmax)
Accumulation ratio based on Cmax
Rac(AUC)
Accumulation ratio based on AUC
9.3.1.1
Plasma for PK Measurements
Blood samples for plasma TAK-831 concentration will be collected (Table 9.b). The sampling 
schedule may change based on emerging data but the number of samples will not exceed the 
number of planned samples.
Table 9.b
Blood Sample Collection for PK Analysis
Dose Levels:
Date of 
administration
Sampling time
Single dose
1
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
9
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
1
Predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, and 48 hours postdose
4, 11, 14
Predose
17
Predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 16, and 24 hours postdose
9.3.2
PD Analysis
The following PD parameters will be calculated from plasma concentrations of D-serine and 
L-serine, unless otherwise specified
Mark/Term
Definition
Plasma
AUEC24
Area under the effect-time curve from time 0 to 24 hours postdose
Emax
Maximum effect
time to Emax
Time to reach maximum PD effect
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9.3.2.1
Plasma Samples for PD Analysis
Blood samples will be collected to measure plasma D-serine and L-serine concentrations (Table 
9.c). The sampling schedule may change based on emerging data but the number of samples will 
not exceed the number of planned samples.
Table 9.c
Blood Sample Collection for PD Analysis
Dose Levels:
Specimen
Date of 
administration
Sampling time
Single dose
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, 24, 36, 48 and 
72 hours postdose
9
Predose, 1, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, and 24 hours 
postdose
11, 14
Predose
17
Predose, 1, 4, 8, 12, and 24 hours postdose
9.3.2.2
Cerebrospinal fluid samples for PD Analysis
Cerebrospinal fluid will be collected to measure D-serine and L-serine concentrations (3.0 mL per 
scheduled time). The cerebrospinal fluid sampling schedule may change based on emerging data 
but the number of samples will not exceed the number of planned samples. After Cohort 2, 
collection of cerebrospinal fluid in the next Cohorts will be determined based on the results of 
plasma D-serine and L-serine concentrations obtained from the previous Cohorts.
9.3.3
PGx Measurements
9.3.3.1
Blood Sample for DNA PGx Measurements
When sampling of whole blood for pharmacogenomic analysis occurs, the subject must sign 
informed consent/be consented separately for PGx sampling, storage and analysis. PGx 
measurement is a part of the study, but participation of a subject is optional.
One 6-mL of whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected 
prior to the single dosing on Day 1 from each consenting subject in the study.
The samples will be stored for no longer than 15 years after completion of the TAK-831 study 
and/or until the drug development of TAK-831 is no longer actively pursued. No samples will be 
stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification by the Sponsor. “Stored samples” are defined as samples that are coded (the samples 
are stripped of all personal identifying information but a key links the samples to the clinical data 
collected from the sample donor) and are used in the analysis of the study drug or related drug.
The sampling of whole blood for PGx and genotyping analysis is mandatory. Every subject must 
sign informed consent separately for PGx sampling. DNA samples will be used to evaluate drug 
metabolic enzyme and transporter polymorphisms.
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Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of some of this gene in drug response, which may lead to additional 
exploratory research with the samples for PGx measurements.
9.3.4
Confinement
Cohort 1:
Subjects will be hospitalized from Day -1 to Day 4 and Day 8 to Day 12 and will be discharged 
after the investigator or sub-investigator confirm no clinically significant health problems based 
on the examination and tests on Days 4 and 12.
Cohorts 2-4:
Subjects will be hospitalized from Day -1 to Day 19 and will be discharged after the investigator or 
sub-investigator confirm no clinically significant health problems based on the examination and 
tests on Day 19.
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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 clinical study; it does not necessarily have to have a 
causal relationship with the the treatment (including the study drug) 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 treatment (including the study drug) or study 
procedures.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing 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 may be considered as 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 for an abnormal value are not considered as 
an intervention. In addition, repeated or additional non-invasive tests for verification and 
evaluation of abnormality or monitoring purpose will not be considered as an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a
concurrent medical history conditions and should NOT be recorded as an AE. The
observations or evaluations of first examination at baseline (eg, laboratory test, ECG, X-ray, 
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etc) should NOT be recorded as AEs unless related to a study procedure. However, if the 
subject experiences a worsening or complication of such a concurrent medical history 
condition, the worsening or complication should be recorded appropriately as an AE 
(worsening or complication occurs after informed consent is signed). 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. 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 pre-existing chronic 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. 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 drug or after any change in study drug, the worsening or complication should be
recorded as a new AE. The investigator or sub-investigator should ensure that the event term 
reported captures the change in adverse event (eg, “worsening of…”).
Changes in severity of AEs:

If a subject experiences a change in the severity of an AE that is not associated with a change in 
study drug, 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 the signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
earlier (eg, as an emergency) due to a worsening of a 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 study 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 sub-investigator to decide whether a dose is 
to be considered as overdose, in consultation with the Sponsor.
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in 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 (ADRS)
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Malignant hypertension
Convulsive seizures (includes convulsion and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (includes interstitial pneumonia)
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Confirmed or suspected endotoxin shock
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
Severity/Intensity of AEs will be classified or defined as follows:
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 causality 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 disease, 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 the underlying disease, complications, 
concomitant medications and concurrent treatments.
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.
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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 or sub-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 drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable - a study drug was stopped for a reason other than the particular AE; eg, the 
clinical study has been terminated, the subject died, dosing with study drug had not yet started 
or dosing with study drug 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/signs/symptoms have almost disappeared; the abnormal laboratory values improved, 
but have 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 values on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
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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 and continue until the follow-up visit or phone call.
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 the study drug must be monitored until the 
symptoms have resolved and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Nonserious AEs that begin prior to 
the first exposure to the study drug, regardless of related or unrelated to the study procedure, need 
not be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug 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 Adverse Event (Frequency)

Severity/Intensity.

The Investigator’s or sub-investigator’s opinion of the causal relationship between the event 
and administration of study drug(s). (Related/Not related)

Action taken with the study drug

Outcome of the event.

Seriousness.

Timing of occurrence (after administration of the study drug)
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 within 1 
business day of the first onset or notification of the SAE, along with any relevant information. The 
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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 drug(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 the follow-up SAE form or provide other written 
documentation immediately to the Sponsor. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory values, discharge summary, postmortem results) in the institution should be 
submitted to the Sponsor, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.
10.2.9.4 Reporting of Abnormal LFTs
If a subject experiences 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 will contact the monitor for discussion 
and investigation of the relevant subject details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease, medical history/ongoing disease. Follow-up 
laboratory tests as described in Section 9.2.9 must also be performed.
10.2.10
Safety Reporting to Investigators, IRBs and Regulatory Authorities
The Sponsor will report all suspected unexpected serious adverse reactions (SUSARs) and any 
other applicable SAEs to regulatory authorities, investigators, IRBs and the head of the study site. 
Relative to the first awareness of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening events and 15 
days for other serious events, unless otherwise required by national regulations. The Sponsor will 
also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of the study drug or that would be sufficient to consider changes in 
the study drug administration or in the overall conduct of the trial. The study 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 unblinding of subject’s 
treatment assignment. 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, 3 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.
The Sponsor will verify the validity of the definitions of the analysis sets and the rules for handling
data in consultation with a medical expert, as needed, prior to unblinding the study drug 
assignment. The Sponsor will address all remaining uncertainties not specified at planning, and 
will finalize the SAP prior to unblinding of subject’s treatment assignment.
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, and who 
were appropriately evaluable for at least 1 PK parameter.
11.1.1.3 PD Analysis Set
The PD Analysis Set will consist of subjects who received at least one dose of study drug, and who 
were appropriately evaluable for at least 1 PD parameter.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the Safety Analysis 
Set.
11.1.3
PK Analysis
Endpoints and its analytical method
[Endpoints]
Secondary endpoints: Cmax (Cohort 1, Day 1 in Cohorts 2 to 4), Cmax,ss (Day 17 in Cohorts 2 to 4), 
tmax (Cohort 1, Days 1 and 17 in Cohort 2 to 4), AUClast (Cohort 1, Day 1 in Cohorts 2 to 4), AUC∞
(Cohort 1, Day 1 in Cohorts 2 to 4), AUCτ (Days 1 and 17 in Cohorts 2 to 4)
Exploratory endpoints: Rac(Cmax) and Rac(AUC) (Cohort 2 to 4) on Days 1 and 17, t1/2z, CL/F, Vz/F
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[Analytical method]
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and treatment period for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of TAK-831 in plasma will be summarized by each scheduled sampling time using 
summary statistics. Individual plasma concentration data versus time will be presented. Plasma PK 
parameters, including dose-normalized Cmax and AUC, will be summarized by dose and day using 
summary statistics. Accumulation of TAK-831 from Day 1 to Day 17 will be assessed by 
summarizing the ratio of Cmax and AUC at Days 1 and 17 by dose. Dose linearity in plasma PK 
parameters (Cmax and AUC) will be assessed graphically for those parameters at Day 1 and Day 9 
for Cohort 1 and Day 1 for Cohorts 2 to 4. Additional analyses on dose linearity will be included if 
appropriate.
11.1.4
PD Analysis
Endpoints and its analytical method
[Endpoints]

Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (on Days -1 and 18) (if available)
[Analytical method]
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and each scheduled sampling time for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in plasma and 
concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal fluid 
(if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of 
D-serine to total serine in plasma, and change and percent the change from baseline will be 
summarized by day using summary statistics. The potential relationship between TAK-831 
exposure and biomarker response will be explored graphically. Additional statistical or PK-PD 
analyses will be included if appropriate.
11.1.5
Safety Analysis
Endpoints and its analytical method
[Endpoints]
AEs, laboratory findings, vital signs, weight, 12-lead ECG
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[Analytical method]
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for 
Cohorts 2 and 4, and for Cohort 3.
11.1.5.1 AEs
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset occurs on or 
after the start of study drug.
The followings will be analyzed for TEAEs. TEAEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT).

Frequency of all TEAEs

Frequency of drug-related TEAEs

Frequency of all TEAEs by intensity

Frequency of drug-related TEAEs by intensity

Frequency of TEAEs leading to study drug discontinuation

Frequency of serious TEAEs
11.1.5.2 Clinical Laboratory Evaluation
Summary statistics will be provided for observed values and change from baseline at each 
evaluation time point. Pre- and post-dose shift tables will be prepared for categorical variables.
11.1.5.3 Vital Signs
Summary statistics will be provided for the observed values at each evaluation time point and 
changes from baseline.
11.1.5.4 Other Safety Parameters
The ECG parameters will be summarized as follows. Summary statistics will be calculated for 
observed values and change from baseline at each evaluation time point. Pre- and post-dose shift 
tables will be prepared for categorical variables. The analysis methods for other endpoints will be 
specified in detail in the SAP.
11.2
Determination of Sample Size
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size 
required to assess the safety, tolerability, and PK of each cohort. This is not based on any statistical 
rationale.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its
designee (Contract Research Organization) and by the IRB.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, and 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 study site of the deviation
or changes 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 study 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 study site also may be subject to quality assurance audits by the Sponsor or designees. In this
circumstance, the Sponsor-designated auditor will contact the study 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], and the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory authority, the Sponsor should be notified immediately. The investigator and the head of 
the institution 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 Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline for GCP. The
investigator will conduct the study according to applicable local or regional regulatory 
requirements in accordance with the “Responsibilities of the Investigator” that are listed in
Appendix A.
13.1
IRB Approval
The IRB must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or the designee will require documentation noting all names and titles of the 
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 the 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 
written informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements, if applicable, and other documents required by all applicable laws and regulations, 
must be submitted to the IRB for approval. The IRB’s written approval of the protocol and subject 
written informed consent must be obtained and submitted to the Sponsor or the 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, written informed consent 
form) reviewed; and state the approval date. The Sponsor will notify the study site that the Sponsor 
has confirmed the adequacy of the study site regulatory documentation. Until the study site
receives a notification, no protocol activities, including screening, may occur.
The study site must adhere to all requirements stipulated by its respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the written 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 the Sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The written informed consent form describes the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
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The informed consent form will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care.
The investigator is responsible for the preparation, content, and IRB approval of the written 
informed consent form. The written informed consent form must be approved by both the IRB and 
the Sponsor prior to use.
The informed consent form must be described 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 or she will participate 
in the clinical 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 by 
the investigator or sub-investigator to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator or sub-investigator must also sign and date the informed 
consent form 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 will 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.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify the Sponsor of consent 
withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this 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.
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, and PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
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including 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 the facility name, investigator’s city, state (for Americas
investigators), country, and recruiting status will be registered and available for public viewing.
13.5
Clinical Trial Results Disclosure
Takeda will post the results of the clinical study on ClinicalTrials.gov or publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.6
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study subjects. 
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator or sub-investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.2
Investigator Agreement
A separate agreement will be provided to the study site.
14.1.3
Study-Related Responsibilities
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.4
List of Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUEC
area under the effect-time curve
BMI
body mass index
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
DAAO
D-amino acid oxidase
DNA
deoxyribonucleic acid
Emax
maximum effect
FDA
Food and Drug Administration
FRDA
Friedreich ataxia
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
γ-GTP
gamma-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation of Technical Requrements for Pharmaceuticals for Human 
Use
INR
international normalized ratio
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
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Term
Definition
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
PET
positron emission tomography
PMDA
Pharmaceuticals and Medical Devices Agency
PT
prothrombin time
POC
proof-of-concept
Rac
accumulation ratio
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
tmax
time of first occrurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply the study sites with access to eCRFs. The Sponsor will 
provide training opportunities for the site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the Sponsor 
(or the designee) and will be answered by the study site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs.
The following data will not be recorded in the eCRFs.

