Conditions: Healthy
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of TAK-831 when administered as multiple oral doses at escalating dose levels in healthy participants.

Detailed description:
This study is a randomized, investigator and participant blinded, sponsor unblinded, placebo-controlled, study of the safety, tolerability and pharmacokinetics of TAK-831 in up to 48 healthy volunteers, with 8 subjects in each of the 6 cohorts.

In each cohort, participants will be randomized in a 3:1 ratio to receive TAK-831 or placebo. Two formulations, oral suspension and tablet will be tested in this study. Both blood and cerebrospinal fluid (CSF) samples will be collected from selected cohorts (CSF cohorts); for the rest of the cohorts, only blood samples will be collected (non-CSF cohorts).

This single-center trial will be conducted in the United States. The overall time to participate in this study is 58 days. Participants will make multiple visits to the clinic, and 30 days after last dose of study drug for a follow-up assessment.

Arms:
arm 1: TAK-831 placebo-matching suspension, orally, once daily (QD) for up to Day 16. arm 2: TAK-831 100 mg, tablets, orally, QD on Days 1 and 3 to 16. arm 3: TAK-831 300 mg, tablets, orally, QD on Days 1 and 3 to 16. arm 4: TAK-831 600 mg, tablets, orally, QD on Days 1 and 3 to 16. arm 5: TAK-831 15 mg, suspension, orally, multiple doses (MD) daily, on Days 1 and 3 to 16. arm 6: TAK-831 800 mg, suspension, orally, QD on Day 1, MD on Days 3 to 16. arm 7: TAK-831 1200 mg, suspension, orally, QD on Day 1, MD on Days 3 to 16.

Interventions: intervention 1: TAK-831 Tablet T2 intervention 2: Placebo intervention 3: TAK-831 Suspension
Intervention descriptions: intervention 1: Tak-831 tablets. intervention 2: TAK-831 placebo-matching suspension. intervention 3: TAK-831 Suspension.

Protocol document:
Prot_000.pdf: 


•
Title: A Randomized, Investigator and Subjects Blinded, Sponsor Unblinded, Placebo-Controlled, 
Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Multiple Doses 
of TAK-831 in Healthy Subjects
NCT Number: NCT03224325
Protocol Approve Date: 19 March 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Investigator and Subject Blinded, Sponsor Unblinded, Placebo-Controlled, 
Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Multiple 
Doses of TAK-831 in Healthy Subjects
Study Identifier:
TAK-831-1005
Compound:
TAK-831
Date:
19 March 2018
Version/Amendment 
Number:
Amendment No. 02
Amendment History:
Date
Amendment Number
Region
08 June 2017
Initial version
Global
15 August 2017
01
Global
19 March 2018
02
Global
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
1.1
Protocol Amendment No. 02 Summary of Changes ...................................................9
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 ...................................................................17
5.1
Trial Objectives .......................................................................................................17
5.1.1
Trial Primary Objective......................................................................................17
5.1.2
Trial Secondary Objective..................................................................................17
5.1.3
Trial Exploratory Objectives ..............................................................................17
5.2
Endpoints.................................................................................................................17
5.2.1
Primary Endpoints .............................................................................................17
5.2.2
Secondary Endpoints..........................................................................................17
5.2.3
Exploratory Endpoints .......................................................................................18
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................19
6.1
Trial Design.............................................................................................................19
6.2
Dose Escalation .......................................................................................................20
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................22
6.3.1
Rationale of Trial Design ...................................................................................22
6.3.2
Rationale for Dose .............................................................................................22
6.3.3
Rationale for Endpoints......................................................................................23
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................24
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................24
6.5
Trial Beginning and End/Completion.......................................................................25
6.5.1
Definition of Beginning of the Trial ...................................................................25
6.5.2
Definition of End of the Trial.............................................................................25
6.5.3
Definition of Trial Completion...........................................................................26
6.5.4
Definition of Trial Discontinuation ....................................................................26
6.5.5
Criteria for Premature Termination or Suspension of the Trial............................26
6.5.6
Criteria for Premature Termination or Suspension of a Site................................27