PGx analysis results

Clinical laboratory test results

Drug concentration measurement results

PD measurement results
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 or sub-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 study site during periodic visits 
by the Sponsor or its designee. 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 or the head of the study site agree to keep the records stipulated in Section 15.1
and those documents that include (but not limited to) the study-specific documents, the
identification log of all participating subjects, medical records, all original signed and dated
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its
designees.
The investigator and the head of the study site are required to retain 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 study 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 study 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]
Sham PC, Gottesman, II, MacLean CJ, Kendler KS. Schizophrenia: sex and familial 
morbidity. Psychiatry Res 1994;52(2):125-34.
[2]
Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, et al. 
Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen 
Psychiatry 1999;56(2):162-8.
[3]
Erlenmeyer-Kimling L, Squires-Wheeler E, Adamo UH, Bassett AS, Cornblatt BA, 
Kestenbaum CJ, et al. The New York High-Risk Project. Psychoses and cluster A 
personality disorders in offspring of schizophrenic parents at 23 years of follow-up. Arch 
Gen Psychiatry 1995;52(10):857-65.
[4]
van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
[5]
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor 
antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm 
shift in medication development. Psychopharmacology (Berl) 2003;169(3-4):215-33.
[6]
Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, et al. Plasma 
levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 
2012;142(1-3):83-7.
[7]
Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, et al. Changes in plasma 
glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical 
symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). 
Prog Neuropsychopharmacol Biol Psychiatry 2008;32(8):1905-12.
[8]
Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. 
Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of 
the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen 
Psychiatry 2003;60(6):572-6.
[9]
Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to 
total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog 
Neuropsychopharmacol Biol Psychiatry 2005;29(5):767-9.
[10] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights 
from 108 schizophrenia-associated genetic loci. Nature 2014;511(7510):421-7.
[11] Japan Sciety for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity, 2011 Oct; additional edition.
[12] General Considerations for Clinical Trials (Notification No. 380 of the Evaluation and 
Licensing Division, PMSB dated April 21, 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 study site in advance to get them accepted.
3. Prepare a written informed consent form 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 study 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 study site and the Sponsor 
in writing.
11. Determine the need of emergency key code unblinding 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 study site of the end of the study in writing.
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Appendix B
Pregnancy and Contraception
Male Subjects and Their Female Partners
From the signing of informed consent, throughout the duration of the study, and for 95 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 or subjects should refrain from having sexual 
intercourse from 1 month prior to the first study drug administration throughout the study period 
and until 35 days after the last study drug administration. 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.
Female Subjects and Their Male Partners
Female subjects of childbearing potential* will be excluded from this study.
* 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 device (IUD)
Hormonal contraceptives
Male condoms with a spermicide
Copper T PLUS condom
Progesterone T PLUS condom
Combined pill
Subjects will be provided with information on acceptable methods of contraception for 95 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 95 days after their last dose of study drug.
Pregnancy
If any subject is found to be pregnant during the study, the subject should immediately discontinue 
the study drug and be withdrawn from the study. In addition, if any pregnancies in the partner of a 
male subject, during the study or for 95 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.
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If the female subject or 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 she or his 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).
All female subjects and the the female partners of male subjects who became pregnant will be 
followed to final outcome, using the pregnancy form, with the consent of the female subjects or 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
<Cohort 1>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Study treatment period 
(Part 1)
Day 1 72 hours postdose
Day 4 from awakening
to discharge
Washout period
Day 8
Not applicable
Study treatment period 
(Part 2)
Day 9 72 hours postdose
Day 12 from
awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 and 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 2 and 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicabled
Treatment period (Part 1)
Day 1 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Urinary drug tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Washout period
Day 8
Not applicable
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period (Part 1)
Day 1 predose
Not applicable
Blood samples for PK
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
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Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 1 hour postdose
Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 24 hours postdose
Within ± 2 hours
Treatment period (Part 2)
Day 9 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, and FSH
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<Cohorts 2-4>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Days 5-10 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Days 12-13 predose
From awakening to 
immediately prior to 
dose
Day 14 predose
From awakening to 
immediately prior to 
dose
Days 15-16 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 1, 4, 12, 24, and 48 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 48 hours postdose
Day 19 from
awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 2 and 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period
(Single dose part)
Day 1 predose
Not applicable
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Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PK
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.25, 0.5, 1, 1.5 and 2 hours 
postdose
Within ± 5 minutes
Day 1 4, 8, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
Within 15 minutes 
predose
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 0.25, 0.5, 1, 1.5, and 2 hours 
postdose
Within ± 5 minutes
Day 17 4, 8, 12, 16 and 24 hours 
postdose
Within ± 15 minutes
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, and 24 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 1 hour postdose
Within ± 15 minutes
Day 17 4, 8, 12, and 24 hours postdose Within ± 15 minutes
Cerebrospinal fluid 
samples for PD
(If performed)
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 3 hours
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 24 hours postdose
Within ± 2 hours
Teatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, FSH, and urinary drug tests
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Total blood sampling volumes for an individual subject is shown below:
<Cohort 1>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total Volume
(mL)
Screening
Day -1
Days 1-4
Day 8
Days 9-12
Clinical Laboratory 
Tests
20
1
1
1
1
1
100
Blood sampls for PK
4
-
-
12
-
12
96
Blood sampls for PD
6
-
3
9
-
9
126
Samples for PGx 
Measurements
6
-
-
1
-
-
6
Total Blood Sampling Volume
328
-: No blood collection
<Cohorts 2-4>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total 
Volume
(mL)
Screening Day -1 Day 1
Day 2
Day 3
Day 4 Day 11 Day 14 Days
17-18 Day 19
Clinical Laboratory 
Tests
20
1
1
-
-
-
-
1
-
-
1
80
Blood sampls for PK
4
-
-
9
2
1
1
1
1
11
-
104
Blood sampls for PD
6
-
3
5
1
-
-
1
1
6
-
102
Samples for PGx 
Measurements
6
-
-
1
-
-
-
-
-
-
-
6
Total Blood Sampling Volume
292
-: No blood collection
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CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of 
TAK-831 in Healthy Adult Asian Subjects
Phase 1 Study of TAK-831 in Healthy Adult Asian Subjects
Study Identifier:
TAK-831-1002
Compound:
TAK-831
Date:
5 September 2018
Version/Amendment 
Number:
Amendment 1
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................11
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.2
Rationale for the Proposed Study.............................................................................15
4.3
Benefit/Risk Profile .................................................................................................16
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................18
5.1
Hypothesis...............................................................................................................18
5.2
Trial Objectives .......................................................................................................18
5.2.1
Trial Primary Objective......................................................................................18
5.2.2
Trial Secondary Objective..................................................................................18
5.2.3
Trial Exploratory Objective................................................................................18
5.3
Endpoints.................................................................................................................18
5.3.1
Primary Endpoint...............................................................................................18
5.3.2
Secondary Endpoints..........................................................................................18
5.3.3
Exploratory Endpoints .......................................................................................19
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................20
6.1
Trial Design.............................................................................................................20
6.2
Cohort transition/Dose Escalation............................................................................22
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................22
6.3.1
Rationale for Study Population...........................................................................22
6.3.2
Rationale of Trial Design ...................................................................................23
6.3.3
Rationale for Dose .............................................................................................23
6.3.4
Rationale for Endpoints......................................................................................24
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures ................24
6.4
Trial Beginning and End/Completion.......................................................................25
6.4.1
Definition of Beginning of the Trial ...................................................................25
6.4.2
Definition of End of the Trial.............................................................................25
6.4.3
Definition of Trial Discontinuation ....................................................................25
6.4.4
Criteria for Premature Termination or Suspension of the Trial............................26
6.4.5
Criteria for Premature Termination or Suspension of a Study Site......................26
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27
7.1
Inclusion Criteria .....................................................................................................27
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7.2
Exclusion Criteria ....................................................................................................28
7.3
Excluded Medications Supplements, Dietary Products.............................................30
7.4
Diet, Fluid, Activity.................................................................................................31
7.4.1
Diet and Fluid ....................................................................................................31
7.4.2
Activity..............................................................................................................31
7.5
Documentation of Subject Failure............................................................................32
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................34
7.8
Subject Replacement................................................................................................34
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................35
8.1
Clinical Study Drug .................................................................................................35
8.1.1
Clinical Study Drug Labeling.............................................................................35
8.1.2
Clinical Study Drug Inventory and Storage ........................................................35
8.1.3
Randomization Code Creation and Storage ........................................................35
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................35
8.1.5
Accountability and Destruction of Sponsor-Supplied Drugs...............................36
9.0
STUDY PROCEDURES...............................................................................................37
9.1
Administrative Procedures.......................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.2
Inclusion and Exclusion .....................................................................................37
9.1.3
Medical History/Demography ............................................................................37
9.1.4
Concomitant Medications...................................................................................38
9.2
Clinical Procedures and Assessments.......................................................................38
9.2.1
Full Physical Exam ............................................................................................38
9.2.2
Height and Weight .............................................................................................38
9.2.3
BMI ...................................................................................................................38
9.2.4
Vital Signs .........................................................................................................38
9.2.5
12-Lead ECG.....................................................................................................38
9.2.6
Columbia Suicide Severity Rating Scale (C-SSRS)............................................39
9.2.7
Study Drug Administration ................................................................................39
9.2.8
AE Monitoring...................................................................................................39
9.2.9
Laboratory Procedures and Assessments ............................................................39
9.3
Biomarker, PK, PD, and PGx Samples.....................................................................41
9.3.1
PK Measurements..............................................................................................41
9.3.2
PD Analysis .......................................................................................................42
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9.3.3
PGx Measurements ............................................................................................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................................................48
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.............51
11.0
STATISTICAL METHODS..........................................................................................52
11.1
Statistical and Analytical Plans ................................................................................52
11.1.1 Analysis Sets......................................................................................................52
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................52
11.1.3 PK Analysis .......................................................................................................52
11.1.4 PD Analysis .......................................................................................................53
11.1.5 Safety Analysis ..................................................................................................53
11.2
Determination of Sample Size..................................................................................54
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................55
12.1
Study-Site Monitoring Visits ...................................................................................55
12.2
Protocol Deviations..................................................................................................55
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................55
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................56
13.1
IRB Approval ..........................................................................................................56
13.2
Subject Information, Informed Consent, and Subject Authorization .........................56
13.3
Subject Confidentiality ............................................................................................57
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................58
13.4.1 Publication and Disclosure.................................................................................58
13.4.2 Clinical Trial Registration..................................................................................58
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13.5
Clinical Trial Results Disclosure..............................................................................58
13.6
Insurance and Compensation for Injury....................................................................58
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................59
14.1
Administrative Information......................................................................................59
14.1.1 Study Contact Information .................................................................................59
14.1.2 Investigator Agreement......................................................................................59
14.1.3 Study-Related Responsibilities...........................................................................59
14.1.4 List of Abbreviations .........................................................................................59
15.0
DATA HANDLING AND RECORDKEEPING............................................................61
15.1
eCRFs......................................................................................................................61
15.2
Record Retention .....................................................................................................62
16.0
REFERENCES..............................................................................................................63
17.0
APPENDICES...............................................................................................................64
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Cohorts..........................................................................................21
Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects............................24
Table 7.a
Excluded Medications, Supplements, Dietary Products ......................................31
Table 9.a
Primary Specimen Collections ...........................................................................41
Table 9.b
Blood Sample Collection for PK Analysis..........................................................42
Table 9.c
Blood Sample Collection for PD Analysis..........................................................43
Table 10.a
Takeda Medically Significant AE List................................................................48
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................10
Figure 6.a
Study Schematic ................................................................................................21
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................64
Appendix B
Pregnancy and Contraception.............................................................................65
Appendix C
Acceptable Time Window for Study Procedure..................................................67
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals
Compound:
TAK-831
Study Identifier: TAK-831-1002
Phase: 1
Title of Study: Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of TAK 831 in Healthy Adult Asian Subjects
Trial Design:
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) of TAK-831 in healthy adult Asian subjects.
This study will include up to 4 cohorts of healthy adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered under a 3 sequential dose escalation design, and the safety, 
PK and PD will be assessed. Eight healthy adult Japanese subjects will be randomized in dosing orders of A 
(100 mg→300 mg), B (100 mg→placebo), and C (placebo→300 mg) at a 4:2:2 ratio. A single dose of TAK-831 or 
placebo will be administered on Day 1 and Day 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
Cohort 2 will include 8 healthy adult Japanese subjects. Of these subjects, 6 will be randomly assigned to the TAK-831 
group and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed by their 
multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with subjects followed for 
approximately 72 hours of assessments for safety, PK and PD. Treatment for multiple doses will start with a 
once-daily regimen on Day 4, which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at 
least 48 hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 and 4 will be optional, in which a single dose will be administered followed by multiple doses, and may be 
studied based on emerging data from the prior cohorts.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 will include 8 healthy adult Japanese subjects. Of 
these subjects in the respective cohorts, 6 will be randomly assigned to the TAK-831 group and 2 to the placebo group. 
A single dose of TAK-831 or placebo will be administered, followed by their multiple doses. A single dose of 
TAK-831 or placebo will be administered on Day 1 with subjects followed for approximately 72 hours of assessments 
for safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, which will continue 
to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo dose 
on Day 17 for safety, PK, and PD assessments before discharge.
Trial Primary Objective:
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Secondary Objectives:
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Target: Healthy adult Asian subjects
Planned Number of Subjects:
Cohort 1: 8 subjects
Cohorts 2 to 4: 8 subjects per cohort
Planned Number of Sites:
1 site
Dose Levels:
<Cohort 1>
Single dose at 100 mg on Day 1 (Part 1) and 300 mg on 
Day 9 (Part 2) (fasted)
<Cohort 2>
Single dose at 600 mg on Day 1. Multiple doses 
Route of Administration:
Oral
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CONFIDENTIAL
(once-daily) at 600 mg on Days 4 to 17 (fasted)
<Cohort 3>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
<Cohort 4>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
Duration of Treatment:
<Cohort 1>
Part 1: Single dose on Day 1
Part 2: Single dose on Day 9
<Cohorts 2 to 4>
Single dose on Day 1 and once-daily multiple doses on 
Days 4 to 17, for 14 days, in each Cohort
Planned Trial Duration:
<Cohort 1>
Screening period: Day -28 to -1
Treatment period: Days 1 to 12
Follow-up period: Day 23
<Cohorts 2 to 4>
Screening period: Day -28 to -1
Treatment period: Days 1 to 19
Follow-up period: Day 31
Inclusion Criteria:
Subject eligibility will be determined according to the following criteria.
1.
The subject must understand the study procedures and agree to participate by providing written informed consent 
(for Chinese subjects, an interpreter should be present as necessary).
2.
The subject must be willing and able to comply with all study procedures and restrictions.
3.
The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, inclusive, at the 
Screening.
4.
The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the Screening.
5.
The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing products (e.g., 
nicotine patch) for at least 6 months prior to the Screening.
6.
Chinese subjects are defined as subjects who were born in mainland China, and their biological parents and 
grandparents must all have been of Chinese origin (for Cohort 3 only).
7.
Chinese subjects who have lived out of China for more than 5 years must not have significantly modified their 
diets since leaving China (for Cohort 3 only).
8.
The subject must be judged to be in good health by the investigator or sub-investigator, based on clinical 
evaluations including laboratory tests, medical history, full physical examination, 12-lead electrocardiogram, 
and vital sign measurements performed at the Screening. and prior to the first dose of study drug.
9.
The subject must meet the birth control requirements.
Exclusion Criteria:
The subject must be excluded from participating in the study if the subject meet any of the followings.
1.
The subject has a history of clinically significant endocrine, gastrointestinal (including motility disorder and 
intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, or 
genitourinary, or presents with major neurological (including stroke and chronic seizures) abnormalities or 
diseases.
2.
The subject has participated in another investigational trial within 4 weeks before the pretrial visit (Screening). 
The 4-week window will be derived from the date of the last trial procedure and/or adverse events related to the 
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trial procedure in the previous trial to the Screening Visit of the current trial.
3.
The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the sponsor.
4.
The subject has a history of cancer (malignancy).
5.
The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy) or has had 
an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.
6.
The subject has a positive alcohol or drug or immunological screen.
7.
The subject is of childbearing potential or lactating.
8.
The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 8 weeks prior to 
the first dose of study drug.
9.
The subject with any gastrointestinal surgery that could impact upon the absorption of study drug.
10.
The subject has a known hypersensitivity to any component of the formulation of TAK-831 or related 
compounds.
11.
The subject is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before administration of the initial 
dose of trial drug, throughout the trial (including washout intervals between trial periods), until the Follow-up 
Visit.
12.
The subject has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 
ounce] per day).
13.
The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
14.
The subject has a history of drug abuse.
15.
The subject has a (QT interval with Fridericia’s correction method) QTcF >450 ms (males) or >470 ms (females) 
or PR outside the range of 120 to 220 ms at the Screening Visit or Check-in.
Main Criteria for Evaluation and Analyses:
Primary Endpoint
Safety: Adverse event, laboratory tests, vital signs, weight, 12-lead electrocardiogram
Secondary Endpoints
Pharmacokinetics: The following parameters will be calculated.
Cmax (Cohort 1, Day 1 of Cohorts 2 to 4)
Cmax,ss (Day 17 of Cohorts 2 to 4)
tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 4)
AUClast (Cohort 1, Day 1 of Cohorts 2 to 4)
AUC∞(Cohort 1, Day 1 of Cohorts 2 to 4)
AUCτ (Days 1 and 17 of Cohorts 2 to 4)
Statistical Considerations:
Pharmacokinetics:
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and treatment 
period for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of TAK-831 in plasma will be summarized by each scheduled sampling time using summary statistics. 
Individual plasma concentration data versus time will be presented. Plasma PK parameters, including 
dose-normalized Cmax and AUC, will be summarized by dose and day using summary statistics. Accumulation of 
TAK-831 from Day 1 to Day 17 will be assessed by summarizing the ratio of Cmax and AUC at Days 1 and 17 by dose. 
Dose linearity in plasma PK parameters (Cmax and AUC) will be assessed graphically for those parameters at Days 1 
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and 9 for Cohort 1 and Day 1 for Cohorts 2 to 4. Additional analyses on dose linearity will be included if appropriate.
Pharmacodynamics:
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and each 
scheduled sampling time for Cohorts 2 and 4, as well as Cohort 3. Concentrations of D-serine, L-serine and the ratio of 
D-serine to total serine in plasma and concentrations of D-serine, L-serine and the ratio of D-serine to total serine in 
cerebrospinal fluid (if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of D-serine to total serine in 
plasma, and change and percent change from baseline will be summarized by day using summary statistics. The 
potential relationship between TAK-831 exposure and biomarker response will be explored graphically. Additional 
statistical or PK-PD analyses will be included if appropriate.
Safety:
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for Cohorts 2 and 4, and for 
Cohort 3.
A treatment-emergent adverse event (TEAE) refers to an adverse event that occurs after the start of study treatment. 
The frequency of all TEAEs, drug-related TEAEs , all TEAEs by intensity, drug-related TEAEs by intensity, TEAEs 
leading to study drug discontinuation, and serious TEAEs will be summarized. TEAEs will be coded using Medical 
Dictionary for Regulatory Activities Terminology (MedDRA) and summarized by system organ class (SOC) and 
preferred term (PT).
For continuous values of laboratory findings, vital signs and other safety parameters, summary statistics will be 
provieded for observed values and change from baseline at each evaluation time point. Pre- and post-dose shift tables 
will be prepared for categorical variables.
Sample Size Justification:
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size required to assess the 
safety, tolerability, PK and PD of each cohort. This is not based on any statistical rationale.
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2.0
STUDY SCHEMATIC
Figure 2.a shows the schematic of the trial design.
Figure 2.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
Sequence of 
administration
Part 1
Washout 
interval
Part 2
Day 1 to 4
Day 5 to 8
Day 9 to 12
A
TAK-831 100 mg
Washout
TAK-831 300 mg
B
TAK-831 100 mg
Placebo
C
Placebo
TAK-831 300 mg
<Cohorts 2 to 4>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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3.0
SCHEDULE OF STUDY PROCEDURES
<Cohort 1>
Screening period
Treatment period
Early
Termina
tion
Follow-up 
visit
Screening Hospitali
zation
Part 1
Washout interval
Part 2
Day
-28 to -2
-1
1
2
3
4
5 to 7
8
9
10
11
12
23 (±2)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics, medical history
X
Prior medications
X
Physical examination
X
X
X
X
X
X
X
X (l)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X (l)
Weight, height, BMI (b)
X
X
X
X
X
X
X (l)
12-lead electrocardiogram (ECG) (c)
X
X
X
X
X
X
X
X
X (l)
Laboratory tests (d)
X
X
X
X
X
X
X (l)
Immunological test, alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
X
C-SSRS (f)
X
X
X
X
X
X
Sample collection for pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X(k)
Blood sample collection for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
X
X
Urine sample (for future tests) (j)
X
X
X
X
Study drug administration
X
X
Adverse events
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Concomitant medications
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Hospitalization
X
X-----------------------------------X
X
X-----------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36, 48 and 72 hours postdose on Day 1, on Day 8, predose on Day 9, and 1, 4, 12, 24, 36, 48 and 72 hours 
postdose on Day 9.
(b)
Height will be measured at Screening only. Weight will be measured at Screening visit, Day -1, 72 hours postdose on Day 1, Day 8, 72 hours postdose on Day 9.
(c)
12-lead ECG will be measured at Screening, Day -1, predose, 2 and 72 hours postdose on Day 1, Day 8, predose on Day 9, 2 and 72 hours postdose on Day 9.
(d)
Laboratory tests will be performed at Screening, on Day -1, 72 hours postdose on Day 1, on Day 8, and at 72 hours postdose on Day 9.
(e)
FSH will be measured in postmenopause women only.
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(f)
C-SSRS will be investigate at Screening, Day -1, Day 4, Day 8, and Day 12.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 9, and 0.5, 1. 1.5, 2, 4, 8, 12, 24, 36, 48, 
and 72 hours postdose on Day 9.
(i)
Samples for PD assessment will be collected on Day -1 (at 20, 16, 12 hours predose on Day 1), predose, 1, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose, 1, 4, 8, 
12, 24, 36, 48, and 72 hours postdose on Day 9.
(j)
Urine samples will be collected on Day -1, 24 hours postdose on Day 1, and 24 hours postdose on Day 9.
(k)
Samples for PK assessment at discontinuation will be collected if it is possible.
(l)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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<Cohorts 2 to 4>
Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening Hospitalization Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics, medical 
history
X
Prior medications
X
Physical examination
X
X
X
X
X
X (m)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (m)
Weight, height, BMI (b)
X
X
X
X
X (m)
12-lead 
electrocardiogram 
(ECG) (c)
X
X
X
X
X
X
X
X
X (m)
Laboratory tests (d)
X
X
X
X
X
X (m)
Immunological test, 
alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
C-SSRS (f)
X
X
X
X
Sample collection for 
pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection 
for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X (l)
Blood sample collection 
for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
Cerebrospinal fluid 
sample collection for 
pharmacodynamic (PD) 
assessment (j)
X
X
Urine sample (for future 
tests) (k)
X
X
X
X
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Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening Hospitalization Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Concomitant 
medications
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Hospitalization
X
X-------------------------------------------------------------------------------------------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36 and 48 hours postdose on Day 1, predose on Days 4 to 16, predose on Day 17, and 1, 4, 12, 24, and 
48 hours postdose on Day 17.
(b)
Height will be measured at Screening only. Weight will be measured at Screening, on Day -1, and 48 hours postdose on Day 17.
(c)
12-lead ECG will be measured at Screening, Day -1,presdose and 2 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose, 2 and 48 hours postdose on Day 17.
(d)
Laboratory tests will be performed at Screening, Day -1, predose on Day 11, and at 48 hours postdose on Day 17.
(e)
FSH will be measured in postmenopause women only.
(f)
C-SSRS will be investigate at Screening Visit, Day -1, and Day 19.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose on Day 
14, predose, 0.5, 1. 1.5, 2, 4, 8, 12, 16, and 24 hours postdose on Day 17.
(i)
Samples for PD assessment will be collected at 20, 16, and 12 hours predose on Day 1, predose, 1, 4, 8, 12, and 24 hours postdose on Day 1, predose on Day 11, predose on Day 
14, predose, 1, 4, 8, 12, and 24 hours postdose on Day 17.
(j)
Samples for PD assessment will be collected on Day -1 and 24 hours postdose on Day 17 (if it is performed in Cohort 3 and thereafter).
(k)
Urine samples will be collected on Day -1, at 24 hours postdose on Day 1, and 24 hours postdose on Day 17.
(l)
Samples for PK assessment at discontinuation will be collected if it is possible.
(m)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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4.0
INTRODUCTION
4.1
Background
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and
behaves. Schizophrenia usually develops at late adolescence or early adulthood and manifests in 
maximum 1% of the population. For those who have relatives of first degree with schizophrenia, 
the incidence rate is higher by 10% (the concordance rate for schizophrenia in identical twins is 
40% to 65%) [1][2][3]. Symptoms of schizophrenia can be subdivided into 3 broad classes: 
positive, negative, and cognitive symptoms [4]. Positive symptoms include hallucinations, 
delusions, and disordered thought and speech, and can be summarized as psychosis. Negative 
symptoms include reduced emotion, reduced ability to experience pleasure (anhedonia), lack of 
motivation, and reduced social interaction. Finally, cognitive symptoms include poor information 
processing, impaired ability to focus on objectives, and abnormalities of working memory and 
learning [4]. Currently available antipsychotics are broadly effective for the treatment of positive
symptoms. However, the negative symptoms and cognitive impairment of schizophrenia are the 
known particular aspects that cause dysfunction, for which no therapy has been approved. There 
still are significant unmet medical needs.
Hypofunction of N-methyl-D-aspartic acid (NMDA) receptor is considered a potential mechanism 
in the pathophysiology of schizophrenia, which could be mitigated with increased D-serine levels 
in the brain [5]. D-amino acid oxidase (DAAO) contributes to the metabolism of D-serine in the 
brain and is highly expressed in the cerebellum. Changes in the D-serine levels or D-serine to total 
serine ratios have been reported in the plasma of patients with schizophrenia both naive and under 
drug treatment [6]-[9]. In addition, serine racemase (the D serine generating enzyme) and the 
NMDA NR2A subunit are among the risk genes identified from the recent large scale 
genome-wide association study analysis, indicating the biological relevance to schizophrenia of 
the genetic pathway in which DAAO resides [10]. Therefore, inhibition of DAAO is considered to 
be a promising target in treatment of schizophrenia.
TAK-831 is a highly selective and potent inhibitor of DAAO. TAK-831 increased D-serine levels 
in the cerebellum of normal mice and showed efficacy in a mouse model of Friedreich ataxia 
(FRDA) mouse models. It also demonstrated a positive effect on cognition and social interaction in 
rodent cognition and behavioral models.
As stated above, TAK-831 is expected to provide a therapeutic effect on FRDA and cognitive 
impairment as well as negative symptoms associated with schizophrenia.
4.2
Rationale for the Proposed Study
TAK-831 is currently under development for the treatment of FRDA and cognitive impairment as 
well as negative symptoms of schizophrenia. Three overseas phase 1 studies in healthy adults 
(single and multiple dose study [TAK-831-1001], positron emission tomography [PET] study to 
determine DAAO brain enzyme occupancy [TAK-831-1003], and a study to evaluate the food 
effect [TAK-831-1004]) have been conducted so far, in which TAK-831 was well-tolerated.
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In addition, two phase 1 studies in healthy adults (study with single and multiple doses at high dose 
level [TAK-831-1005] and bioequivalence study [TAK-831-1006]) are being conducted or 
planned. Two phase 2 studies in patients with schizophrenia (small-scale crossover study to 
examine the cerebellar functions [TAK-831-2001], and a study to evaluate the efficacy and safety 
for negative symptoms of schizophrenia [TAK-831-2002]) are also underway. Besides, a phase 2 
proof-of-concept (POC) study in patients with schizophrenia is being planned in China. Based on 
the result of these phase 2 studies, a phase 3 global study (long-term study) has been planned.
In parallel with these development plans, TAK-831 is also being developed in Japan for the 
treatment of cognitive impairment and negative symptoms associated with schizophrenia. In 
respect of FRDA, a genetic disease, since there has been no confirmed report as of June 2018 that 
clearly indicates the existence of Japanese patients, no development plan has been made for FRDA 
in Japan.
Enrollment of Japanese patients into the phase 3 global study and the phase 2 POC study in China 
has been considered. This study was planned to examine the safety and pharmacokinetic (PK) of 
TAK-831 in Japanese as well as to evaluate the safety and PK in Asian healthy subjects for the 
aforementioned studies.
4.3
Benefit/Risk Profile
Because this study will be conducted in healthy adults, there is no benefit to subjects.
The following risk mitigation measures will be implemented in this study. These measures are 
based on what is known about the mechanism of action of TAK-831, nonclinical data, and the 
phase 1 studies (4 studies, including preliminary data of TAK-831-1005). Procedures may be 
added during the study as necessary based on evaluation of any additional clinical or nonclinical 
data.
The safety of TAK-831 has been studied in a prior single dose (up to 750 mg in suspension and 
100 mg T1 tablet formulation) and multiple dose (up to 400 mg once daily [QD] in suspension) 
study in healthy Western subjects (TAK-831-1001), a single dose (up to 500 mg in suspension) 
PET study to investigate DAAO occupancy in the brain (TAK-831-1003) and a single dose food 
effect (400 mg T2 tablet formulation) study (TAK-831-1004). These studies have not resulted in a 
safety signal that would prevent additional studies. Additionally, TAK-831 given as single and 14 
days multiple doses (up to 1200 mg in suspension and 600 mg T2 tablet formulation) is currently 
being studied in healthy adult subjects (TAK-831-1005). TAK-831 has been safe and well 
tolerated to date (provisional data as of end-April 2018).

Acute hypersensitivity/anaphylactic reactions to new chemical entities are always a possible 
risk in any clinical study. Appropriate procedures should be used to manage such possible 
risks.

Study procedure-specific risks include issues relating to blood collection for safety 
assessment/PK and pharmacodynamics (PD) monitoring (venipuncture may cause bruising), 
and the placement of ECG pads (which may cause some local redness and/or 
erythema/itching).
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
In case of serious adverse events (SAE), the investigator has discretion to use his/her clinical 
judgment as to whether to allow a subject to proceed in the study or whether to unblind the 
subject in order to determine his/her treatment allocation.

The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered to monitor 
emergent suicidality.
The Investigator's Brochure should be referred for more detailed safety of TAK-831.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed on the basis of the following hypothesis.

TAK-831 given as single or multiple doses shows no safety issue and is well tolerated.

The PK of TAK-831 given as single or multiple doses to Asian subjects is equivalent to that in 
Western subjects.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult 
Asian subjects.
5.2.2
Trial Secondary Objective
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
5.2.3
Trial Exploratory Objective
To assess the effect of TAK-831 on the concentrations of D-serine and L-serine in plasma (and 
concentrations of D-serine and L-serine in cerebrospinal fluid as necessary) after TAK-831 
administration to healthy Asian subjects.
5.3
Endpoints
5.3.1
Primary Endpoint
Safety: Adverse events (AEs), laboratory tests, vital signs, weight, 12-lead electrocardiogram
(ECG)
5.3.2
Secondary Endpoints
PK: The following parameters will be calculated.

Cmax (Cohort 1, Day 1 of Cohorts 2 to 4)

Cmax,ss (Day 17 of Cohorts 2 to 4)

tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 4)

AUClast (Cohort 1, Day 1 of Cohorts 2 to 4)

AUC∞(Cohort 1, Day 1 of Cohorts 2 to 4)

AUCτ (Days 1 and 17 of Cohorts 2 to 4)
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5.3.3
Exploratory Endpoints

PK: Rac (Cmax) and Rac(AUC) on Days 1 and 17 (Cohorts 2 to 4), t1/2z, CL/F, Vz/F

PD: Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (Days -1 and 18) (may be assessed in Cohort 3 or thereafter based on PD in plasma)
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, PK and 
PD of TAK-831 in healthy adult Asian subjects. This study will include up to 4 cohorts of healthy 
adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered at each dose level under a 3-sequential 
dose escalation design. Eight healthy adult Japanese subjects will be randomized to the sequence 
of administration A, B, and C at a 4:2:2 ratio. A single dose of TAK-831 or placebo will be 
administered on Days 1 and 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
In Cohort 2, a single dose of study drug will be administered to healthy adult Japanese subjects, 
followed by multiple doses. Of these subjects, 6 will be randomly assigned to the TAK-831 group 
and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed 
by their multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with 
subjects followed for approximately 72 hours of assessments for safety, PK and PD. Treatment for 
multiple doses will start with a once-daily regimen on Day 4, which will continue to Day 17 (for 
14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo 
dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 and 4 will be optional, in which a single dose of study drug will be administered 
followed by multiple doses, and may be studied based on emerging data from Cohorts 1 and 2.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 will include 8 healthy adult 
Japanese subjects. Of these subjects in the respective cohorts, 6 will be randomly assigned to the 
TAK-831 group and 2 to the placebo group. A single dose of TAK-831 or placebo will be 
administered, followed by their multiple doses. A single dose of TAK-831 or placebo will be 
administered on Day 1 with subjects followed for approximately 72 hours of assessments for 
safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, 
which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 
hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before 
discharge.
Table 6.a shows the summary of cohorts, and Figure 6.a shows the schematic of the trial design.
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Table 6.a
Summary of Cohorts
Cohort
Subject
Dose
Remarks
1
Japanese
8 subjects
Part 1:
100 mg (4×25 mg T3 tablet formulation)
Fasted, single dose
Wash out period between part 1 and 2 will be 
8 days.
Part 2:
300 mg (1×300 mg T3 tablet formulation)
Fasted, single dose
2
Japanese
8 subjects
600 mg (2×300 mg T3 tablet formulation)
Fasted, single dose + multiple dose (once 
daily)
3
Chinese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 3 may be run if emerging data from 
Cohorts 1 and 2 suggest ethnic-related 
differences in the tolerability and/or PK 
profile. Dose level will be determined based 
on the results from Cohorts 1 and 2.
4
Japanese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 4 may be run based on the emerging 
data from Cohorts 1 and 2 in Asian subjects.
TBD: To be decided
Figure 6.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
<Cohorts 2 to 4>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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6.2
Cohort transition/Dose Escalation
In Cohort 1, TAK-831 100 mg or placebo will be administered on Day 1 (Part 1) followed by 
confirmation of the safety and tolerability (AEs, physical examination, vital signs, weight, 
laboratory tests and 12-lead ECG) up to 72 hours postdose, and then TAK-831 300 mg or placebo 
will be administered on Day 9 (Part 2) followed by confirmation of the safety, tolerability and PK 
up to 72 hours postdose.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohort 1 in a blinded manner and discuss with the sponsor (including the 
medical expert if necessary) as to whether the subsequent cohort should be run.
In Cohort 2, TAK-831 600 mg or placebo will be administered on Day 1, followed by 
confirmation of the safety and tolerability up to 72 hours postdose. Then, multiple doses of 
TAK-831 600 mg or placebo will be administered on Days 4 to 17. The data on safety and 
tolerability as well as PK up to 72 hours postdose will be examined.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohorts 1 and 2 in a blinded manner and discuss with the sponsor 
(including the medical expert if necessary) as to whether Cohorts 3 and 4 should be run.
In Cohort 2 and onwards, the dose will be escalated but the dose escalation will be discontinued 
according to the following discontinuation criteria. The dose in Cohort 2 will be adjusted based on 
the safety and tolerability as well as PK and PD in Cohort 1.
Discontinuation criteria for dose escalation:

Exposures in any cohort exceed those observed at the highest dose tested in monkey (Cmax of 
3680 ng/mL, AUC24 of 35700 hr*ng/mL)

One or more subjects in any single cohort or across more than 1 cohort experience an SAE or 2 
severe or clinically significant AEs occur that are considered related to study drug

One or more subjects in any single cohort or across more than 1 cohort experience severe 
psychiatric symptoms, including (any level of) treatment-emergent suicidal ideation* that are 
considered related to study drug.
*Treatment-emergent suicidality compared to baseline, as measured by changes in suicidal 
ideation or behavior category on the C-SSRS during treatment from the maximum suicidal 
ideation/behavior category at baseline, or any suicidal ideation/behavior during treatment if there 
was none at baseline
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale for Study Population
The subject of this study is Japanese or Chinese with a purpose to support the future conduct of 
studies in Asian subjects. The study will be conducted in healthy adult subjects without any 
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disease including circulatory or cerebrovascular diseases to appropriately assess the safety and 
tolerability as well as PK and PD of TAK-831.
6.3.2
Rationale of Trial Design
With a purpose to assess the safety and tolerability as well as the PK and PD profiles of TAK-831 
when administered to Asian subject for the first time, this study employed a design with both 
single and multiple doses.
6.3.3
Rationale for Dose
To this date, the highest dose of TAK-831 tested in healthy Western subjects is 1200 mg 
(suspension formulation) once daily in the study TAK-831-1005. Based on the preliminary results, 
there were no significant adverse effects reported at this dose level, and as shown in Table 6.b, the 
mean steady-state exposure was Cmax of 3015 ng/mL and AUC24 of 10501 h*ng/mL. The dose 
regimen of 600 mg given once daily (T2 tablet formulation) was also well tolerated and safe in 
healthy Western subjects. As for the mean steady-state exposures, Cmax was 1494 ng/mL and 
AUC24 was 5090 h*ng/mL. This exposure at 600 mg was similar to that of monkeys at 
100 mg/kg/day, the no-observed-adverse-effect-level (NOAEL).
In the study TAK-831-1005, the PK and PD of TAK-831 given as multiple doses at 100 and 
600 mg (per day) to non-Japanese subjects was examined. The dose of 300 mg will be further 
examined in the study.
Based on the above, the doses of 100, 300 and 600 mg were selected for this study in consideration 
to the safety in humans as well as the comparability of PK and PD between non-Japanese and 
Japanese subjects.
In the 13-week repeat dose toxicity study in monkeys that are considered the more sensitive 
species than rats, adverse effects (vomiting, diarrhea, and loose stool) were noted at 
600 mg/kg/day. The NOAEL was 100 mg/kg/day for both sexes.
TAK-831 has been administered at doses up to 1200 mg to non-Japanese, and no SAE has been 
reported with exposures exceeding the NOAEL. Besides, the adverse effects (vomiting, diarrhea, 
and loose stool) noted at a dose of 600 mg/kg/day in the 13-week repeat dose toxicity study in 
monkeys will be easily monitored in clinical trials.
Therefore, it is considered possible to administer doses exceeding the NOAEL exposure by 
carefully examining the safety and PK in each Cohort in this study. However, We have no 
information on toxicity at the level exceeding the exposure at 600 mg/kg/day in the 13-week 
repeated dose toxicity study in monkeys. Dose escalation will be stopped if exposures exceed that 
at 600 mg/kg/day in monkeys.
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Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects
Animal species-Study
Dose
(mg/kg/day or mg)
Cmax
(ng/mL)
AUC24
(h*ng/mL)
Monkey 13-week (Day 91)
100 mg/kg/day (NOAEL)
1340 (male)
1270 (female)
7490 (male)
9190 (female)
600 (300 BID) mg/kg/day
4650 (male)
2710 (female)
45500 (male)
25900 (female)
Human MRD (Day 16)
1200 mg QD (suspension 
formulation)
3015
10501
Human MRD (Day 16)
600 mg QD (T2 tablet 
formulation)
1494
5090
BID, twice daily; MRD, multiple repeated dose; NOAEL, no-observed-adverse-effect-level; QD, once daily
6.3.4
Rationale for Endpoints
6.3.4.1
Safety Endpoint
The safety endpoints in this study were defined to determine the safety and tolerability following a 
single dose and multiple dose of TAK-831. These are standard endpoints in the Phase 1 studies in 
healthy subjects.
Since TAK-831 involves effects on the central nervous system, the C-SSRS will be administered 
to assess the influence on suicidal ideation or suicidal behavior.
6.3.4.2
Pharmacokinetic Endpoint
Concentrations of TAK-831 in plasma will be examined to assess the PK of TAK-831 given as a 
single dose or multiple doses to healthy adult Asian subjects, and then the following PK 
parameters will be calculated.

PK parameters: Cmax, Cmax,ss (Cohorts 2 to 4), tmax, AUClast, AUC∞, AUCτ (Cohorts 2 to 4), 
Rac(Cmax) (Cohorts 2 to 4), Rac(AUC) (Cohorts 2 to 4), t1/2, CL/F, Vz/F
6.3.4.3
Pharmacodynamic Endpoint
Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, AUEC24, 
Emax and time to Emax following TAK-831 doses will be examined to assess the PD of TAK-831 in 
healthy adult Asian subjects. Concentrations of D-serine, L-serine and the ratio of D-serine to total 
serine in cerebrospinal fluid may be assessed as necessary.
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures
The objective of this section is to specify the sequence of procedures in the cases where the timing 
of each procedure overlaps.
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
Safety evaluation will be conducted within the predetermined allowance window as far as 
possible.

Blood samples for PK assessment will be collected at time points as close to the specified time
as possible.

Other procedures must be completed at time points as close to the specified or planned hours as 
possible irrespective of before or after the specified times.

If the timing of blood sampling and ECG or vital signs measurement overlap, blood sampling 
should be prioritized. ECG or vital signs measurement may be performed within an acceptable 
time window (Appendix C).

The priority may be changed upon agreement between the investigator and the sponsor based 
on discussion.

Any test and procedure necessary to immediately assess safety concerns at the time of AEs 
must be prioritized over other regular predetermined procedures.

The safety of subjects in the follow-up period may be confirmed by telephone unless abnormal, 
clinically significant findings are observed upon discharge.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The entire study will start when the first subject signs the informed consent form to participate in 
this study.
6.4.2
Definition of End of the Trial
The study will end when the last subject completes the last planned visit or follow-up visit (or last 
communication [may be via telephone] relating to the planned visit) or is withdrawn from the 
study or lost to follow up (the status that the subject cannot be reached by the investigator).
6.4.3
Definition of Trial Discontinuation
The study may be discontinued for reasons other than safety such as the followings:

A finding (eg, PK, pharmacodynamics, efficacy, biologic targets) from the other nonclinical or
clinical studies results with the study drug in the study discontinuation for non-safety related
reasons.

Data from drugs classified in the same class as the study drug, or methodologies used in this 
study become available and results in the study being stopped for a non-safety related reason.

Study discontinuation due to non-scientific and non-safety-related reasons, such as slow
enrollment.
Discontinuation of the clinical study for safety reasons:
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
The study is prematurely terminated because other clinical or non-clinical trials where 
TAK-831 or other drugs of the same class are administered have confirmed unexpected safety 
concerns based on the methodology used in this study
6.4.4
Criteria for Premature Termination or Suspension of the Trial
6.4.4.1
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 met that
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the compound, such that the
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.
6.4.4.2
Procedures for Premature Termination or Suspension of the Trial
In the event that the Sponsor, an institutional review board (IRB), or a regulatory authority elects
to terminate or suspend the study, a study-specific procedure for early termination or suspension
will be provided by the Sponsor; the procedure will be followed by the applicable study sites 
during the course of termination or study suspension.
6.4.5
Criteria for Premature Termination or Suspension of a Study Site
6.4.5.1
Criteria for Premature Termination or Suspension of a Study Site
A study 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 is permitted by the contractual agreement.
6.4.5.2
Procedure for Premature Termination or Suspension in a Study Site
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend of the
study site, a study-specific procedure for early termination or suspension will be provided by the
Sponsor; the procedure will be followed by the applicable study sites during the course of 
termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria.
1. The subject must understand the study procedures and agree to participate by providing written 
informed consent (for Chinese subjects, an interpreter should be present as necessary).
2. The subject must be willing and able to comply with all study procedures and restrictions.
3. The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, 
inclusive, at the Screening.
4. The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the 
Screening.
5. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing 
products (e.g., nicotine patch) for at least 6 months prior to the Screening.
6. Chinese subjects are defined as subjects who were born in mainland China, and their biological 
parents and grandparents must all have been of Chinese origin (for Cohort 3 only).
7. Chinese subjects who have lived out of China for more than 5 years must not have significantly 
modified their diets since leaving China (for Cohort 3 only).
8. The subject must be judged to be in good health by the investigator or sub-investigator, based 
on clinical evaluations including laboratory tests, medical history, full physical examination, 
12-lead electrocardiogram, and vital sign measurements performed at the Screening. and prior 
to the first dose of study drug.
9. The subject must meet the following birth control requirements:
•
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicidal cream or jelly, from the first dose of study drug until 
95 days (5 half-lives plus 90 days) after the last dose of study drug. No restrictions will be
required for a vasectomized male subject provided the subject is at least 1 year post 
bilateral vasectomy procedure prior to the first dose of study drug. A male subject whose 
vasectomy procedure was performed less than 1 year prior to the first dose of study drug 
must follow the same restrictions as a nonvasectomized man. Appropriate documentation 
of surgical procedure should be provided.
•
Is a male subject who agrees to not donate sperm from the first dose of study drug until 95 
days (5 half-lives plus 90 days) after the last dose of study drug.
•
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a)
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years or ≥6 months of spontaneous amenorrhea in females aged >45 years with 
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serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate 
documentation of follicle-stimulating hormone levels should be required.
b)
Hysterectomy and/or bilateral oophorectomy with appropriate documentation of 
surgical procedure.
c)
Had a tubal ligation with appropriate documentation of surgical procedure.
d)
Congenital conditions such as uterine aplasia etc.
[Rationale for the inclusion criteria]
Inclusion criteria 1, 2, 5, 8 and 9:
These are standard criteria for clinical pharmacology studies in healthy adult subjects and defined 
in consideration to the safety of subjects.
Inclusion Criterion 3:
This is a standard criterion for clinical pharmacology studies in healthy adult subjects for sex. This 
is a standard criterion for clinical pharmacology studies in healthy adult subjects for age.
Inclusion Criterion 4:
This is the range of normal weight in the diagnosis criteria for obesity and obesity disease [11]
proposed by the Japan Society for the Study of Obesity.
Inclusion Criterion 6:
This is set to appropriately assess the safety and PK in Chinese.
Inclusion Criterion 7:
This is set to eliminate the influence by dietary habits on the PK.
7.2
Exclusion Criteria
The subject will be excluded from participating in the study if the subject meet any of the 
followings.
1. The subject has a history of clinically significant endocrine, gastrointestinal (including 
motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, or genitourinary, or presents with major neurological 
(including stroke and chronic seizures) abnormalities or diseases.
2. The subject has participated in another investigational trial within 4 weeks before the pretrial 
visit (Screening). The 4-week window will be derived from the date of the last trial procedure 
and/or adverse events related to the trial procedure in the previous trial to the Screening Visit 
of the current trial.
3. The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) 
of the sponsor.
4. The subject has a history of cancer (malignancy).
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5. The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerability to prescription or 
nonprescription drugs or food.
6. The subject has a positive alcohol or drug or immunological screen.
7. The subject is of childbearing potential or lactating.
8. The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 
8 weeks prior to the first dose of study drug.
9. The subject with any gastrointestinal surgery that could impact upon the absorption of study 
drug.
10. The subject has a known hypersensitivity to any component of the formulation of TAK-831 or 
related compounds.
11. The subject is unable to refrain from or anticipates the use of any medication, including 
prescription and nonprescription drugs or herbal remedies, beginning approximately 7 days 
before administration of the initial dose of trial drug, throughout the trial (including washout 
intervals between trial periods), until the Follow-up Visit.
12. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on 
average (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).
13. The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
14. The subject has a history of drug abuse.
15. The subject has a (QT interval with Fridericia’s correction method) QTcF >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec at the Screening Visit or 
Check-in.
[Rationale for the exclusion criteria]
Exclusion Criteria 1, 15:
This is set to eliminate the influence on safety evaluation for TAK-831.
Exclusion Criterion 2:
This is a minimum duration in which the previous clinical trial is considered to have no influence 
in reference to “General Considerations for Clinical Trials” [12] in order to ensure the safety of 
subjects.
Exclusion Criteria 3, 4, 6, 7, 12, 13, 14:
These are standard criteria for clinical pharmacology studies and defined in consideration to the 
safety of subjects.
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Exclusion Criterion 5:
This is defined in consideration to the safety of subjects.
Exclusion Criteria 8, 9, 11:
This is defined in consideration to the safety of subjects. This is also defined for potential influence 
on PK and PD assessment.
Exclusion Criterion 10:
This is set to exclude subjects who have a known hypersensitivity to any component of the 
formulation of TAK-831 or related compounds in consideration of the safety of subjects.
7.3
Excluded Medications Supplements, Dietary Products
Table 7.a shows excluded medications, supplements, and dietary products.
Use of the drugs listed on Table 7.a (prescribed drugs and over-the-counter [OTC] drugs), 
vitamins, supplements, and dietary products will be excluded from a specified time point to until 
discharge given the effect on the safety and PK. Use of prohibited concomitant drugs will be
allowed when the investigator or sub-investigator deems it necessary to use any of the concomitant
drugs for reasons including treatment of an AE.
Subjects must be instructed not to take any medications including OTC products, without first
consulting with the investigator or sub-investigator.
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Table 7.a
Excluded Medications, Supplements, Dietary Products
From 28 days before admission (Day -1)
to the last discharge
7 days before admission (Day -1)
to the last discharge
72 hours before admission (Day -1)
to the last discharge
• Prescription drugs
• Supplements (St. John's wort, ginseng, 
kava kava, ginkgoes, chinese herbal 
medicine, and melatonin)
• OTC drugs (including aspirin or 
aspirin-containing drugs) (a)
• Vitamins
• Caffeine or xanthine containing 
products
• Vaccination/vaccine (b)
• Beverages containing grapefruit 
(fruit juice, flesh), star fruits (fruit 
juice, flesh), citrus aurantiums 
(high acidity), orange (seville 
oranges), or marmalade
• Apple, orange or pineapple juice
• Brassicaceae vegetables (kale, 
cress, collard greens, kohlrabi, 
brussels sprouts, and mustard).
• Meat cocked over the charcoal
• Nicotine-containing products
• CYP 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1 and 2A6 inhibitors/inducers 
OTC drugs (c)
• Alcohol containing products
CYP: cytochrome P-450, OTC drugs: over-the-counter drugs
Note: Excludes the drug needs to be administered to treat an AE and if the investigator or sub-investigator considers 
necessary to use the drug
(a)
Use of paracetamol (≤1 g/daily) will be allowed.
(b)
Includes H1N1 and other influenza vaccines, however, not limited to these medications.
(c)
Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Diet and fluid (except water) must be ingested at least10 hours before clinical laboratory tests.
On the day before clinical laboratory tests, evening meal must be ingested by 21:00.
During hospitalization, pre-specified diets must be ingested, and other diets will be prohibited. 
After discharge, excessive drinking and eating must be avoided until completion of follow-up 
period.
7.4.2
Activity
Smoking is prohibited during the study.
Excessive exercise is prohibited during the study.
Blood donation is prohibited for at least 12 weeks (84 days) from completion of the last test.
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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 or sub-investigator should
communicate that medical institution about the subject’s participation in the study.
7.5
Documentation of Subject Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a
subject discontinues the study before the first study drug administration, the investigator or
sub-investigator should complete the electronic case report form (eCRF).
The primary reason for subject failure is to be recorded in the eCRF using the following categories:

Death

AE

Screening failure (failed inclusion criteria or did meet exclusion criteria) <specify the reasons>