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6.5.7
Procedures for Premature Termination or Suspension of the Study or a Site.......27
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............28
7.1
Inclusion Criteria .....................................................................................................28
7.2
Exclusion Criteria ....................................................................................................28
7.2.1
Additional Exclusion Criteria for Cohort(s) With CSF Collection ......................30
7.3
Excluded Medications, Supplements, Dietary Products............................................31
7.4
Diet, Fluid, Activity.................................................................................................32
7.4.1
Diet and Fluid ....................................................................................................32
7.4.2
Activity..............................................................................................................32
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................33
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................34
7.7
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
Clinical Study Drug Blinding.............................................................................35
8.1.4
Randomization Code Creation and Storage ........................................................35
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................35
8.1.6
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 .....................................................................................38
9.1.3
Medical History/Demography ............................................................................38
9.1.4
Medication History/Concomitant Medications ...................................................38
9.2
Clinical Procedures and Assessments.......................................................................38
9.2.1
Full Physical Examination..................................................................................38
9.2.2
Height and Weight .............................................................................................39
9.2.3
BMI ...................................................................................................................39
9.2.4
Vital Signs .........................................................................................................39
9.2.5
ECGs .................................................................................................................39
9.2.6
C-SSRS..............................................................................................................41
9.2.7
Study Drug Administration ................................................................................41
9.2.8
AE Monitoring...................................................................................................42


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9.2.9
Laboratory Procedures and Assessments ............................................................42
9.3
PK, PD, and PGx, Samples ......................................................................................43
9.3.1
PK Measurements..............................................................................................44
9.3.2
PD Measurements..............................................................................................44
9.3.3
PGx Measurements ............................................................................................45
9.3.4
Total Blood Volume...........................................................................................45
9.3.5
Confinement ......................................................................................................45
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions and Elements of AEs .............................................................................47
10.1.1 SAEs..................................................................................................................49
10.1.2 Special Interest AEs...........................................................................................50
10.2
AE Procedures.........................................................................................................50
10.2.1 Assigning Severity/Intensity of AEs...................................................................50
10.2.2 Assigning Causality of AEs................................................................................50
10.2.3 Start Date...........................................................................................................50
10.2.4 End Date............................................................................................................51
10.2.5 Pattern of AE (Frequency) .................................................................................51
10.2.6 Action Taken With Study Treatment..................................................................51
10.2.7 Outcome ............................................................................................................51
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................52
10.2.9 Safety Reporting to Investigators, IRBs or IECs, 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 .......................................................................................................56
11.1.4 PD Analysis .......................................................................................................56
11.1.5 Safety Analysis ..................................................................................................56
11.2
Interim Analysis and Criteria for Early Termination ................................................57
11.3
Determination of Sample Size..................................................................................57
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................58
12.1
Study-Site Monitoring Visits ...................................................................................58
12.2
Protocol Deviations..................................................................................................58
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................58
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................59