Protocol deviation

Lost to follow up

Withdrawal by subject <specify the reasons>

Study terminated by the Sponsor

Pregnancy

Sample size sufficient

Other <specify the reasons>
Any subject identification number, once assigned to a subject, should not be reused if the assigned
subject discontinues the study prior to the first study drug administration. Nevertheless, if a reserve 
subject is enrolled in the other 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 the subject who is withdrawn from the
study before the first study drug administration in Period 1, 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 a serious adverse event 
(SAE). Refer to Section 10.2.9.3 for reporting procedures.
2. AE
The subject has experienced an AE that requires early termination because continued
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participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to
continue because of the AE.
The study drug will be immediately discontinued if a condition meets any following criteria 
during the treatment, and appropriate follow-up will be performed (clinical laboratory tests 
will be repeatedly performed until the clinical laboratory test profiles have normalized or 
returned to baseline, refer to Section 9.2.9.1):
•
Liver Function Test (LFT) Abnormalities
-
ALT or AST >8×the upper limit of normal (ULN), or
-
ALT or AST >5×ULN and persists for more than 2 weeks, or
-
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (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%)
•
Prolonged QT/QTcF intervals
If at least one remarkable prolonged QT interval was observed on 12-lead ECG (eg, 
absolute value of QTcF intervals >500 msec or an increase >60 msec from baseline), and 
the investigator or sub-investigator considered inappropriate to continue the study.
3. Protocol deviation
The discovery after the start of the first study drug administration 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. Pregnancy
If a subject was found to be pregnant.
Note: Participation in the study is immediately discontinued for any pregnancy. Refer to 
Appendix B for the procedures.
6. Voluntary withdrawal
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).
7. Study terminated by the Sponsor
The Sponsor terminates the study.
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8. 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
The Part 1 in Cohort 1 and Cohorts 2-4 can have a few reserve subjects considered eligible for 
participation in the study based on screening test. If a subject has not received the study drug as 
scheduled during the study owing to any reason occurring before the study drug administration, a 
reserve subject will be allowed to participate in the study.
If a subject withdraws from the study after initiation of the study drug, the subject will not be 
replaced with a reserve subject.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
[Drug product]
Code name: TAK-831
Dosage form and strength:
TAK-831 tablet is a yellowish-red film-coated tablet containing 25 or 300 mg of TAK-831.
TAK-831 placebo tablet contains no TAK-831 and has same appearance as TAK-831 tablet.
8.1.1
Clinical Study Drug Labeling
Study drug labeling will show name of the study drug, quantity and storage condition of the study 
drug, manufacture number, expiration date, protocol number, name and address of the Sponsor, 
and statement the drug is for clinical trial use only.
8.1.2
Clinical Study Drug Inventory and Storage
TAK-831 is stored at a room temperature (1°C to 30°C).
Study drug must be kept in an appropriate, limited-access, secure place until it is used, or returned
to the Sponsor or its designee. Study drug must be stored under the conditions specified on the
label, and remain in the original container until dispensed.
8.1.3
Randomization Code Creation and Storage
The personnel responsible for randomization (the Sponsor's designee) will prepare the
randomization table/schedule prior to the start of the study. All randomization information will be 
stored in a secured area, accessible only by authorized personnel.
8.1.4
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 will be 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.
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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 eCRF.
If the investigator or sub-investigator breaks the blinding of the study drug, 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 (except cases where the 
investigator or sub-investigator is not informed of unblinding information [unblinding for 
open-label analysis for the Sponsor]).
8.1.5
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 managing 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.
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 Number
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
In Cohorts 1-2 and Cohorts 3-4 (if added), the subjects will be assigned in the order of medication 
identification number by Cohort according to the randomization code. The medication 
identification number will be a 4-digit number, starting with the following number:
Cohort 1: 1001, Cohort 2: 2001, Cohort 3: 3001, Cohort 4: 4001
The assigned medication identification number will be used to identify the samples for PK by the 
study site and the only number to identity a subject during blood sampling for PK. The number will 
be always shown on the sample vials, which are sent to the laboratory to evaluate the PK. The 
laboratory will report the results using this number. The number will be used for only the purpose 
described in this section and cannot be replaced with the 7-digit subject identification number, 
which is assigned at the time of informed consent procedure and used in all other procedures 
during the clinical study period to identify a subject. In case of subject replacement, the study drug 
with a medication identification number for the withdrawn subject will be used by the replacing 
subject.
9.1.2
Inclusion and Exclusion
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, height, weight, caffeine 
use, alcohol use, and smoking status of the subject.
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Medical history to be obtained will include determining whether the subject has any clinically 
significant conditions or diseases that resolved within 1 year prior to the signing of informed 
consent. Ongoing conditions will be considered concurrent medical conditions. Medication history
information to be obtained will include 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. 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 drugs, 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 is calculated using the formula provided below.
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.
9.2.4
Vital Signs
Vital signs will include body temperature (axilla measurement), sitting blood pressure (systolic 
and diastolic, after resting more than 5 minutes), and pulse (beats per minute).
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.
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The investigator or sub-investigator (or a qualified observer at the investigational site) will 
interpret the ECG using one 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.
9.2.6
Columbia Suicide Severity Rating Scale (C-SSRS)
C-SSRS will be performed at the study procedures-specified time point. The investigator or 
sub-investigator will evaluate suicide risks based on the information obtained from C-SSRS. For 
any suicidal ideation and suicidal behavior will be documented as an adverse event.
9.2.7
Study Drug Administration
In Cohort 1, a single dose of TAK-831 T3 tablet 25 mg×4 tablets or placebo will be orally 
administered on Day 1 (Part 1), and a single dose of TAK-831 T3 tablet 300 mg×1 tablet or 
placebo will be orally administered on Day 9 (Part 2).
In Cohort 2, a single dose of TAK-831 T3 tablet 300 mg×2 tablets or placebo will be orally 
administered on Day 1, followed by multiple doses of TAK-831 T3 tablet 300 mg×2 tablets (once 
daily) or placebo on Days 4-17.
The study drug will be orally administered with 150 mL of water at a fasted state (fasted at least 10 
hours before administration).
In Cohorts 3 and 4, the dose of the study drug will be determined based on the data obtained from 
Cohorts 1 and 2.
9.2.8
AE Monitoring
AE monitoring will begin after the signing of informed consent. A complete description of AE
collections and procedures is provided in Section 10.2.
9.2.9
Laboratory Procedures and Assessments
Laboratory samples will be taken following a minimum 10 hour overnight fast on the days 
stipulated in the Schedule of Study Procedures (Section 3.0). Refer to Appendix C for the amount 
of blood samples.
The investigator or sub-investigator will take responsibility for evaluation of the clinical 
laboratory test results and storage. The investigator will maintain a copy of the reference ranges for 
the laboratory used.
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
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Red blood cell count
White blood cell count and differential leukocytes 
(lymphocytes, neutrophils, eosinophils, basophils, and 
monocytes)
Hemoglobin
Hematocrit
Platelet count
Chemistry
Chemistry evaluations will consist of the following chemistry tests:
Albumin
Creatinine
ALP
Glucose
ALT
Sodium
AST
Calcium
γ-GTP
Creatine kinase
Total bilirubin
Potassium
Direct bilirubin
Chloride
Total protein
PT
Urea nitrogen
APTT
Urinalysis
Urinalysis will consist of the following tests:
pH
Specific gravity
Qualitative (protein, glucose, occult blood, and nitrite)
Urinary sediment (erythrocytes, leukocytes, and cylinder) 
(a)
(a)
Will be performed for any abnormal urinalysis parameter.
Other
Immunological tests
HIV antibody and antigen tests, hepatitis tests (HBs antigen and HCV antibody)
Alcohol tests (urinalysis or breath test)
Urinary drug tests
FSH (postmenopausal female subjects only)
HIV: human immunodeficiency virus, HBs: hepatitis B surface antigen, HCV: hepatitis C virus, FSH: 
follicle-stimulating hormone
Note: The investigator or sub-investigator will report the results of immunology, urine drug tests, and alcohol tests
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.
If subjects experience an ALT or AST of >3×ULN (except the tests at Screening), follow-up 
laboratory tests (at a minimum, serum alkaline phosphatase [ALP], ALT, AST, total bilirubin, 
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gamma-glutamyl transferase [γ-GTP], 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 10.2.9.4 for the discontinuation or withdrawal criteria of a subject
and the appropriate guidance on reporting abnormal LFTs as SAEs, respectively.
9.2.9.2
Urine sample for Future Tests
Urine samples for future tests will be collected according to the Schedule of Study Procedures 
(Section 3.0).
If acute renal failure is suspected, urinary biomarkers such as KIM-1, NGAL, and cyctatin C may 
be measured using the collected sample.
9.3
Biomarker, PK, PD, and PGx Samples
Samples for PK, PD, and PGx will be collected according to the schedule of study procedures 
(Section 3.0). Separated procedures describe the details of sampling, handling, and transferring to 
central laboratory. The actual sampling time for PK and PD analyses will be documented in the 
subject’s source documents and eCRF.
Table 9.a shows primary specimen collections.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of
Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
PK Analysis
Mandatory
Plasma sample for PD
Blood
Plasma
PD analysis
Mandatory
Cerebrospinal fluid sample for PD Cerebrospinal fluid Cerebrospinal fluid
PD analysis
Optional
Blood sample for DNA PGx
Blood
DNA
PGx analysis
Optional
9.3.1
PK Measurements
The following PK parameters will be calculated from plasma concentrations of TAK-831, unless 
otherwise specified.
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Mark/Term
Definition
Plasma
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
Area under the plasma concentration-time curve from time 0 to time of infinity
AUCτ
Area under the plasma concentration-time curve during a dosing interval
Cmax
Maximum observed plasma concentration (measured value)
Cmax, ss
Maximum observed steady-state plasma concentration during a dosing interval (measured value)
tmax
Time of first occurrence of Cmax
t1/2z
Terminal disposition phase half-life
λz
Terminal disposition phase rate constant
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration
CL/F
Apparent clearance after extravascular administration
Rac(Cmax)
Accumulation ratio based on Cmax
Rac(AUC)
Accumulation ratio based on AUC
9.3.1.1
Plasma for PK Measurements
Blood samples for plasma TAK-831 concentration will be collected (Table 9.b). The sampling 
schedule may change based on emerging data but the number of samples will not exceed the 
number of planned samples.
Table 9.b
Blood Sample Collection for PK Analysis
Dose Levels:
Date of 
administration
Sampling time
Single dose
1
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
9
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
1
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, and 48 hours postdose
4, 11, 14
Predose
17
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 16, and 24 hours postdose
9.3.2
PD Analysis
The following PD parameters will be calculated from plasma concentrations of D-serine and 
L-serine, unless otherwise specified
Mark/Term
Definition
Plasma
AUEC24
Area under the effect-time curve from time 0 to 24 hours postdose
Emax
Maximum effect
time to Emax
Time to reach maximum PD effect
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9.3.2.1
Plasma Samples for PD Analysis
Blood samples will be collected to measure plasma D-serine and L-serine concentrations (Table 
9.c). The sampling schedule may change based on emerging data but the number of samples will 
not exceed the number of planned samples.
Table 9.c
Blood Sample Collection for PD Analysis
Dose Levels:
Specimen
Date of 
administration
Sampling time
Single dose
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, 24, 36, 48 and 
72 hours postdose
9
Predose, 1, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, and 24 hours 
postdose
11, 14
Predose
17
Predose, 1, 4, 8, 12, and 24 hours postdose
9.3.2.2
Cerebrospinal fluid samples for PD Analysis
Cerebrospinal fluid will be collected to measure D-serine and L-serine concentrations (3.0 mL per 
scheduled time). The cerebrospinal fluid sampling schedule may change based on emerging data 
but the number of samples will not exceed the number of planned samples. After Cohort 3, 
collection of cerebrospinal fluid in the next Cohorts will be determined based on the results of 
plasma D-serine and L-serine concentrations obtained from the previous Cohorts.
9.3.3
PGx Measurements
9.3.3.1
Blood Sample for DNA PGx Measurements
When sampling of whole blood for pharmacogenomic analysis occurs, the subject must sign 
informed consent/be consented separately for PGx sampling, storage and analysis. PGx 
measurement is a part of the study, but participation of a subject is optional.
One 6-mL of whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected 
prior to the single dosing on Day 1 from each consenting subject in the study.
The samples will be stored for no longer than 15 years after completion of the TAK-831 study 
and/or until the drug development of TAK-831 is no longer actively pursued. No samples will be 
stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification by the Sponsor. “Stored samples” are defined as samples that are coded (the samples 
are stripped of all personal identifying information but a key links the samples to the clinical data 
collected from the sample donor) and are used in the analysis of the study drug or related drug.
The sampling of whole blood for PGx and genotyping analysis is mandatory. Every subject must 
sign informed consent separately for PGx sampling. DNA samples will be used to evaluate drug 
metabolic enzyme and transporter polymorphisms.
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Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of some of this gene in drug response, which may lead to additional 
exploratory research with the samples for PGx measurements.
9.3.4
Confinement
Cohort 1:
Subjects will be hospitalized from Day -1 to Day 4 and Day 8 to Day 12 and will be discharged 
after the investigator or sub-investigator confirm no clinically significant health problems based 
on the examination and tests on Days 4 and 12.
Cohorts 2-4:
Subjects will be hospitalized from Day -1 to Day 19 and will be discharged after the investigator or 
sub-investigator confirm no clinically significant health problems based on the examination and 
tests on Day 19.
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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 clinical study; it does not necessarily have to have a 
causal relationship with the the treatment (including the study drug) 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 treatment (including the study drug) or study 
procedures.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing 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 may be considered as 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 for an abnormal value are not considered as 
an intervention. In addition, repeated or additional non-invasive tests for verification and 
evaluation of abnormality or monitoring purpose will not be considered as an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a
concurrent medical history conditions and should NOT be recorded as an AE. The
observations or evaluations of first examination at baseline (eg, laboratory test, ECG, X-ray, 
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etc) should NOT be recorded as AEs unless related to a study procedure. However, if the 
subject experiences a worsening or complication of such a concurrent medical history 
condition, the worsening or complication should be recorded appropriately as an AE 
(worsening or complication occurs after informed consent is signed). 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. 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 pre-existing chronic 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. 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 drug or after any change in study drug, the worsening or complication should be
recorded as a new AE. The investigator or sub-investigator should ensure that the event term 
reported captures the change in adverse event (eg, “worsening of…”).
Changes in severity of AEs:

If a subject experiences a change in the severity of an AE that is not associated with a change in 
study drug, 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 the signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
earlier (eg, as an emergency) due to a worsening of a 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 study 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 sub-investigator to decide whether a dose is 
to be considered as overdose, in consultation with the Sponsor.
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in 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 (ADRS)
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Malignant hypertension
Convulsive seizures (includes convulsion and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (includes interstitial pneumonia)
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Confirmed or suspected endotoxin shock
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
Severity/Intensity of AEs will be classified or defined as follows:
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 causality 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 disease, 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 the underlying disease, complications, 
concomitant medications and concurrent treatments.
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.
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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 or sub-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 drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable - a study drug was stopped for a reason other than the particular AE; eg, the 
clinical study has been terminated, the subject died, dosing with study drug had not yet started 
or dosing with study drug 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/signs/symptoms have almost disappeared; the abnormal laboratory values improved, 
but have 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 values on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
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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 and continue until the follow-up visit or phone call.
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 the study drug must be monitored until the 
symptoms have resolved and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Nonserious AEs that begin prior to 
the first exposure to the study drug, regardless of related or unrelated to the study procedure, need 
not be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug 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 Adverse Event (Frequency)

Severity/Intensity.

The Investigator’s or sub-investigator’s opinion of the causal relationship between the event 
and administration of study drug(s). (Related/Not related)

Action taken with the study drug

Outcome of the event.

Seriousness.

Timing of occurrence (after administration of the study drug)
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 within 1 
business day of the first onset or notification of the SAE, along with any relevant information. The 
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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 drug(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 the follow-up SAE form or provide other written 
documentation immediately to the Sponsor. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory values, discharge summary, postmortem results) in the institution should be 
submitted to the Sponsor, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.
10.2.9.4 Reporting of Abnormal LFTs
If a subject experiences 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 will contact the monitor for discussion 
and investigation of the relevant subject details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease, medical history/ongoing disease. Follow-up 
laboratory tests as described in Section 9.2.9 must also be performed.
10.2.10
Safety Reporting to Investigators, IRBs and Regulatory Authorities
The Sponsor will report all suspected unexpected serious adverse reactions (SUSARs) and any 
other applicable SAEs to regulatory authorities, investigators, IRBs and the head of the study site. 
Relative to the first awareness of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening events and 15 
days for other serious events, unless otherwise required by national regulations. The Sponsor will 
also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of the study drug or that would be sufficient to consider changes in 
the study drug administration or in the overall conduct of the trial. The study 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 unblinding of subject’s 
treatment assignment. 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, 3 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.
The Sponsor will verify the validity of the definitions of the analysis sets and the rules for handling
data in consultation with a medical expert, as needed, prior to unblinding the study drug 
assignment. The Sponsor will address all remaining uncertainties not specified at planning, and 
will finalize the SAP prior to unblinding of subject’s treatment assignment.
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, and who 
were appropriately evaluable for at least 1 PK parameter.
11.1.1.3 PD Analysis Set
The PD Analysis Set will consist of subjects who received at least one dose of study drug, and who 
were appropriately evaluable for at least 1 PD parameter.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the Safety Analysis 
Set.
11.1.3
PK Analysis
Endpoints and its analytical method
[Endpoints]
Secondary endpoints: Cmax (Cohort 1, Day 1 in Cohorts 2 to 4), Cmax,ss (Day 17 in Cohorts 2 to 4), 
tmax (Cohort 1, Days 1 and 17 in Cohort 2 to 4), AUClast (Cohort 1, Day 1 in Cohorts 2 to 4), AUC∞
(Cohort 1, Day 1 in Cohorts 2 to 4), AUCτ (Days 1 and 17 in Cohorts 2 to 4)
Exploratory endpoints: Rac(Cmax) and Rac(AUC) (Cohort 2 to 4) on Days 1 and 17, t1/2z, CL/F, Vz/F
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[Analytical method]
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and treatment period for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of TAK-831 in plasma will be summarized by each scheduled sampling time using 
summary statistics. Individual plasma concentration data versus time will be presented. Plasma PK 
parameters, including dose-normalized Cmax and AUC, will be summarized by dose and day using 
summary statistics. Accumulation of TAK-831 from Day 1 to Day 17 will be assessed by 
summarizing the ratio of Cmax and AUC at Days 1 and 17 by dose. Dose linearity in plasma PK 
parameters (Cmax and AUC) will be assessed graphically for those parameters at Day 1 and Day 9 
for Cohort 1 and Day 1 for Cohorts 2 to 4. Additional analyses on dose linearity will be included if 
appropriate.
11.1.4
PD Analysis
Endpoints and its analytical method
[Endpoints]

Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (on Days -1 and 18) (if available)
[Analytical method]
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and each scheduled sampling time for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in plasma and 
concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal fluid 
(if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of 
D-serine to total serine in plasma, and change and percent the change from baseline will be 
summarized by day using summary statistics. The potential relationship between TAK-831 
exposure and biomarker response will be explored graphically. Additional statistical or PK-PD 
analyses will be included if appropriate.
11.1.5
Safety Analysis
Endpoints and its analytical method
[Endpoints]
AEs, laboratory findings, vital signs, weight, 12-lead ECG
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[Analytical method]
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for 
Cohorts 2 and 4, and for Cohort 3.
11.1.5.1 AEs
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset occurs on or 
after the start of study drug.
The followings will be analyzed for TEAEs. TEAEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT).

Frequency of all TEAEs

Frequency of drug-related TEAEs

Frequency of all TEAEs by intensity

Frequency of drug-related TEAEs by intensity

Frequency of TEAEs leading to study drug discontinuation

Frequency of serious TEAEs
11.1.5.2 Clinical Laboratory Evaluation
Summary statistics will be provided for observed values and change from baseline at each 
evaluation time point. Pre- and post-dose shift tables will be prepared for categorical variables.
11.1.5.3 Vital Signs
Summary statistics will be provided for the observed values at each evaluation time point and 
changes from baseline.
11.1.5.4 Other Safety Parameters
The ECG parameters will be summarized as follows. Summary statistics will be calculated for 
observed values and change from baseline at each evaluation time point. Pre- and post-dose shift 
tables will be prepared for categorical variables. The analysis methods for other endpoints will be 
specified in detail in the SAP.
11.2
Determination of Sample Size
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size 
required to assess the safety, tolerability, and PK of each cohort. This is not based on any statistical 
rationale.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its
designee (Contract Research Organization) and by the IRB.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, and 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 study site of the deviation
or changes 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 study 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 study site also may be subject to quality assurance audits by the Sponsor or designees. In this
circumstance, the Sponsor-designated auditor will contact the study 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], and the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory authority, the Sponsor should be notified immediately. The investigator and the head of 
the institution 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 Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline for GCP. The
investigator will conduct the study according to applicable local or regional regulatory 
requirements in accordance with the “Responsibilities of the Investigator” that are listed in
Appendix A.
13.1
IRB Approval
The IRB must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or the designee will require documentation noting all names and titles of the 
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 the 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 
written informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements, if applicable, and other documents required by all applicable laws and regulations, 
must be submitted to the IRB for approval. The IRB’s written approval of the protocol and subject 
written informed consent must be obtained and submitted to the Sponsor or the 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, written informed consent 
form) reviewed; and state the approval date. The Sponsor will notify the study site that the Sponsor 
has confirmed the adequacy of the study site regulatory documentation. Until the study site
receives a notification, no protocol activities, including screening, may occur.
The study site must adhere to all requirements stipulated by its respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the written 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 the Sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The written informed consent form describes the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
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The informed consent form will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care.
The investigator is responsible for the preparation, content, and IRB approval of the written 
informed consent form. The written informed consent form must be approved by both the IRB and 
the Sponsor prior to use.
The informed consent form must be described 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 or she will participate 
in the clinical 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 by 
the investigator or sub-investigator to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator or sub-investigator must also sign and date the informed 
consent form 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 will 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.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify the Sponsor of consent 
withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this 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.
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, and PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
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including 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 the facility name, investigator’s city, state (for Americas
investigators), country, and recruiting status will be registered and available for public viewing.
13.5
Clinical Trial Results Disclosure
Takeda will post the results of the clinical study on ClinicalTrials.gov or publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.6
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study subjects.
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator or sub-investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.2
Investigator Agreement
A separate agreement will be provided to the study site.
14.1.3
Study-Related Responsibilities
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.4
List of Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUEC
area under the effect-time curve
BMI
body mass index
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
DAAO
D-amino acid oxidase
DNA
deoxyribonucleic acid
Emax
maximum effect
FDA
Food and Drug Administration
FRDA
Friedreich ataxia
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
γ-GTP
gamma-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation of Technical Requrements for Pharmaceuticals for Human 
Use
INR
international normalized ratio
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
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Term
Definition
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
PET
positron emission tomography
PMDA
Pharmaceuticals and Medical Devices Agency
PT
prothrombin time
POC
proof-of-concept
Rac
accumulation ratio
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
tmax
time of first occrurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply the study sites with access to eCRFs. The Sponsor will 
provide training opportunities for the site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the Sponsor 
(or the designee) and will be answered by the study site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs.
The following data will not be recorded in the eCRFs.

PGx analysis results

Clinical laboratory test results

Drug concentration measurement results

PD measurement results
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 or sub-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 study site during periodic visits 
by the Sponsor or its designee. 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 or the head of the study site agree to keep the records stipulated in Section 15.1
and those documents that include (but not limited to) the study-specific documents, the
identification log of all participating subjects, medical records, all original signed and dated
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its
designees.
The investigator and the head of the study site are required to retain 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 study 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 study 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]
Sham PC, Gottesman, II, MacLean CJ, Kendler KS. Schizophrenia: sex and familial 
morbidity. Psychiatry Res 1994;52(2):125-34.
[2]
Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, et al. 
Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen 
Psychiatry 1999;56(2):162-8.
[3]
Erlenmeyer-Kimling L, Squires-Wheeler E, Adamo UH, Bassett AS, Cornblatt BA, 
Kestenbaum CJ, et al. The New York High-Risk Project. Psychoses and cluster A 
personality disorders in offspring of schizophrenic parents at 23 years of follow-up. Arch 
Gen Psychiatry 1995;52(10):857-65.
[4]
van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
[5]
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor 
antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm 
shift in medication development. Psychopharmacology (Berl) 2003;169(3-4):215-33.
[6]
Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, et al. Plasma 
levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 
2012;142(1-3):83-7.
[7]
Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, et al. Changes in plasma 
glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical 
symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). 
Prog Neuropsychopharmacol Biol Psychiatry 2008;32(8):1905-12.
[8]
Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. 
Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of 
the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen 
Psychiatry 2003;60(6):572-6.
[9]
Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to 
total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog 
Neuropsychopharmacol Biol Psychiatry 2005;29(5):767-9.
[10] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights 
from 108 schizophrenia-associated genetic loci. Nature 2014;511(7510):421-7.
[11] Japan Sciety for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity, 2011 Oct; additional edition.
[12] General Considerations for Clinical Trials (Notification No. 380 of the Evaluation and 
Licensing Division, PMSB dated April 21, 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 study site in advance to get them accepted.
3. Prepare a written informed consent form 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 study 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 study site and the Sponsor 
in writing.
11. Determine the need of emergency key code unblinding 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 study site of the end of the study in writing.
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Appendix B
Pregnancy and Contraception
Male Subjects and Their Female Partners
From the signing of informed consent, throughout the duration of the study, and for 95 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 or subjects should refrain from having sexual 
intercourse from 1 month prior to the first study drug administration throughout the study period 
and until 35 days after the last study drug administration. 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.
Female Subjects and Their Male Partners
Female subjects of childbearing potential* will be excluded from this study.
* 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 device (IUD)
Hormonal contraceptives
Male condoms with a spermicide
Copper T PLUS condom
Progesterone T PLUS condom
Combined pill
Subjects will be provided with information on acceptable methods of contraception for 95 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 95 days after their last dose of study drug.
Pregnancy
If any subject is found to be pregnant during the study, the subject should immediately discontinue 
the study drug and be withdrawn from the study. In addition, if any pregnancies in the partner of a 
male subject, during the study or for 95 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.
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If the female subject or 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 she or his 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).
All female subjects and the the female partners of male subjects who became pregnant will be 
followed to final outcome, using the pregnancy form, with the consent of the female subjects or 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
<Cohort 1>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Study treatment period 
(Part 1)
Day 1 72 hours postdose
Day 4 from awakening
to discharge
Washout period
Day 8
Not applicable
Study treatment period 
(Part 2)
Day 9 72 hours postdose
Day 12 from
awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 and 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 2 and 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicabled
Treatment period (Part 1)
Day 1 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Urinary drug tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Washout period
Day 8
Not applicable
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period (Part 1)
Day 1 predose
Not applicable
Blood samples for PK
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
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Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 1 hour postdose
Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 24 hours postdose
Within ± 2 hours
Treatment period (Part 2)
Day 9 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, and FSH
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<Cohorts 2-4>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Days 5-10 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Days 12-13 predose
From awakening to 
immediately prior to 
dose
Day 14 predose
From awakening to 
immediately prior to 
dose
Days 15-16 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 1, 4, 12, 24, and 48 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 48 hours postdose
Day 19 from
awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 2 and 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period
(Single dose part)
Day 1 predose
Not applicable
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Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PK
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 1 4, 8, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
Within 15 minutes 
predose
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 0.5, 1, 1.5, and 2 hours 
postdose
Within ± 5 minutes
Day 17 4, 8, 12, 16 and 24 hours 
postdose
Within ± 15 minutes
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, and 24 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 1 hour postdose
Within ± 15 minutes
Day 17 4, 8, 12, and 24 hours postdose Within ± 15 minutes
Cerebrospinal fluid 
samples for PD
(If performed after 
Cohort 3)
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 3 hours
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 24 hours postdose
Within ± 2 hours
Teatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, FSH, and urinary drug tests
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Total blood sampling volumes for an individual subject is shown below:
<Cohort 1>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total Volume
(mL)
Screening
Day -1
Days 1-4
Day 8
Days 9-12
Clinical Laboratory 
Tests
20
1
1
1
1
1
100
Blood sampls for PK
4
-
-
12
-
12
96
Blood sampls for PD
6
-
3
9
-
9
126
Samples for PGx 
Measurements
6
-
-
1
-
-
6
Total Blood Sampling Volume
328
-: No blood collection
<Cohorts 2-4>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total 
Volume
(mL)
Screening Day -1 Day 1
Day 2
Day 3
Day 4 Day 11 Day 14 Days
17-18 Day 19
Clinical Laboratory 
Tests
20
1
1
-
-
-
-
1
-
-
1
80
Blood sampls for PK
4
-
-
8
2
1
1
1
1
10
-
96
Blood sampls for PD
6
-
3
5
1
-
-
1
1
6
-
102
Samples for PGx 
Measurements
6
-
-
1
-
-
-
-
-
-
-
6
Total Blood Sampling Volume
284
-: No blood collection
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CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of 
TAK 831 in Healthy Adult Asian Subjects
Phase 1 Study of TAK-831 in Healthy Adult Asian Subjects
Study Identifier:
TAK-831-1002
Compound:
TAK-831
Date:
30 July 2018
Version/Amendment 
Number:
Original 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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CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................11
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.2
Rationale for the Proposed Study.............................................................................15
4.3
Benefit/Risk Profile .................................................................................................16
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................18
5.1
Hypothesis...............................................................................................................18
5.2
Trial Objectives .......................................................................................................18
5.2.1
Trial Primary Objective......................................................................................18
5.2.2
Trial Secondary Objective..................................................................................18
5.2.3
Trial Exploratory Objective................................................................................18
5.3
Endpoints.................................................................................................................18
5.3.1
Primary Endpoint...............................................................................................18
5.3.2
Secondary Endpoints..........................................................................................18
5.3.3
Exploratory Endpoints .......................................................................................19
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................20
6.1
Trial Design.............................................................................................................20
6.2
Cohort transition/Dose Escalation............................................................................22
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................22
6.3.1
Rationale for Study Population...........................................................................22
6.3.2
Rationale of Trial Design ...................................................................................23
6.3.3
Rationale for Dose .............................................................................................23
6.3.4
Rationale for Endpoints......................................................................................24
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures ................24
6.4
Trial Beginning and End/Completion.......................................................................25
6.4.1
Definition of Beginning of the Trial ...................................................................25
6.4.2
Definition of End of the Trial.............................................................................25
6.4.3
Definition of Trial Discontinuation ....................................................................25
6.4.4
Criteria for Premature Termination or Suspension of the Trial............................26
6.4.5
Criteria for Premature Termination or Suspension of a Study Site......................26
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............27
7.1
Inclusion Criteria .....................................................................................................27
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7.2
Exclusion Criteria ....................................................................................................28
7.3
Excluded Medications Supplements, Dietary Products.............................................30
7.4
Diet, Fluid, Activity.................................................................................................31
7.4.1
Diet and Fluid ....................................................................................................31
7.4.2
Activity..............................................................................................................31
7.5
Documentation of Subject Failure............................................................................32
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................34
7.8
Subject Replacement................................................................................................34
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................35
8.1
Clinical Study Drug .................................................................................................35
8.1.1
Clinical Study Drug Labeling.............................................................................35
8.1.2
Clinical Study Drug Inventory and Storage ........................................................35
8.1.3
Randomization Code Creation and Storage ........................................................35
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................35
8.1.5
Accountability and Destruction of Sponsor-Supplied Drugs...............................36
9.0
STUDY PROCEDURES...............................................................................................37
9.1
Administrative Procedures.......................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.2
Inclusion and Exclusion .....................................................................................37
9.1.3
Medical History/Demography ............................................................................37
9.1.4
Concomitant Medications...................................................................................38
9.2
Clinical Procedures and Assessments.......................................................................38
9.2.1
Full Physical Exam ............................................................................................38
9.2.2
Height and Weight .............................................................................................38
9.2.3
BMI ...................................................................................................................38
9.2.4
Vital Signs .........................................................................................................38
9.2.5
12-Lead ECG.....................................................................................................38
9.2.6
Columbia Suicide Severity Rating Scale (C-SSRS)............................................39
9.2.7
Study Drug Administration ................................................................................39
9.2.8
AE Monitoring...................................................................................................39
9.2.9
Laboratory Procedures and Assessments ............................................................39
9.3
Biomarker, PK, PD, and PGx Samples.....................................................................41
9.3.1
PK Measurements..............................................................................................41
9.3.2
PD Analysis .......................................................................................................42
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9.3.3
PGx Measurements ............................................................................................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................................................48
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.............51
11.0
STATISTICAL METHODS..........................................................................................52
11.1
Statistical and Analytical Plans ................................................................................52
11.1.1 Analysis Sets......................................................................................................52
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................52
11.1.3 PK Analysis .......................................................................................................52
11.1.4 PD Analysis .......................................................................................................53
11.1.5 Safety Analysis ..................................................................................................53
11.2
Determination of Sample Size..................................................................................54
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................55
12.1
Study-Site Monitoring Visits ...................................................................................55
12.2
Protocol Deviations..................................................................................................55
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................55
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................56
13.1
IRB Approval ..........................................................................................................56
13.2
Subject Information, Informed Consent, and Subject Authorization .........................56
13.3
Subject Confidentiality ............................................................................................57
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................58
13.4.1 Publication and Disclosure.................................................................................58
13.4.2 Clinical Trial Registration..................................................................................58
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13.5
Clinical Trial Results Disclosure..............................................................................58
13.6
Insurance and Compensation for Injury....................................................................58
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................59
14.1
Administrative Information......................................................................................59
14.1.1 Study Contact Information .................................................................................59
14.1.2 Investigator Agreement......................................................................................59
14.1.3 Study-Related Responsibilities...........................................................................59
14.1.4 List of Abbreviations .........................................................................................59
15.0
DATA HANDLING AND RECORDKEEPING............................................................61
15.1
eCRFs......................................................................................................................61
15.2
Record Retention .....................................................................................................62
16.0
REFERENCES..............................................................................................................63
17.0
APPENDICES...............................................................................................................64
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Cohorts..........................................................................................21
Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects............................24
Table 7.a
Excluded Medications, Supplements, Dietary Products ......................................31
Table 9.a
Primary Specimen Collections ...........................................................................41
Table 9.b
Blood Sample Collection for PK Analysis..........................................................42
Table 9.c
Blood Sample Collection for PD Analysis..........................................................43
Table 10.a
Takeda Medically Significant AE List................................................................48
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................10
Figure 6.a
Study Schematic ................................................................................................21
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................64
Appendix B
Pregnancy and Contraception.............................................................................65
Appendix C
Acceptable Time Window for Study Procedure..................................................67
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals
Compound:
TAK-831
Study Identifier: TAK-831-1002
Phase: 1
Title of Study: Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of TAK 831 in Healthy Adult Asian Subjects
Trial Design:
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) of TAK-831 in healthy adult Asian subjects.
This study will include up to 4 cohorts of healthy adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered under a 3 sequential dose escalation design, and the safety, 
PK and PD will be assessed. Eight healthy adult Japanese subjects will be randomized in dosing orders of A 
(100 mg→300 mg), B (100 mg→placebo), and C (placebo→300 mg) at a 4:2:2 ratio. A single dose of TAK-831 or 
placebo will be administered on Day 1 and Day 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
Cohort 2 will include 8 healthy adult Japanese subjects. Of these subjects, 6 will be randomly assigned to the TAK-831 
group and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed by their 
multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with subjects followed for 
approximately 72 hours of assessments for safety, PK and PD. Treatment for multiple doses will start with a 
once-daily regimen on Day 4, which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at 
least 48 hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 and 4 will be optional, in which a single dose will be administered followed by multiple doses, and may be 
studied based on emerging data from the prior cohorts.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 will include 8 healthy adult Japanese subjects. Of 
these subjects in the respective cohorts, 6 will be randomly assigned to the TAK-831 group and 2 to the placebo group. 
A single dose of TAK-831 or placebo will be administered, followed by their multiple doses. A single dose of 
TAK-831 or placebo will be administered on Day 1 with subjects followed for approximately 72 hours of assessments 
for safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, which will continue 
to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo dose 
on Day 17 for safety, PK, and PD assessments before discharge.
Trial Primary Objective:
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Secondary Objectives:
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
Target: Healthy adult Asian subjects
Planned Number of Subjects:
Cohort 1: 8 subjects
Cohorts 2 to 4: 8 subjects per cohort
Planned Number of Sites:
1 site
Dose Levels:
<Cohort 1>
Single dose at 100 mg on Day 1 (Part 1) and 300 mg on 
Day 9 (Part 2) (fasted)
<Cohort 2>
Single dose at 600 mg on Day 1. Multiple doses 
Route of Administration:
Oral
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(once-daily) at 600 mg on Days 4 to 17 (fasted)
<Cohort 3>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
<Cohort 4>
Single dose+multiple dose (once daily). The dose will 
be defined based on the result of Cohort 1 or Cohort 2. 
(fasted)
Duration of Treatment:
<Cohort 1>
Part 1: Single dose on Day 1
Part 2: Single dose on Day 9
<Cohorts 2 to 4>
Single dose on Day 1 and once-daily multiple doses on 
Days 4 to 17, for 14 days, in each Cohort
Planned Trial Duration:
<Cohort 1>
Screening period: Day -28 to -1
Treatment period: Days 1 to 12
Follow-up period: Day 23
<Cohorts 2 to 4>
Screening period: Day -28 to -1
Treatment period: Days 1 to 19
Follow-up period: Day 31
Inclusion Criteria:
Subject eligibility will be determined according to the following criteria.
1.
The subject must understand the study procedures and agree to participate by providing written informed consent 
(for Chinese subjects, an interpreter should be present as necessary).
2.
The subject must be willing and able to comply with all study procedures and restrictions.
3.
The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, inclusive, at the 
Screening.
4.
The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the Screening.
5.
The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing products (e.g., 
nicotine patch) for at least 6 months prior to the Screening.
6.
Chinese subjects are defined as subjects who were born in mainland China, and their biological parents and 
grandparents must all have been of Chinese origin (for Cohort 3 only).
7.
Chinese subjects who have lived out of China for more than 5 years must not have significantly modified their 
diets since leaving China (for Cohort 3 only).
8.
The subject must be judged to be in good health by the investigator or sub-investigator, based on clinical 
evaluations including laboratory tests, medical history, full physical examination, 12-lead electrocardiogram, 
and vital sign measurements performed at the Screening. and prior to the first dose of study drug.
9.
The subject must meet the birth control requirements.
Exclusion Criteria:
The subject must be excluded from participating in the study if the subject meet any of the followings.
1.
The subject has a history of clinically significant endocrine, gastrointestinal (including motility disorder and 
intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, or 
genitourinary, or presents with major neurological (including stroke and chronic seizures) abnormalities or 
diseases.
2.
The subject has participated in another investigational trial within 4 weeks before the pretrial visit (Screening). 
The 4-week window will be derived from the date of the last trial procedure and/or adverse events related to the 
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trial procedure in the previous trial to the Screening Visit of the current trial.
3.
The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the sponsor.
4.
The subject has a history of cancer (malignancy).
5.
The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy) or has had 
an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food.
6.
The subject has a positive alcohol or drug or immunological screen.
7.
The subject is of childbearing potential or lactating.
8.
The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 8 weeks prior to 
the first dose of study drug.
9.
The subject with any gastrointestinal surgery that could impact upon the absorption of study drug.
10.
The subject has a known hypersensitivity to any component of the formulation of TAK-831 or related 
compounds.
11.
The subject is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before administration of the initial 
dose of trial drug, throughout the trial (including washout intervals between trial periods), until the Follow-up 
Visit.
12.
The subject has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 
ounce] per day).
13.
The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
14.
The subject has a history of drug abuse.
15.
The subject has a (QT interval with Fridericia’s correction method) QTcF >450 ms (males) or >470 ms (females) 
or PR outside the range of 120 to 220 ms at the Screening Visit or Check-in.
Main Criteria for Evaluation and Analyses:
Primary Endpoint
Safety: Adverse event, laboratory tests, vital signs, weight, 12-lead electrocardiogram
Secondary Endpoints
Pharmacokinetics: The following parameters will be calculated.
Cmax (Cohort 1, Day 1 of Cohorts 2 to 4)
Cmax,ss (Day 17 of Cohorts 2 to 4)
tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 4)
AUClast (Cohort 1, Day 1 of Cohorts 2 to 4)
AUC∞(Cohort 1, Day 1 of Cohorts 2 to 4)
AUCτ (Days 1 and 17 of Cohorts 2 to 4)
Statistical Considerations:
Pharmacokinetics:
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and treatment 
period for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of TAK-831 in plasma will be summarized by each scheduled sampling time using summary statistics. 
Individual plasma concentration data versus time will be presented. Plasma PK parameters, including 
dose-normalized Cmax and AUC, will be summarized by dose and day using summary statistics. Accumulation of 
TAK-831 from Day 1 to Day 17 will be assessed by summarizing the ratio of Cmax and AUC at Days 1 and 17 by dose. 
Dose linearity in plasma PK parameters (Cmax and AUC) will be assessed graphically for those parameters at Days 1 
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and 9 for Cohort 1 and Day 1 for Cohorts 2 to 4. Additional analyses on dose linearity will be included if appropriate.
Pharmacodynamics:
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by dose and each 
scheduled sampling time for Cohorts 2 and 4, as well as Cohort 3. Concentrations of D-serine, L-serine and the ratio of 
D-serine to total serine in plasma and concentrations of D-serine, L-serine and the ratio of D-serine to total serine in 
cerebrospinal fluid (if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of D-serine to total serine in 
plasma, and change and percent change from baseline will be summarized by day using summary statistics. The 
potential relationship between TAK-831 exposure and biomarker response will be explored graphically. Additional 
statistical or PK-PD analyses will be included if appropriate.
Safety:
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for Cohorts 2 and 4, and for 
Cohort 3.
A treatment-emergent adverse event (TEAE) refers to an adverse event that occurs after the start of study treatment. 
The frequency of all TEAEs, drug-related TEAEs , all TEAEs by intensity, drug-related TEAEs by intensity, TEAEs 
leading to study drug discontinuation, and serious TEAEs will be summarized. TEAEs will be coded using Medical 
Dictionary for Regulatory Activities Terminology (MedDRA) and summarized by system organ class (SOC) and 
preferred term (PT).
For continuous values of laboratory findings, vital signs and other safety parameters, summary statistics will be 
provieded for observed values and change from baseline at each evaluation time point. Pre- and post-dose shift tables 
will be prepared for categorical variables.
Sample Size Justification:
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size required to assess the 
safety, tolerability, PK and PD of each cohort. This is not based on any statistical rationale.
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2.0
STUDY SCHEMATIC
Figure 2.a shows the schematic of the trial design.
Figure 2.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
Sequence of 
administration
Part 1
Washout 
interval
Part 2
Day 1 to 4
Day 5 to 8
Day 9 to 12
A
TAK-831 100 mg
Washout
TAK-831 300 mg
B
TAK-831 100 mg
Placebo
C
Placebo
TAK-831 300 mg
<Cohorts 2 to 4>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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3.0
SCHEDULE OF STUDY PROCEDURES
<Cohort 1>
Screening period
Treatment period
Early
Termina
tion
Follow-up 
visit
Screening Hospitali
zation
Part 1
Washout interval
Part 2
Day
-28 to -2
-1
1
2
3
4
5 to 7
8
9
10
11
12
23 (±2)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics, medical history
X
Prior medications
X
Physical examination
X
X
X
X
X
X
X
X (l)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X (l)
Weight, height, BMI (b)
X
X
X
X
X
X
X (l)
12-lead electrocardiogram (ECG) (c)
X
X
X
X
X
X
X
X
X (l)
Laboratory tests (d)
X
X
X
X
X
X
X (l)
Immunological test, alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
X
C-SSRS (f)
X
X
X
X
X
X
Sample collection for pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X(k)
Blood sample collection for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
X
X
Urine sample (for future tests) (j)
X
X
X
X
Study drug administration
X
X
Adverse events
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Concomitant medications
X
X
X-----------------------------------------------continuous monitoring---------------------------------------------X
Hospitalization
X
X-----------------------------------X
X
X-----------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36, 48 and 72 hours postdose on Day 1, on Day 8, predose on Day 9, and 1, 4, 12, 24, 36, 48 and 72 hours 
postdose on Day 9.
(b)
Height will be measured at Screening only. Weight will be measured at Screening visit, Day -1, 72 hours postdose on Day 1, Day 8, 72 hours postdose on Day 9.
(c)
12-lead ECG will be measured at Screening, Day -1, predose, 2 and 72 hours postdose on Day 1, Day 8, predose on Day 9, 2 and 72 hours postdose on Day 9.
(d)
Laboratory tests will be performed at Screening, on Day -1, 72 hours postdose on Day 1, on Day 8, and at 72 hours postdose on Day 9.
(e)
FSH will be measured in postmenopause women only.
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(f)
C-SSRS will be investigate at Screening, Day -1, Day 4, Day 8, and Day 12.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 9, and 0.5, 1. 1.5, 2, 4, 8, 12, 24, 36, 48, 
and 72 hours postdose on Day 9.
(i)
Samples for PD assessment will be collected on Day -1 (at 20, 16, 12 hours predose on Day 1), predose, 1, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose, 1, 4, 8, 
12, 24, 36, 48, and 72 hours postdose on Day 9.
(j)
Urine samples will be collected on Day -1, 24 hours postdose on Day 1, and 24 hours postdose on Day 9.
(k)
Samples for PK assessment at discontinuation will be collected if it is possible.
(l)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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<Cohorts 2 to 4>
Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening Hospitalization Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics, medical 
history
X
Prior medications
X
Physical examination
X
X
X
X
X
X (m)
Vital signs (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (m)
Weight, height, BMI (b)
X
X
X
X
X (m)
12-lead 
electrocardiogram 
(ECG) (c)
X
X
X
X
X
X
X
X
X (m)
Laboratory tests (d)
X
X
X
X
X
X (m)
Immunological test, 
alcohol tests
X
FSH (e)
X
Urinary drug tests
X
X
C-SSRS (f)
X
X
X
X
Sample collection for 
pharmacogenomic (PGx)
Measurements (g)
X
Blood sample collection 
for pharmacokinetic
(PK) assessment (h)
X
X
X
X
X
X
X
X
X (l)
Blood sample collection 
for pharmacodynamic
(PD) assessment (i)
X
X
X
X
X
X
X
Cerebrospinal fluid 
sample collection for 
pharmacodynamic (PD) 
assessment (j)
X
X
Urine sample (for future 
tests) (k)
X
X
X
X
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Screening period
Treatment period
Early
Termination
Follow-up 
visit
Screening Hospitalization Single dose part
Multiple dose part
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
31 (±2)
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Concomitant 
medications
X
X
X---------------------------------------------continuous monitoring-------------------------------------------X
X
X
Hospitalization
X
X-------------------------------------------------------------------------------------------------------------------X
BMI, body mass index; C-SSRS, Columbia Suicide Severity Rating Scale; FSH, follicle-stimulating hormone
(a)
Vital signs will be measured at Screening, Day -1, predose, 1, 4, 12, 24, 36 and 48 hours postdose on Day 1, predose on Days 4 to 16, predose on Day 17, and 1, 4, 12, 24, and 
48 hours postdose on Day 17.
(b)
Height will be measured at Screening only. Weight will be measured at Screening, on Day -1, and 48 hours postdose on Day 17.
(c)
12-lead ECG will be measured at Screening, Day -1,presdose and 2 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose, 2 and 48 hours postdose on Day 17.
(d)
Laboratory tests will be performed at Screening, Day -1, predose on Day 11, and at 48 hours postdose on Day 17.
(e)
FSH will be measured in postmenopause women only.
(f)
C-SSRS will be investigate at Screening Visit, Day -1, and Day 19.
(g)
Samples for PGx measurements will be collected predose on Day 1.
(h)
Samples for PK assessment will be collected predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, and 72 hours postdose on Day 1, predose on Day 4, predose on Day 11, predose on Day 
14, predose, 0.5, 1. 1.5, 2, 4, 8, 12, 16, and 24 hours postdose on Day 17.
(i)
Samples for PD assessment will be collected at 20, 16, and 12 hours predose on Day 1, predose, 1, 4, 8, 12, and 24 hours postdose on Day 1, predose on Day 11, predose on Day 
14, predose, 1, 4, 8, 12, and 24 hours postdose on Day 17.
(j)
Samples for PD assessment will be collected on Day -1 and 24 hours postdose on Day 17 (if it is performed in Cohort 3 and thereafter).
(k)
Urine samples will be collected on Day -1, at 24 hours postdose on Day 1, and 24 hours postdose on Day 17.
(l)
Samples for PK assessment at discontinuation will be collected if it is possible.
(m)
The Follow-up Visit will occur by telephone or at the study site if the subject visits the site.
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4.0
INTRODUCTION
4.1
Background
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and
behaves. Schizophrenia usually develops at late adolescence or early adulthood and manifests in 
maximum 1% of the population. For those who have relatives of first degree with schizophrenia, 
the incidence rate is higher by 10% (the concordance rate for schizophrenia in identical twins is 
40% to 65%) [1][2][3]. Symptoms of schizophrenia can be subdivided into 3 broad classes: 
positive, negative, and cognitive symptoms [4]. Positive symptoms include hallucinations, 
delusions, and disordered thought and speech, and can be summarized as psychosis. Negative 
symptoms include reduced emotion, reduced ability to experience pleasure (anhedonia), lack of 
motivation, and reduced social interaction. Finally, cognitive symptoms include poor information 
processing, impaired ability to focus on objectives, and abnormalities of working memory and 
learning [4]. Currently available antipsychotics are broadly effective for the treatment of positive
symptoms. However, the negative symptoms and cognitive impairment of schizophrenia are the 
known particular aspects that cause dysfunction, for which no therapy has been approved. There 
still are significant unmet medical needs.
Hypofunction of N-methyl-D-aspartic acid (NMDA) receptor is considered a potential mechanism 
in the pathophysiology of schizophrenia, which could be mitigated with increased D-serine levels 
in the brain [5]. D-amino acid oxidase (DAAO) contributes to the metabolism of D-serine in the 
brain and is highly expressed in the cerebellum. Changes in the D-serine levels or D-serine to total 
serine ratios have been reported in the plasma of patients with schizophrenia both naive and under 
drug treatment [6]-[9]. In addition, serine racemase (the D serine generating enzyme) and the 
NMDA NR2A subunit are among the risk genes identified from the recent large scale 
genome-wide association study analysis, indicating the biological relevance to schizophrenia of 
the genetic pathway in which DAAO resides [10]. Therefore, inhibition of DAAO is considered to 
be a promising target in treatment of schizophrenia.
TAK-831 is a highly selective and potent inhibitor of DAAO. TAK-831 increased D-serine levels 
in the cerebellum of normal mice and showed efficacy in a mouse model of Friedreich ataxia 
(FRDA) mouse models. It also demonstrated a positive effect on cognition and social interaction in 
rodent cognition and behavioral models.
As stated above, TAK-831 is expected to provide a therapeutic effect on FRDA and cognitive 
impairment as well as negative symptoms associated with schizophrenia.
4.2
Rationale for the Proposed Study
TAK-831 is currently under development for the treatment of FRDA and cognitive impairment as 
well as negative symptoms of schizophrenia. Three overseas phase 1 studies in healthy adults 
(single and multiple dose study [TAK-831-1001], positron emission tomography [PET] study to 
determine DAAO brain enzyme occupancy [TAK-831-1003], and a study to evaluate the food 
effect [TAK-831-1004]) have been conducted so far, in which TAK-831 was well-tolerated.
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In addition, two phase 1 studies in healthy adults (study with single and multiple doses at high dose 
level [TAK-831-1005] and bioequivalence study [TAK-831-1006]) are being conducted or 
planned. Two phase 2 studies in patients with schizophrenia (small-scale crossover study to 
examine the cerebellar functions [TAK-831-2001], and a study to evaluate the efficacy and safety 
for negative symptoms of schizophrenia [TAK-831-2002]) are also underway. Besides, a phase 2 
proof-of-concept (POC) study in patients with schizophrenia is being planned in China. Based on 
the result of these phase 2 studies, a phase 3 global study (long-term study) has been planned.
In parallel with these development plans, TAK-831 is also being developed in Japan for the 
treatment of cognitive impairment and negative symptoms associated with schizophrenia. In 
respect of FRDA, a genetic disease, since there has been no confirmed report as of June 2018 that 
clearly indicates the existence of Japanese patients, no development plan has been made for FRDA 
in Japan.
Enrollment of Japanese patients into the phase 3 global study and the phase 2 POC study in China 
has been considered. This study was planned to examine the safety and pharmacokinetic (PK) of 
TAK-831 in Japanese as well as to evaluate the safety and PK in Asian healthy subjects for the 
aforementioned studies.
4.3
Benefit/Risk Profile
Because this study will be conducted in healthy adults, there is no benefit to subjects.
The following risk mitigation measures will be implemented in this study. These measures are 
based on what is known about the mechanism of action of TAK-831, nonclinical data, and the 
phase 1 studies (4 studies, including preliminary data of TAK-831-1005). Procedures may be 
added during the study as necessary based on evaluation of any additional clinical or nonclinical 
data.
The safety of TAK-831 has been studied in a prior single dose (up to 750 mg in suspension and 
100 mg T1 tablet formulation) and multiple dose (up to 400 mg once daily [QD] in suspension) 
study in healthy Western subjects (TAK-831-1001), a single dose (up to 500 mg in suspension) 
PET study to investigate DAAO occupancy in the brain (TAK-831-1003) and a single dose food 
effect (400 mg T2 tablet formulation) study (TAK-831-1004). These studies have not resulted in a 
safety signal that would prevent additional studies. Additionally, TAK-831 given as single and 14 
days multiple doses (up to 1200 mg in suspension and 600 mg T2 tablet formulation) is currently 
being studied in healthy adult subjects (TAK-831-1005). TAK-831 has been safe and well 
tolerated to date (provisional data as of end-April 2018).

Acute hypersensitivity/anaphylactic reactions to new chemical entities are always a possible 
risk in any clinical study. Appropriate procedures should be used to manage such possible 
risks.

Study procedure-specific risks include issues relating to blood collection for safety 
assessment/PK and pharmacodynamics (PD) monitoring (venipuncture may cause bruising), 
and the placement of ECG pads (which may cause some local redness and/or 
erythema/itching).
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
In case of serious adverse events (SAE), the investigator has discretion to use his/her clinical 
judgment as to whether to allow a subject to proceed in the study or whether to unblind the 
subject in order to determine his/her treatment allocation.

The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered to monitor 
emergent suicidality.
The Investigator's Brochure should be referred for more detailed safety of TAK-831.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed on the basis of the following hypothesis.

TAK-831 given as single or multiple doses shows no safety issue and is well tolerated.

The PK of TAK-831 given as single or multiple doses to Asian subjects is equivalent to that in 
Western subjects.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
To evaluate the safety and tolerability of single and multiple doses of TAK-831 in healthy adult 
Asian subjects.
5.2.2
Trial Secondary Objective
To evaluate the PK of single and multiple doses of TAK-831 in healthy adult Asian subjects.
5.2.3
Trial Exploratory Objective
To assess the effect of TAK-831 on the concentrations of D-serine and L-serine in plasma (and 
concentrations of D-serine and L-serine in cerebrospinal fluid as necessary) after TAK-831 
administration to healthy Asian subjects.
5.3
Endpoints
5.3.1
Primary Endpoint
Safety: Adverse events (AEs), laboratory tests, vital signs, weight, 12-lead electrocardiogram
(ECG)
5.3.2
Secondary Endpoints
PK: The following parameters will be calculated.

Cmax (Cohort 1, Day 1 of Cohorts 2 to 4)

Cmax,ss (Day 17 of Cohorts 2 to 4)

tmax (Cohort 1, Days 1 and 17 of Cohorts 2 to 4)

AUClast (Cohort 1, Day 1 of Cohorts 2 to 4)

AUC∞(Cohort 1, Day 1 of Cohorts 2 to 4)

AUCτ (Days 1 and 17 of Cohorts 2 to 4)
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5.3.3
Exploratory Endpoints

PK: Rac (Cmax) and Rac(AUC) on Days 1 and 17 (Cohorts 2 to 4), t1/2z, CL/F, Vz/F

PD: Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (Days -1 and 18) (may be assessed in Cohort 3 or thereafter based on PD in plasma)
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This is a double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, PK and 
PD of TAK-831 in healthy adult Asian subjects. This study will include up to 4 cohorts of healthy 
adult Japanese or Chinese subjects.
In Cohort 1, a single dose of TAK-831 will be administered at each dose level under a 3-sequential 
dose escalation design. Eight healthy adult Japanese subjects will be randomized to the sequence 
of administration A, B, and C at a 4:2:2 ratio. A single dose of TAK-831 or placebo will be 
administered on Days 1 and 9 with subjects followed for approximately 72 hours of assessments 
for safety, tolerability, and PK and PD before discharge.
In Cohort 2, a single dose of study drug will be administered to healthy adult Japanese subjects, 
followed by multiple doses. Of these subjects, 6 will be randomly assigned to the TAK-831 group 
and 2 to the placebo group. A single dose of TAK-831 or placebo will be administered, followed 
by their multiple doses. A single dose of TAK-831 or placebo will be administered on Day 1 with 
subjects followed for approximately 72 hours of assessments for safety, PK and PD. Treatment for 
multiple doses will start with a once-daily regimen on Day 4, which will continue to Day 17 (for 
14 days). Subjects will be kept in the study site for at least 48 hours after the last TAK-831/Placebo 
dose on Day 17 for safety, PK, and PD assessments before discharge.
Cohorts 3 and 4 will be optional, in which a single dose of study drug will be administered 
followed by multiple doses, and may be studied based on emerging data from Cohorts 1 and 2.
Cohort 3 will include 8 healthy adult Chinese subjects, and Cohort 4 will include 8 healthy adult 
Japanese subjects. Of these subjects in the respective cohorts, 6 will be randomly assigned to the 
TAK-831 group and 2 to the placebo group. A single dose of TAK-831 or placebo will be 
administered, followed by their multiple doses. A single dose of TAK-831 or placebo will be 
administered on Day 1 with subjects followed for approximately 72 hours of assessments for 
safety, PK and PD. Treatment for multiple doses will start with a once-daily regimen on Day 4, 
which will continue to Day 17 (for 14 days). Subjects will be kept in the study site for at least 48 
hours after the last TAK-831/Placebo dose on Day 17 for safety, PK, and PD assessments before 
discharge.
Table 6.a shows the summary of cohorts, and Figure 6.a shows the schematic of the trial design.
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Table 6.a
Summary of Cohorts
Cohort
Subject
Dose
Remarks
1
Japanese
8 subjects
Part 1:
100 mg (4×25 mg T3 tablet formulation)
Fasted, single dose
Wash out period between part 1 and 2 will be 
8 days.
Part 2:
300 mg (1×300 mg T3 tablet formulation)
Fasted, single dose
2
Japanese
8 subjects
600 mg (2×300 mg T3 tablet formulation)
Fasted, single dose + multiple dose (once 
daily)
3
Chinese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 3 may be run if emerging data from 
Cohorts 1 and 2 suggest ethnic-related 
differences in the tolerability and/or PK 
profile. Dose level will be determined based 
on the results from Cohorts 1 and 2.
4
Japanese
8 subjects
TBD
Fasted, single dose + multiple dose (once 
daily)
Cohort 4 may be run based on the emerging 
data from Cohorts 1 and 2 in Asian subjects.
TBD: To be decided
Figure 6.a
Study Schematic
<Cohort 1>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Part 1
Washout interval
Part 2
Day -28 to -2
Day -1
Day 1 to 4
Day 5 to 7
Day 8
Day 9 to 12
23 (±2)
Hospitalization
Hospitalization
(a)
TAK-831 or placebo will be administered on Days 1 and 9.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
<Cohorts 2 to 4>
Screening period
Treatment period (a)
Safety, Pharmacokinetic and Pharmacodynamic assessment
Follow-up 
period (b)
Screening
Hospitalization
Single dose part
Multiple dose part
Day -28 to -2
Day -1
Day 1 to 3
Day 4 to 19
31 (±2)
Hospitalization
(a)
TAK-831 or placebo will be administered on Day 1 in the single dose part and on Days 4 to 17 in the multiple 
dose part.
(b)
The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge. In these cases, subjects may then be brought back to the study site for re-evaluation per investigator’s 
discretion
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6.2
Cohort transition/Dose Escalation
In Cohort 1, TAK-831 100 mg or placebo will be administered on Day 1 (Part 1) followed by 
confirmation of the safety and tolerability (AEs, physical examination, vital signs, weight, 
laboratory tests and 12-lead ECG) up to 72 hours postdose, and then TAK-831 300 mg or placebo 
will be administered on Day 9 (Part 2) followed by confirmation of the safety, tolerability and PK 
up to 72 hours postdose.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohort 1 in a blinded manner and discuss with the sponsor (including the 
medical expert if necessary) as to whether the subsequent cohort should be run.
In Cohort 2, TAK-831 600 mg or placebo will be administered on Day 1, followed by 
confirmation of the safety and tolerability up to 72 hours postdose. Then, multiple doses of 
TAK-831 600 mg or placebo will be administered on Days 4 to 17. The data on safety and 
tolerability as well as PK up to 72 hours postdose will be examined.
The investigator will comprehensively examine the safety and tolerability data as well as PK and 
PD data emerging from Cohorts 1 and 2 in a blinded manner and discuss with the sponsor 
(including the medical expert if necessary) as to whether Cohorts 3 and 4 should be run.
In Cohort 2 and onwards, the dose will be escalated but the dose escalation will be discontinued 
according to the following discontinuation criteria. The dose in Cohort 2 will be adjusted based on 
the safety and tolerability as well as PK and PD in Cohort 1.
Discontinuation criteria for dose escalation:

Exposures in any cohort exceed those observed at the highest dose tested in monkey (Cmax of 
3680 ng/mL, AUC24 of 35700 hr*ng/mL)

One or more subjects in any single cohort or across more than 1 cohort experience an SAE or 2 
severe or clinically significant AEs occur that are considered related to study drug

One or more subjects in any single cohort or across more than 1 cohort experience severe 
psychiatric symptoms, including (any level of) treatment-emergent suicidal ideation* that are 
considered related to study drug.
*Treatment-emergent suicidality compared to baseline, as measured by changes in suicidal 
ideation or behavior category on the C-SSRS during treatment from the maximum suicidal 
ideation/behavior category at baseline, or any suicidal ideation/behavior during treatment if there 
was none at baseline
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale for Study Population
The subject of this study is Japanese or Chinese with a purpose to support the future conduct of 
studies in Asian subjects. The study will be conducted in healthy adult subjects without any 
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disease including circulatory or cerebrovascular diseases to appropriately assess the safety and 
tolerability as well as PK and PD of TAK-831.
6.3.2
Rationale of Trial Design
With a purpose to assess the safety and tolerability as well as the PK and PD profiles of TAK-831 
when administered to Asian subject for the first time, this study employed a design with both 
single and multiple doses.
6.3.3
Rationale for Dose
To this date, the highest dose of TAK-831 tested in healthy Western subjects is 1200 mg 
(suspension formulation) once daily in the study TAK-831-1005. Based on the preliminary results, 
there were no significant adverse effects reported at this dose level, and as shown in Table 6.b, the 
mean steady-state exposure was Cmax of 3015 ng/mL and AUC24 of 10501 h*ng/mL. The dose 
regimen of 600 mg given once daily (T2 tablet formulation) was also well tolerated and safe in 
healthy Western subjects. As for the mean steady-state exposures, Cmax was 1494 ng/mL and 
AUC24 was 5090 h*ng/mL. This exposure at 600 mg was similar to that of monkeys at 
100 mg/kg/day, the no-observed-adverse-effect-level (NOAEL).
In the study TAK-831-1005, the PK and PD of TAK-831 given as multiple doses at 100 and 
600 mg (per day) to non-Japanese subjects was examined. The dose of 300 mg will be further 
examined in the study.
Based on the above, the doses of 100, 300 and 600 mg were selected for this study in consideration 
to the safety in humans as well as the comparability of PK and PD between non-Japanese and 
Japanese subjects.
In the 13-week repeat dose toxicity study in monkeys that are considered the more sensitive 
species than rats, adverse effects (vomiting, diarrhea, and loose stool) were noted at 
600 mg/kg/day. The NOAEL was 100 mg/kg/day for both sexes.
TAK-831 has been administered at doses up to 1200 mg to non-Japanese, and no SAE has been 
reported with exposures exceeding the NOAEL. Besides, the adverse effects (vomiting, diarrhea, 
and loose stool) noted at a dose of 600 mg/kg/day in the 13-week repeat dose toxicity study in 
monkeys will be easily monitored in clinical trials.
Therefore, it is considered possible to administer doses exceeding the NOAEL exposure by 
carefully examining the safety and PK in each Cohort in this study. However, We have no 
information on toxicity at the level exceeding the exposure at 600 mg/kg/day in the 13-week 
repeated dose toxicity study in monkeys. Dose escalation will be stopped if exposures exceed that 
at 600 mg/kg/day in monkeys.
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Table 6.b
PK Parameters in 13-week Repeated Dose Toxicity Study in Monkeys and 
TAK-831 Given as Multiple Doses to Healthy Adult Subjects
Animal species-Study
Dose
(mg/kg/day or mg)
Cmax
(ng/mL)
AUC24
(h*ng/mL)
Monkey 13-week (Da 91)
100 mg/kg/day (NOAEL)
1340 (male)
1270 (female)
7490 (male)
9190 (female)
600 (300 BID) mg/kg/day
4650 (male)
2179 (female)
45500 (male)
25900 (female)
Human MRD (Day 16)
1200 mg QD (suspension 
formulation)
3015
10501
Human MRD (Day 16)
600 mg QD (T2 tablet 
formulation)
1494
5090
BID, twice daily; MRD, multiple repeated dose; NOAEL, no-observed-adverse-effect-level; QD, once daily
6.3.4
Rationale for Endpoints
6.3.4.1
Safety Endpoint
The safety endpoints in this study were defined to determine the safety and tolerability following a 
single dose and multiple dose of TAK-831. These are standard endpoints in the Phase 1 studies in 
healthy subjects.
Since TAK-831 involves effects on the central nervous system, the C-SSRS will be administered 
to assess the influence on suicidal ideation or suicidal behavior.
6.3.4.2
Pharmacokinetic Endpoint
Concentrations of TAK-831 in plasma will be examined to assess the PK of TAK-831 given as a 
single dose or multiple doses to healthy adult Asian subjects, and then the following PK 
parameters will be calculated.

PK parameters: Cmax, Cmax,ss (Cohorts 2 to 4), tmax, AUClast, AUC∞, AUCτ (Cohorts 2 to 4), 
Rac(Cmax) (Cohorts 2 to 4), Rac(AUC) (Cohorts 2 to 4), t1/2, CL/F, Vz/F
6.3.4.3
Pharmacodynamic Endpoint
Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, AUEC24, 
Emax and time to Emax following TAK-831 doses will be examined to assess the PD of TAK-831 in 
healthy adult Asian subjects. Concentrations of D-serine, L-serine and the ratio of D-serine to total 
serine in cerebrospinal fluid may be assessed as necessary.
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures
The objective of this section is to specify the sequence of procedures in the cases where the timing 
of each procedure overlaps.
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
Safety evaluation will be conducted within the predetermined allowance window as far as 
possible.

Blood samples for PK assessment will be collected at time points as close to the specified time
as possible.

Other procedures must be completed at time points as close to the specified or planned hours as 
possible irrespective of before or after the specified times.

If the timing of blood sampling and ECG or vital signs measurement overlap, blood sampling 
should be prioritized. ECG or vital signs measurement may be performed within an acceptable 
time window (Appendix C).

The priority may be changed upon agreement between the investigator and the sponsor based 
on discussion.

Any test and procedure necessary to immediately assess safety concerns at the time of AEs 
must be prioritized over other regular predetermined procedures.

The safety of subjects in the follow-up period may be confirmed by telephone unless abnormal, 
clinically significant findings are observed upon discharge.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The entire study will start when the first subject signs the informed consent form to participate in 
this study.
6.4.2
Definition of End of the Trial
The study will end when the last subject completes the last planned visit or follow-up visit (or last 
communication [may be via telephone] relating to the planned visit) or is withdrawn from the 
study or lost to follow up (the status that the subject cannot be reached by the investigator).
6.4.3
Definition of Trial Discontinuation
The study may be discontinued for reasons other than safety such as the followings:

A finding (eg, PK, pharmacodynamics, efficacy, biologic targets) from the other nonclinical or
clinical studies results with the study drug in the study discontinuation for non-safety related
reasons.

Data from drugs classified in the same class as the study drug, or methodologies used in this 
study become available and results in the study being stopped for a non-safety related reason.

Study discontinuation due to non-scientific and non-safety-related reasons, such as slow
enrollment.
Discontinuation of the clinical study for safety reasons:
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
The study is prematurely terminated because other clinical or non-clinical trials where 
TAK-831 or other drugs of the same class are administered have confirmed unexpected safety 
concerns based on the methodology used in this study
6.4.4
Criteria for Premature Termination or Suspension of the Trial
6.4.4.1
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 met that
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the compound, such that the
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.
6.4.4.2
Procedures for Premature Termination or Suspension of the Trial
In the event that the Sponsor, an institutional review board (IRB), or a regulatory authority elects
to terminate or suspend the study, a study-specific procedure for early termination or suspension
will be provided by the Sponsor; the procedure will be followed by the applicable study sites 
during the course of termination or study suspension.
6.4.5
Criteria for Premature Termination or Suspension of a Study Site
6.4.5.1
Criteria for Premature Termination or Suspension of a Study Site
A study 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 is permitted by the contractual agreement.
6.4.5.2
Procedure for Premature Termination or Suspension in a Study Site
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend of the
study site, a study-specific procedure for early termination or suspension will be provided by the
Sponsor; the procedure will be followed by the applicable study sites during the course of 
termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria.
1. The subject must understand the study procedures and agree to participate by providing written 
informed consent (for Chinese subjects, an interpreter should be present as necessary).
2. The subject must be willing and able to comply with all study procedures and restrictions.
3. The subject must be male or female (of nonchildbearing potential) aged 20 to 55 years, 
inclusive, at the Screening.
4. The subject must have a body mass index (BMI) ≥18.5 kg/m2 and ≤25.0 kg/m2 at the 
Screening.
5. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing 
products (e.g., nicotine patch) for at least 6 months prior to the Screening.
6. Chinese subjects are defined as subjects who were born in mainland China, and their biological 
parents and grandparents must all have been of Chinese origin (for Cohort 3 only).
7. Chinese subjects who have lived out of China for more than 5 years must not have significantly 
modified their diets since leaving China (for Cohort 3 only).
8. The subject must be judged to be in good health by the investigator or sub-investigator, based 
on clinical evaluations including laboratory tests, medical history, full physical examination, 
12-lead electrocardiogram, and vital sign measurements performed at the Screening. and prior 
to the first dose of study drug.
9. The subject must meet the following birth control requirements:
•
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicidal cream or jelly, from the first dose of study drug until 
95 days (5 half-lives plus 90 days) after the last dose of study drug. No restrictions will be
required for a vasectomized male subject provided the subject is at least 1 year post 
bilateral vasectomy procedure prior to the first dose of study drug. A male subject whose 
vasectomy procedure was performed less than 1 year prior to the first dose of study drug 
must follow the same restrictions as a nonvasectomized man. Appropriate documentation 
of surgical procedure should be provided.
•
Is a male subject who agrees to not donate sperm from the first dose of study drug until 95 
days (5 half-lives plus 90 days) after the last dose of study drug.
•
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a)
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years or ≥6 months of spontaneous amenorrhea in females aged >45 years with 
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serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate 
documentation of follicle-stimulating hormone levels should be required.
b)
Hysterectomy and/or bilateral oophorectomy with appropriate documentation of 
surgical procedure.
c)
Had a tubal ligation with appropriate documentation of surgical procedure.
d)
Congenital conditions such as uterine aplasia etc.
[Rationale for the inclusion criteria]
Inclusion criteria 1, 2, 5, 8 and 9:
These are standard criteria for clinical pharmacology studies in healthy adult subjects and defined 
in consideration to the safety of subjects.
Inclusion Criterion 3:
This is a standard criterion for clinical pharmacology studies in healthy adult subjects for sex. This 
is a standard criterion for clinical pharmacology studies in healthy adult subjects for age.
Inclusion Criterion 4:
This is the range of normal weight in the diagnosis criteria for obesity and obesity disease [11]
proposed by the Japan Society for the Study of Obesity.
Inclusion Criterion 6:
This is set to appropriately assess the safety and PK in Chinese.
Inclusion Criterion 7:
This is set to eliminate the influence by dietary habits on the PK.
7.2
Exclusion Criteria
The subject will be excluded from participating in the study if the subject meet any of the 
followings.
1. The subject has a history of clinically significant endocrine, gastrointestinal (including 
motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, or genitourinary, or presents with major neurological 
(including stroke and chronic seizures) abnormalities or diseases.
2. The subject has participated in another investigational trial within 4 weeks before the pretrial 
visit (Screening). The 4-week window will be derived from the date of the last trial procedure 
and/or adverse events related to the trial procedure in the previous trial to the Screening Visit 
of the current trial.
3. The subject is an employee or immediate family member (e.g., spouse, parent, child, sibling) 
of the sponsor.
4. The subject has a history of cancer (malignancy).
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5. The subject has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerability to prescription or 
nonprescription drugs or food.
6. The subject has a positive alcohol or drug or immunological screen.
7. The subject is of childbearing potential or lactating.
8. The subject had major surgery, received or lost 1 unit of blood (approximately 500 mL) within 
8 weeks prior to the first dose of study drug.
9. The subject with any gastrointestinal surgery that could impact upon the absorption of study 
drug.
10. The subject has a known hypersensitivity to any component of the formulation of TAK-831 or 
related compounds.
11. The subject is unable to refrain from or anticipates the use of any medication, including 
prescription and nonprescription drugs or herbal remedies, beginning approximately 7 days 
before administration of the initial dose of trial drug, throughout the trial (including washout 
intervals between trial periods), until the Follow-up Visit.
12. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on 
average (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).
13. The subject who consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
14. The subject has a history of drug abuse.
15. The subject has a (QT interval with Fridericia’s correction method) QTcF >450 msec (males) 
or >470 msec (females) or PR outside the range of 120 to 220 msec at the Screening Visit or 
Check-in.
[Rationale for the exclusion criteria]
Exclusion Criteria 1, 15:
This is set to eliminate the influence on safety evaluation for TAK-831.
Exclusion Criterion 2:
This is a minimum duration in which the previous clinical trial is considered to have no influence 
in reference to “General Considerations for Clinical Trials” [12] in order to ensure the safety of 
subjects.
Exclusion Criteria 3, 4, 6, 7, 12, 13, 14:
These are standard criteria for clinical pharmacology studies and defined in consideration to the 
safety of subjects.
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Exclusion Criterion 5:
This is defined in consideration to the safety of subjects.
Exclusion Criteria 8, 9, 11:
This is defined in consideration to the safety of subjects. This is also defined for potential influence 
on PK and PD assessment.
Exclusion Criterion 10:
This is set to exclude subjects who have a known hypersensitivity to any component of the 
formulation of TAK-831 or related compounds in consideration of the safety of subjects.
7.3
Excluded Medications Supplements, Dietary Products
Table 7.a shows excluded medications, supplements, and dietary products.
Use of the drugs listed on Table 7.a (prescribed drugs and over-the-counter [OTC] drugs), 
vitamins, supplements, and dietary products will be excluded from a specified time point to until 
discharge given the effect on the safety and PK. Use of prohibited concomitant drugs will be
allowed when the investigator or sub-investigator deems it necessary to use any of the concomitant
drugs for reasons including treatment of an AE.
Subjects must be instructed not to take any medications including OTC products, without first
consulting with the investigator or sub-investigator.
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Table 7.a
Excluded Medications, Supplements, Dietary Products
From 28 days before admission (Day -1)
to the last discharge
7 days before admission (Day -1)
to the last discharge
72 hours before admission (Day -1)
to the last discharge
• Prescription drugs
• Supplements (St. John's wort, ginseng, 
kava kava, ginkgoes, chinese herbal 
medicine, and melatonin)
• OTC drugs (including aspirin or 
aspirin-containing drugs) (a)
• Vitamins
• Caffeine or xanthine containing 
products
• Vaccination/vaccine (b)
• Beverages containing grapefruit 
(fruit juice, flesh), star fruits (fruit 
juice, flesh), citrus aurantiums 
(high acidity), orange (seville 
oranges), or marmalade
• Apple, orange or pineapple juice
• Brassicaceae vegetables (kale, 
cress, collard greens, kohlrabi, 
brussels sprouts, and mustard).
• Meat cocked over the charcoal
• Nicotine-containing products
• CYP 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1 and 2A6 inhibitors/inducers 
OTC drugs (c)
• Alcohol containing products
CYP: cytochrome P-450, OTC drugs: over-the-counter drugs
Note: Excludes the drug needs to be administered to treat an AE and if the investigator or sub-investigator considers 
necessary to use the drug
(a)
Use of paracetamol (≤1 g/daily) will be allowed.
(b)
Includes H1N1 and other influenza vaccines, however, not limited to these medications.
(c)
Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Diet and fluid (except water) must be ingested at least10 hours before clinical laboratory tests.
On the day before clinical laboratory tests, evening meal must be ingested by 21:00.
During hospitalization, pre-specified diets must be ingested, and other diets will be prohibited. 
After discharge, excessive drinking and eating must be avoided until completion of follow-up 
period.
7.4.2
Activity
Smoking is prohibited during the study.
Excessive exercise is prohibited during the study.
Blood donation is prohibited for at least 12 weeks (84 days) from completion of the last test.
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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 or sub-investigator should
communicate that medical institution about the subject’s participation in the study.
7.5
Documentation of Subject Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a
subject discontinues the study before the first study drug administration, the investigator or
sub-investigator should complete the electronic case report form (eCRF).
The primary reason for subject failure is to be recorded in the eCRF using the following categories:

Death

AE

Screening failure (failed inclusion criteria or did meet exclusion criteria) <specify the reasons>

Protocol deviation

Lost to follow up

Withdrawal by subject <specify the reasons>

Study terminated by the Sponsor

Pregnancy

Sample size sufficient

Other <specify the reasons>
Any subject identification number, once assigned to a subject, should not be reused if the assigned
subject discontinues the study prior to the first study drug administration. Nevertheless, if a reserve 
subject is enrolled in the other 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 the subject who is withdrawn from the
study before the first study drug administration in Period 1, 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 a serious adverse event 
(SAE). Refer to Section 10.2.9.3 for reporting procedures.
2. AE
The subject has experienced an AE that requires early termination because continued
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participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to
continue because of the AE.
The study drug will be immediately discontinued if a condition meets any following criteria 
during the treatment, and appropriate follow-up will be performed (clinical laboratory tests 
will be repeatedly performed until the clinical laboratory test profiles have normalized or 
returned to baseline, refer to Section 9.2.9.1):
•
Liver Function Test (LFT) Abnormalities
-
ALT or AST >8×the upper limit of normal (ULN), or
-
ALT or AST >5×ULN and persists for more than 2 weeks, or
-
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (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%)
•
Prolonged QT/QTcF intervals
If at least one remarkable prolonged QT interval was observed on 12-lead ECG (eg, 
absolute value of QTcF intervals >500 msec or an increase >60 msec from baseline), and 
the investigator or sub-investigator considered inappropriate to continue the study.
3. Protocol deviation
The discovery after the start of the first study drug administration 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. Pregnancy
If a subject was found to be pregnant.
Note: Participation in the study is immediately discontinued for any pregnancy. Refer to 
Appendix B for the procedures.
6. Voluntary withdrawal
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).
7. Study terminated by the Sponsor
The Sponsor terminates the study.
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8. 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
The Part 1 in Cohort 1 and Cohorts 2-4 can have a few reserve subjects considered eligible for 
participation in the study based on screening test. If a subject has not received the study drug as 
scheduled during the study owing to any reason occurring before the study drug administration, a 
reserve subject will be allowed to participate in the study.
If a subject withdraws from the study after initiation of the study drug, the subject will not be 
replaced with a reserve subject.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
[Drug product]
Code name: TAK-831
Dosage form and strength:
TAK-831 tablet is a yellowish-red film-coated tablet containing 25 or 300 mg of TAK-831.
TAK-831 placebo tablet contains no TAK-831 and has same appearance as TAK-831 tablet.
8.1.1
Clinical Study Drug Labeling
Study drug labeling will show name of the study drug, quantity and storage condition of the study 
drug, manufacture number, expiration date, protocol number, name and address of the Sponsor, 
and statement the drug is for clinical trial use only.
8.1.2
Clinical Study Drug Inventory and Storage
TAK-831 is stored at a room temperature (1°C to 30°C).
Study drug must be kept in an appropriate, limited-access, secure place until it is used, or returned
to the Sponsor or its designee. Study drug must be stored under the conditions specified on the
label, and remain in the original container until dispensed.
8.1.3
Randomization Code Creation and Storage
The personnel responsible for randomization (the Sponsor's designee) will prepare the
randomization table/schedule prior to the start of the study. All randomization information will be 
stored in a secured area, accessible only by authorized personnel.
8.1.4
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 will be 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.
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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 eCRF.
If the investigator or sub-investigator breaks the blinding of the study drug, 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 (except cases where the 
investigator or sub-investigator is not informed of unblinding information [unblinding for 
open-label analysis for the Sponsor]).
8.1.5
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 managing 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.
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 Number
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
In Cohorts 1-2 and Cohorts 3-4 (if added), the subjects will be assigned in the order of medication 
identification number by Cohort according to the randomization code. The medication 
identification number will be a 4-digit number, starting with the following number:
Cohort 1: 1001, Cohort 2: 2001, Cohort 3: 3001, Cohort 4: 4001
The assigned medication identification number will be used to identify the samples for PK by the 
study site and the only number to identity a subject during blood sampling for PK. The number will 
be always shown on the sample vials, which are sent to the laboratory to evaluate the PK. The 
laboratory will report the results using this number. The number will be used for only the purpose 
described in this section and cannot be replaced with the 7-digit subject identification number, 
which is assigned at the time of informed consent procedure and used in all other procedures 
during the clinical study period to identify a subject. In case of subject replacement, the study drug 
with a medication identification number for the withdrawn subject will be used by the replacing 
subject.
9.1.2
Inclusion and Exclusion
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, height, weight, caffeine 
use, alcohol use, and smoking status of the subject.
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Medical history to be obtained will include determining whether the subject has any clinically 
significant conditions or diseases that resolved within 1 year prior to the signing of informed 
consent. Ongoing conditions will be considered concurrent medical conditions. Medication history 
information to be obtained will include 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. 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 drugs, 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 is calculated using the formula provided below.
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.
9.2.4
Vital Signs
Vital signs will include body temperature (axilla measurement), sitting blood pressure (systolic 
and diastolic, after resting more than 5 minutes), and pulse (beats per minute).
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.
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The investigator or sub-investigator (or a qualified observer at the investigational site) will 
interpret the ECG using one 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.
9.2.6
Columbia Suicide Severity Rating Scale (C-SSRS)
C-SSRS will be performed at the study procedures-specified time point. The investigator or 
sub-investigator will evaluate suicide risks based on the information obtained from C-SSRS. For 
any suicidal ideation and suicidal behavior will be documented as an adverse event.
9.2.7
Study Drug Administration
In Cohort 1, a single dose of TAK-831 T3 tablet 25 mg×4 tablets or placebo will be orally 
administered on Day 1 (Part 1), and a single dose of TAK-831 T3 tablet 300 mg×1 tablet or 
placebo will be orally administered on Day 9 (Part 2).
In Cohort 2, a single dose of TAK-831 T3 tablet 300 mg×2 tablets or placebo will be orally 
administered on Day 1, followed by multiple doses of TAK-831 T3 tablet 300 mg×2 tablets (once 
daily) or placebo on Days 4-17.
The study drug will be orally administered with 150 mL of water at a fasted state (fasted at least 10 
hours before administration).
In Cohorts 3 and 4, the dose of the study drug will be determined based on the data obtained from 
Cohorts 1 and 2.
9.2.8
AE Monitoring
AE monitoring will begin after the signing of informed consent. A complete description of AE
collections and procedures is provided in Section 10.2.
9.2.9
Laboratory Procedures and Assessments
Laboratory samples will be taken following a minimum 10 hour overnight fast on the days 
stipulated in the Schedule of Study Procedures (Section 3.0). Refer to Appendix C for the amount 
of blood samples.
The investigator or sub-investigator will take responsibility for evaluation of the clinical 
laboratory test results and storage. The investigator will maintain a copy of the reference ranges for 
the laboratory used.
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
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Red blood cell count
White blood cell count and differential leukocytes 
(lymphocytes, neutrophils, eosinophils, basophils, and 
monocytes)
Hemoglobin
Hematocrit
Platelet count
Chemistry
Chemistry evaluations will consist of the following chemistry tests:
Albumin
Creatinine
ALP
Glucose
ALT
Sodium
AST
Calcium
γ-GTP
Creatine kinase
Total bilirubin
Potassium
Direct bilirubin
Chloride
Total protein
PT
Urea nitrogen
APTT
Urinalysis
Urinalysis will consist of the following tests:
pH
Specific gravity
Qualitative (protein, glucose, occult blood, and nitrite)
Urinary sediment (erythrocytes, leukocytes, and cylinder) 
(a)
(a)
Will be performed for any abnormal urinalysis parameter.
Other
Immunological tests
HIV antibody and antigen tests, hepatitis tests (HBs antigen and HCV antibody)
Alcohol tests (urinalysis or breath test)
Urinary drug tests
FSH (postmenopausal female subjects only)
HIV: human immunodeficiency virus, HBs: hepatitis B surface antigen, HCV: hepatitis C virus, FSH: 
follicle-stimulating hormone
Note: The investigator or sub-investigator will report the results of immunology, urine drug tests, and alcohol tests
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.
If subjects experience an ALT or AST of >3×ULN (except the tests at Screening), follow-up 
laboratory tests (at a minimum, serum alkaline phosphatase [ALP], ALT, AST, total bilirubin, 
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gamma-glutamyl transferase [γ-GTP], 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 10.2.9.4 for the discontinuation or withdrawal criteria of a subject
and the appropriate guidance on reporting abnormal LFTs as SAEs, respectively.
9.2.9.2
Urine sample for Future Tests
Urine samples for future tests will be collected according to the Schedule of Study Procedures 
(Section 3.0).
If acute renal failure is suspected, urinary biomarkers such as KIM-1, NGAL, and cyctatin C may 
be measured using the collected sample.
9.3
Biomarker, PK, PD, and PGx Samples
Samples for PK, PD, and PGx will be collected according to the schedule of study procedures 
(Section 3.0). Separated procedures describe the details of sampling, handling, and transferring to 
central laboratory. The actual sampling time for PK and PD analyses will be documented in the 
subject’s source documents and eCRF.
Table 9.a shows primary specimen collections.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of
Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
PK Analysis
Mandatory
Plasma sample for PD
Blood
Plasma
PD analysis
Mandatory
Cerebrospinal fluid sample for PD Cerebrospinal fluid Cerebrospinal fluid
PD analysis
Optional
Blood sample for DNA PGx
Blood
DNA
PGx analysis
Optional
9.3.1
PK Measurements
The following PK parameters will be calculated from plasma concentrations of TAK-831, unless 
otherwise specified.
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Mark/Term
Definition
Plasma
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
Area under the plasma concentration-time curve from time 0 to time of infinity
AUCτ
Area under the plasma concentration-time curve during a dosing interval
Cmax
Maximum observed plasma concentration (measured value)
Cmax, ss
Maximum observed steady-state plasma concentration during a dosing interval (measured value)
tmax
Time of first occurrence of Cmax
t1/2z
Terminal disposition phase half-life
λz
Terminal disposition phase rate constant
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration
CL/F
Apparent clearance after extravascular administration
Rac(Cmax)
Accumulation ratio based on Cmax
Rac(AUC)
Accumulation ratio based on AUC
9.3.1.1
Plasma for PK Measurements
Blood samples for plasma TAK-831 concentration will be collected (Table 9.b). The sampling 
schedule may change based on emerging data but the number of samples will not exceed the 
number of planned samples.
Table 9.b
Blood Sample Collection for PK Analysis
Dose Levels:
Date of 
administration
Sampling time
Single dose
1
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
9
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
1
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, and 48 hours postdose
4, 11, 14
Predose
17
Predose, 0.5, 1, 1.5, 2, 4, 8, 12, 16, and 24 hours postdose
9.3.2
PD Analysis
The following PD parameters will be calculated from plasma concentrations of D-serine and 
L-serine, unless otherwise specified
Mark/Term
Definition
Plasma
AUEC24
Area under the effect-time curve from time 0 to 24 hours postdose
Emax
Maximum effect
time to Emax
Time to reach maximum PD effect
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9.3.2.1
Plasma Samples for PD Analysis
Blood samples will be collected to measure plasma D-serine and L-serine concentrations (Table 
9.c). The sampling schedule may change based on emerging data but the number of samples will 
not exceed the number of planned samples.
Table 9.c
Blood Sample Collection for PD Analysis
Dose Levels:
Specimen
Date of 
administration
Sampling time
Single dose
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, 24, 36, 48 and 
72 hours postdose
9
Predose, 1, 4, 8, 12, 24, 36, 48 and 72 hours postdose
Single 
dose+multiple dose 
(once daily)
Plasma
1
20, 16, and 12 hours predose, predose, 1, 4, 8, 12, and 24 hours 
postdose
11, 14
Predose
17
Predose, 1, 4, 8, 12, and 24 hours postdose
9.3.2.2
Cerebrospinal fluid samples for PD Analysis
Cerebrospinal fluid will be collected to measure D-serine and L-serine concentrations (3.0 mL per 
scheduled time). The cerebrospinal fluid sampling schedule may change based on emerging data 
but the number of samples will not exceed the number of planned samples. After Cohort 3, 
collection of cerebrospinal fluid in the next Cohorts will be determined based on the results of 
plasma D-serine and L-serine concentrations obtained from the previous Cohorts.
9.3.3
PGx Measurements
9.3.3.1
Blood Sample for DNA PGx Measurements
When sampling of whole blood for pharmacogenomic analysis occurs, the subject must sign 
informed consent/be consented separately for PGx sampling, storage and analysis. PGx 
measurement is a part of the study, but participation of a subject is optional.
One 6-mL of whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected 
prior to the single dosing on Day 1 from each consenting subject in the study.
The samples will be stored for no longer than 15 years after completion of the TAK-831 study 
and/or until the drug development of TAK-831 is no longer actively pursued. No samples will be 
stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification by the Sponsor. “Stored samples” are defined as samples that are coded (the samples 
are stripped of all personal identifying information but a key links the samples to the clinical data 
collected from the sample donor) and are used in the analysis of the study drug or related drug.
The sampling of whole blood for PGx and genotyping analysis is mandatory. Every subject must 
sign informed consent separately for PGx sampling. DNA samples will be used to evaluate drug 
metabolic enzyme and transporter polymorphisms.
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Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of some of this gene in drug response, which may lead to additional 
exploratory research with the samples for PGx measurements.
9.3.4
Confinement
Cohort 1:
Subjects will be hospitalized from Day -1 to Day 4 and Day 8 to Day 12 and will be discharged 
after the investigator or sub-investigator confirm no clinically significant health problems based 
on the examination and tests on Days 4 and 12.
Cohorts 2-4:
Subjects will be hospitalized from Day -1 to Day 19 and will be discharged after the investigator or 
sub-investigator confirm no clinically significant health problems based on the examination and 
tests on Day 19.
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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 clinical study; it does not necessarily have to have a 
causal relationship with the the treatment (including the study drug) 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 treatment (including the study drug) or study 
procedures.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing 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 may be considered as 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 for an abnormal value are not considered as 
an intervention. In addition, repeated or additional non-invasive tests for verification and 
evaluation of abnormality or monitoring purpose will not be considered as an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a
concurrent medical history conditions and should NOT be recorded as an AE. The
observations or evaluations of first examination at baseline (eg, laboratory test, ECG, X-ray, 
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etc) should NOT be recorded as AEs unless related to a study procedure. However, if the 
subject experiences a worsening or complication of such a concurrent medical history 
condition, the worsening or complication should be recorded appropriately as an AE 
(worsening or complication occurs after informed consent is signed). 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. 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 pre-existing chronic 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. 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 drug or after any change in study drug, the worsening or complication should be
recorded as a new AE. The investigator or sub-investigator should ensure that the event term 
reported captures the change in adverse event (eg, “worsening of…”).
Changes in severity of AEs:

If a subject experiences a change in the severity of an AE that is not associated with a change in 
study drug, 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 the signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
earlier (eg, as an emergency) due to a worsening of a 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 study 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 sub-investigator to decide whether a dose is 
to be considered as overdose, in consultation with the Sponsor.
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in 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 (ADRS)
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Malignant hypertension
Convulsive seizures (includes convulsion and epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (includes interstitial pneumonia)
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Confirmed or suspected endotoxin shock
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
Severity/Intensity of AEs will be classified or defined as follows:
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 causality 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 disease, 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 the underlying disease, complications, 
concomitant medications and concurrent treatments.
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.
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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 or sub-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 drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable - a study drug was stopped for a reason other than the particular AE; eg, the 
clinical study has been terminated, the subject died, dosing with study drug had not yet started 
or dosing with study drug 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/signs/symptoms have almost disappeared; the abnormal laboratory values improved, 
but have 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 values on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
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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 and continue until the follow-up visit or phone call.
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 the study drug must be monitored until the 
symptoms have resolved and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Nonserious AEs that begin prior to 
the first exposure to the study drug, regardless of related or unrelated to the study procedure, need 
not be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug 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 Adverse Event (Frequency)

Severity/Intensity.

The Investigator’s or sub-investigator’s opinion of the causal relationship between the event 
and administration of study drug(s). (Related/Not related)

Action taken with the study drug

Outcome of the event.

Seriousness.

Timing of occurrence (after administration of the study drug)
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 within 1 
business day of the first onset or notification of the SAE, along with any relevant information. The 
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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 drug(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 the follow-up SAE form or provide other written 
documentation immediately to the Sponsor. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory values, discharge summary, postmortem results) in the institution should be 
submitted to the Sponsor, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event.
10.2.9.4 Reporting of Abnormal LFTs
If a subject experiences 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 will contact the monitor for discussion 
and investigation of the relevant subject details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease, medical history/ongoing disease. Follow-up 
laboratory tests as described in Section 9.2.9 must also be performed.
10.2.10
Safety Reporting to Investigators, IRBs and Regulatory Authorities
The Sponsor will report all suspected unexpected serious adverse reactions (SUSARs) and any 
other applicable SAEs to regulatory authorities, investigators, IRBs and the head of the study site. 
Relative to the first awareness of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening events and 15 
days for other serious events, unless otherwise required by national regulations. The Sponsor will 
also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of the study drug or that would be sufficient to consider changes in 
the study drug administration or in the overall conduct of the trial. The study 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 unblinding of subject’s 
treatment assignment. 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, 3 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.
The Sponsor will verify the validity of the definitions of the analysis sets and the rules for handling
data in consultation with a medical expert, as needed, prior to unblinding the study drug 
assignment. The Sponsor will address all remaining uncertainties not specified at planning, and 
will finalize the SAP prior to unblinding of subject’s treatment assignment.
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, and who 
were appropriately evaluable for at least 1 PK parameter.
11.1.1.3 PD Analysis Set
The PD Analysis Set will consist of subjects who received at least one dose of study drug, and who 
were appropriately evaluable for at least 1 PD parameter.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the Safety Analysis 
Set.
11.1.3
PK Analysis
Endpoints and its analytical method
[Endpoints]
Secondary endpoints: Cmax (Cohort 1, Day 1 in Cohorts 2 to 4), Cmax,ss (Day 17 in Cohorts 2 to 4), 
tmax (Cohort 1, Days 1 and 17 in Cohort 2 to 4), AUClast (Cohort 1, Day 1 in Cohorts 2 to 4), AUC∞
(Cohort 1, Day 1 in Cohorts 2 to 4), AUCτ (Days 1 and 17 in Cohorts 2 to 4)
Exploratory endpoints: Rac(Cmax) and Rac(AUC) (Cohort 2 to 4) on Days 1 and 17, t1/2z, CL/F, Vz/F
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[Analytical method]
In the “PK analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and treatment period for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of TAK-831 in plasma will be summarized by each scheduled sampling time using 
summary statistics. Individual plasma concentration data versus time will be presented. Plasma PK 
parameters, including dose-normalized Cmax and AUC, will be summarized by dose and day using 
summary statistics. Accumulation of TAK-831 from Day 1 to Day 17 will be assessed by 
summarizing the ratio of Cmax and AUC at Days 1 and 17 by dose. Dose linearity in plasma PK 
parameters (Cmax and AUC) will be assessed graphically for those parameters at Day 1 and Day 9 
for Cohort 1 and Day 1 for Cohorts 2 to 4. Additional analyses on dose linearity will be included if 
appropriate.
11.1.4
PD Analysis
Endpoints and its analytical method
[Endpoints]

Concentrations of D-serine, L-serine, and the ratio of D-serine to total serine in plasma, 
AUEC24, Emax and time to Emax

Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal 
fluid (on Days -1 and 18) (if available)
[Analytical method]
In the “PD analysis set”, the following analyses will be performed by dose for Cohort 1 and by 
dose and each scheduled sampling time for Cohorts 2 and 4, as well as Cohort 3.
Concentrations of D-serine, L-serine and the ratio of D-serine to total serine in plasma and 
concentrations of D-serine, L-serine and the ratio of D-serine to total serine in cerebrospinal fluid 
(if available) will be summarized by each scheduled sampling time using summary statistics. 
AUEC, Emax and time to Emax of D-serine, L-serine at Days -1 and 1 and 17, and the ratio of 
D-serine to total serine in plasma, and change and percent the change from baseline will be 
summarized by day using summary statistics. The potential relationship between TAK-831 
exposure and biomarker response will be explored graphically. Additional statistical or PK-PD 
analyses will be included if appropriate.
11.1.5
Safety Analysis
Endpoints and its analytical method
[Endpoints]
AEs, laboratory findings, vital signs, weight, 12-lead ECG
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[Analytical method]
In the “safety analysis set”, the following analyses will be performed by dose for Cohort 1, for 
Cohorts 2 and 4, and for Cohort 3.
11.1.5.1 AEs
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset occurs on or 
after the start of study drug.
The followings will be analyzed for TEAEs. TEAEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT).

Frequency of all TEAEs

Frequency of drug-related TEAEs

Frequency of all TEAEs by intensity

Frequency of drug-related TEAEs by intensity

Frequency of TEAEs leading to study drug discontinuation

Frequency of serious TEAEs
11.1.5.2 Clinical Laboratory Evaluation
Summary statistics will be provided for observed values and change from baseline at each 
evaluation time point. Pre- and post-dose shift tables will be prepared for categorical variables.
11.1.5.3 Vital Signs
Summary statistics will be provided for the observed values at each evaluation time point and 
changes from baseline.
11.1.5.4 Other Safety Parameters
The ECG parameters will be summarized as follows. Summary statistics will be calculated for 
observed values and change from baseline at each evaluation time point. Pre- and post-dose shift 
tables will be prepared for categorical variables. The analysis methods for other endpoints will be 
specified in detail in the SAP.
11.2
Determination of Sample Size
Each cohort will include 8 subjects (6 for TAK-831, 2 for placebo) which is the sample size 
required to assess the safety, tolerability, and PK of each cohort. This is not based on any statistical 
rationale.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its
designee (Contract Research Organization) and by the IRB.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, and 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 study site of the deviation
or changes 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 study 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 study site also may be subject to quality assurance audits by the Sponsor or designees. In this
circumstance, the Sponsor-designated auditor will contact the study 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], and the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). If the study site is contacted for an inspection by a 
regulatory authority, the Sponsor should be notified immediately. The investigator and the head of 
the institution 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 Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline for GCP. The
investigator will conduct the study according to applicable local or regional regulatory 
requirements in accordance with the “Responsibilities of the Investigator” that are listed in
Appendix A.
13.1
IRB Approval
The IRB must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or the designee will require documentation noting all names and titles of the 
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 the 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 
written informed consent form, and, if applicable, subject recruitment materials and/or 
advertisements, if applicable, and other documents required by all applicable laws and regulations, 
must be submitted to the IRB for approval. The IRB’s written approval of the protocol and subject 
written informed consent must be obtained and submitted to the Sponsor or the 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, written informed consent 
form) reviewed; and state the approval date. The Sponsor will notify the study site that the Sponsor 
has confirmed the adequacy of the study site regulatory documentation. Until the study site
receives a notification, no protocol activities, including screening, may occur.
The study site must adhere to all requirements stipulated by its respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the written 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 the Sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The written informed consent form describes the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
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The informed consent form will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care.
The investigator is responsible for the preparation, content, and IRB approval of the written 
informed consent form. The written informed consent form must be approved by both the IRB and 
the Sponsor prior to use.
The informed consent form must be described 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 or she will participate 
in the clinical 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 by 
the investigator or sub-investigator to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator or sub-investigator must also sign and date the informed 
consent form 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 will 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.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify the Sponsor of consent 
withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this 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.
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, and PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
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including 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 the facility name, investigator’s city, state (for Americas
investigators), country, and recruiting status will be registered and available for public viewing.
13.5
Clinical Trial Results Disclosure
Takeda will post the results of the clinical study on ClinicalTrials.gov or publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.6
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
study site where the subject is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to study subjects.
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator or sub-investigator has questions regarding this policy, he 
or she should contact the Sponsor or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.2
Investigator Agreement
A separate agreement will be provided to the study site.
14.1.3
Study-Related Responsibilities
A separate contact information list (Protocol attachment 1) will be provided to the study site.
14.1.4
List of Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUEC
area under the effect-time curve
BMI
body mass index
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
DAAO
D-amino acid oxidase
DNA
deoxyribonucleic acid
Emax
maximum effect
FDA
Food and Drug Administration
FRDA
Friedreich ataxia
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
γ-GTP
gamma-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation of Technical Requrements for Pharmaceuticals for Human 
Use
INR
international normalized ratio
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
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Term
Definition
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
PET
positron emission tomography
PMDA
Pharmaceuticals and Medical Devices Agency
PT
prothrombin time
POC
proof-of-concept
Rac
accumulation ratio
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
tmax
time of first occrurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply the study sites with access to eCRFs. The Sponsor will 
provide training opportunities for the site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the Sponsor 
(or the designee) and will be answered by the study site.
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The investigator must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the eCRFs.
The following data will not be recorded in the eCRFs.

PGx analysis results

Clinical laboratory test results

Drug concentration measurement results

PD measurement results
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 or sub-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 study site during periodic visits 
by the Sponsor or its designee. 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 or the head of the study site agree to keep the records stipulated in Section 15.1
and those documents that include (but not limited to) the study-specific documents, the
identification log of all participating subjects, medical records, all original signed and dated
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its
designees.
The investigator and the head of the study site are required to retain 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 study 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 study 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]
Sham PC, Gottesman, II, MacLean CJ, Kendler KS. Schizophrenia: sex and familial 
morbidity. Psychiatry Res 1994;52(2):125-34.
[2]
Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, et al. 
Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen 
Psychiatry 1999;56(2):162-8.
[3]
Erlenmeyer-Kimling L, Squires-Wheeler E, Adamo UH, Bassett AS, Cornblatt BA, 
Kestenbaum CJ, et al. The New York High-Risk Project. Psychoses and cluster A 
personality disorders in offspring of schizophrenic parents at 23 years of follow-up. Arch 
Gen Psychiatry 1995;52(10):857-65.
[4]
van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
[5]
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor 
antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm 
shift in medication development. Psychopharmacology (Berl) 2003;169(3-4):215-33.
[6]
Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, et al. Plasma 
levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 
2012;142(1-3):83-7.
[7]
Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, et al. Changes in plasma 
glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical 
symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). 
Prog Neuropsychopharmacol Biol Psychiatry 2008;32(8):1905-12.
[8]
Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. 
Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of 
the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen 
Psychiatry 2003;60(6):572-6.
[9]
Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to 
total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog 
Neuropsychopharmacol Biol Psychiatry 2005;29(5):767-9.
[10] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights 
from 108 schizophrenia-associated genetic loci. Nature 2014;511(7510):421-7.
[11] Japan Sciety for the Study of Obesity. Diagnostic Criteria for Obesity 2011. Journal of Japan 
Society for the Study of Obesity, 2011 Oct; additional edition.
[12] General Considerations for Clinical Trials (Notification No. 380 of the Evaluation and 
Licensing Division, PMSB dated April 21, 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 study site in advance to get them accepted.
3. Prepare a written informed consent form 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 study 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 study site and the Sponsor 
in writing.
11. Determine the need of emergency key code unblinding 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 study site of the end of the study in writing.
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Appendix B
Pregnancy and Contraception
Male Subjects and Their Female Partners
From the signing of informed consent, throughout the duration of the study, and for 95 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 or subjects should refrain from having sexual 
intercourse from 1 month prior to the first study drug administration throughout the study period 
and until 35 days after the last study drug administration. 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.
Female Subjects and Their Male Partners
Female subjects of childbearing potential* will be excluded from this study.
* 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 device (IUD)
Hormonal contraceptives
Male condoms with a spermicide
Copper T PLUS condom
Progesterone T PLUS condom
Combined pill
Subjects will be provided with information on acceptable methods of contraception for 95 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 95 days after their last dose of study drug.
Pregnancy
If any subject is found to be pregnant during the study, the subject should immediately discontinue 
the study drug and be withdrawn from the study. In addition, if any pregnancies in the partner of a 
male subject, during the study or for 95 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.
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If the female subject or 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 she or his 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).
All female subjects and the the female partners of male subjects who became pregnant will be 
followed to final outcome, using the pregnancy form, with the consent of the female subjects or 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
<Cohort 1>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 1, 4, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Study treatment period 
(Part 1)
Day 1 72 hours postdose
Day 4 from awakening
to discharge
Washout period
Day 8
Not applicable
Study treatment period 
(Part 2)
Day 9 72 hours postdose
Day 12 from
awakening to 
discharge
Follow-up period
Day 23
Within ± 2 days
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Variables
Timing of procedures (standard)
Acceptable window
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 and 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 predose
From awakening to 
immediately prior to 
dose
Day 9 2 and 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicabled
Treatment period (Part 1)
Day 1 72 hours postdose
Within ± 15 minutes
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 9 72 hours postdose
Within ± 15 minutes
Follow-up period
Day 23
Within ± 2 days
Urinary drug tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Washout period
Day 8
Not applicable
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 4
From awakening to 
discharge
Washout period
Day 8
Not applicable
Treatment period (Part 2)
Day 12
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period (Part 1)
Day 1 predose
Not applicable
Blood samples for PK
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
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Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period (Part 1)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Treatment period (Part 2)
Day 9 predose
Within 15 minutes 
predose
Day 9 1 hour postdose
Within ± 5 minutes
Day 9 4, 8, 12, 24, 36, 48, and 72 hours 
postdose
Within ± 15 minutes
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period (Part 1)
Day 1 24 hours postdose
Within ± 2 hours
Treatment period (Part 2)
Day 9 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, and FSH
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TAK-831
Study ID: TAK-831-1002
Page 70 of 73
Protocol
30 July 2018
CONFIDENTIAL
<Cohorts 2-4>
Variables
Timing of procedures (standard)
Acceptable window
Testing at the time of 
determination of 
eligibility (a)
Screening
Days -28 to -2
Not applicable
Physical Exam
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
Vital Signs
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 1, 4, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Days 5-10 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Days 12-13 predose
From awakening to 
immediately prior to 
dose
Day 14 predose
From awakening to 
immediately prior to 
dose
Days 15-16 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 1, 4, 12, 24, and 48 hours 
postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
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TAK-831
Study ID: TAK-831-1002
Page 71 of 73
Protocol
30 July 2018
CONFIDENTIAL
Variables
Timing of procedures (standard)
Acceptable window
Weight
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 48 hours postdose
Day 19 from
awakening to 
discharge
Follow-up period
Day 31
Within ± 2 days
12-Lead ECG
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 predose
From awakening to 
immediately prior to 
dose
Day 1 2 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
From awakening to 
immediately prior to 
dose
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 predose
From awakening to 
immediately prior to 
dose
Day 17 2 and 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
Clinical Laboratory 
Tests
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 11 predose
From awakening to 
immediately prior to 
dose
Day 17 48 hours postdose
Within ± 15 minutes
Follow-up period
Day 31
Within ± 2 days
C-SSRS
Screening
Days -28 to -2
Not applicable
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 19
From awakening to 
discharge
Samples for PGx 
measurements
Treatment period
(Single dose part)
Day 1 predose
Not applicable
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TAK-831
Study ID: TAK-831-1002
Page 72 of 73
Protocol
30 July 2018
CONFIDENTIAL
Variables
Timing of procedures (standard)
Acceptable window
Blood samples for PK
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 0.5, 1, 1.5 and 2 hours postdose Within ± 5 minutes
Day 1 4, 8, 12, 24, 36 and 48 hours 
postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 4 predose
Within 15 minutes 
predose
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 0.5, 1, 1.5, and 2 hours 
postdose
Within ± 5 minutes
Day 17 4, 8, 12, 16 and 24 hours 
postdose
Within ± 15 minutes
Blood samples for PD
Hospitalization
Day 1 20, 16, and 12 hours predose
Within ± 15 minutes
Treatment period
(Single dose part)
Day 1 predose
Within 15 minutes 
predose
Day 1 1 hour postdose
Within ± 5 minutes
Day 1 4, 8, 12, and 24 hours postdose
Within ± 15 minutes
Treatment period
(Multiple dose part)
Day 11 predose
Within 15 minutes 
predose
Day 14 predose
Within 15 minutes 
predose
Day 17 predose
Within 15 minutes 
predose
Day 17 1 hour postdose
Within ± 15 minutes
Day 17 4, 8, 12, and 24 hours postdose Within ± 15 minutes
Cerebrospinal fluid 
samples for PD
(If performed after 
Cohort 3)
Hospitalization
Day -1
Not applicable
Treatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 3 hours
Urine sample (for 
future tests)
Hospitalization
Day -1
Not applicable
Treatment period
(Single dose part)
Day 1 24 hours postdose
Within ± 2 hours
Teatment period
(Multiple dose part)
Day 17 24 hours postdose
Within ± 2 hours
(a)
Includes height, BMI, HIV antibody and antigen tests, hepatitis tests, FSH, and urinary drug tests
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TAK-831
Study ID: TAK-831-1002
Page 73 of 73
Protocol
30 July 2018
CONFIDENTIAL
Total blood sampling volumes for an individual subject is shown below:
<Cohort 1>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total Volume
(mL)
Screening
Day -1
Days 1-4
Day 8
Days 9-12
Clinical Laboratory 
Tests
20
1
1
1
1
1
100
Blood sampls for PK
4
-
-
12
-
12
96
Blood sampls for PD
6
-
3
9
-
9
126
Samples for PGx 
Measurements
6
-
-
1
-
-
6
Total Blood Sampling Volume
328
-: No blood collection
<Cohorts 2-4>
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total 
Volume
(mL)
Screening Day -1 Day 1
Day 2
Day 3
Day 4 Day 11 Day 14 Days
17-18 Day 19
Clinical Laboratory 
Tests
20
1
1
-
-
-
-
1
-
-
1
80
Blood sampls for PK
4
-
-
8
2
1
1
1
1
10
-
96
Blood sampls for PD
6
-
3
5
1
-
-
1
1
6
-
102
Samples for PGx 
Measurements
6
-
-
1
-
-
-
-
-
-
-
6
Total Blood Sampling Volume
284
-: No blood collection
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use