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13.1
IRB and/or IEC Approval ........................................................................................59
13.2
Subject Information, Informed Consent, and Subject Authorization .........................60
13.3
Subject Confidentiality ............................................................................................61
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................61
13.4.1 Publication and Disclosure.................................................................................61
13.4.2 Clinical Trial Registration..................................................................................62
13.4.3 Clinical Trial Results Disclosure ........................................................................62
13.5
Insurance and Compensation for Injury....................................................................62
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................63
14.1
Administrative Information......................................................................................63
14.1.1 Study Contact Information .................................................................................63
14.1.2 INVESTIGATOR AGREEMENT......................................................................64
14.1.3 Study-Related Responsibilities...........................................................................65
14.1.4 List of Abbreviations .........................................................................................65
15.0
DATA HANDLING AND RECORDKEEPING............................................................67
15.1
CRFs (Electronic and Paper)....................................................................................67
15.2
Record Retention .....................................................................................................67
16.0
REFERENCES..............................................................................................................69
17.0
APPENDICES...............................................................................................................70
LIST OF IN-TEXT TABLES
Table 6.a
Proposed Doses and Cohort Dose Escalation......................................................20
Table 6.b
Exposure Margins..............................................................................................23
Table 7.a
Prohibited Medications, Supplements, and Dietary Products ..............................31
Table 9.a
Primary Specimen Collections ...........................................................................43
Table 10.a
Takeda Medically Significant AE List................................................................49
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................70
Appendix B
Elements of the Subject Informed Consent.........................................................72
Appendix C
Investigator Consent to the Use of Personal Information ....................................75
Appendix D
Pregnancy and Contraception.............................................................................76
Appendix E
Detailed Description of Amendments to Text.....................................................80


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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Compound:
TAK-831
Study Identifier: TAK-831-1005 
Phase: 1
Protocol Title: A Randomized, Investigator and Subject Blinded, Sponsor Unblinded, Placebo-Controlled, Phase 1 
Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Multiple Doses of TAK-831 in Healthy 
Subjects
Trial Design:
The study is an investigator and subject blinded, sponsor unblinded, placebo-controlled clinical study progressively 
assessing independent cohorts of healthy subjects to continue evaluation of the safety, tolerability, and 
pharmacokinetics (PK) of escalating multiple doses of TAK-831 at doses higher than those achieved in the initial 
multiple rising dose study (TAK-831-1001). 
Up to 6 cohorts will be run either singly or in parallel as non- cerebrospinal fluid (CSF) cohorts with plasma analysis 
or CSF cohorts with CSF analysis in addition to plasma analysis to assess TAK-831 exposure and 
 
 levels in the central nervous system (CNS). After meeting all the selection criteria, there will be 8 subjects 
enrolled in each cohort. They will be randomized on Day 1 in a 1:3 ratio to receive placebo or TAK-831. 
In CSF cohorts, lumbar CSF samples will be collected through either a single lumbar puncture or an indwelling 
temporary catheter on 2 separate occasions. In CSF cohorts that use an indwelling temporary catheter on both 
occasions, the first collection will occur on Day 1 and the second on Day 16. In CSF cohorts where the predose CSF 
sample is collected through a single lumbar puncture, the first CSF sample will be collected on Day -1 prior to the start 
of 
 monitoring and the second collection will be obtained through use of an indwelling temporary catheter 
on Day 16. If an indwelling temporary catheter is being used, it will collect serial CSF samples for 24 hours.
Subjects in each cohort will be confined during dosing and be kept in the study unit for 24 hours after the last dose for 
non-CSF cohorts and 48 hours after catheter removal in CSF cohorts. The total confinement period in non-CSF 
cohorts will be 19 days (Day -2 to Day 17), 20 days in CSF cohorts where an indwelling temporary catheter is being 
used on Day 1 and Day 16 (confinement from Day -1 to Day 19); and 21 days in CSF cohorts where CSF is collected 
through a single predose lumbar puncture on Day -1 and through an indwelling catheter on Day 16 (confinement from 
Day -2 to Day 19). Follow-up assessments will occur on Day 30 (±2) for all cohorts. An exception to these minimum 
confinement periods will be made if a determination is made to evaluate QT/QTc intervals for additional single doses 
of TAK-831 in non-CSF cohorts based on the established tolerated dose range.
Trial Primary Objective:
To evaluate the safety and tolerability of TAK-831 when administered as multiple oral doses at escalating dose levels 
in healthy subjects.
Secondary Objectives:
To evaluate the PK of TAK-831 when administered as multiple oral doses at escalating dose levels in healthy subjects. 
Trial Subject Population: Healthy male subjects and female subjects not of childbearing potential, aged 18 to 55 
years, inclusive.
Planned Number of Subjects:
Approximately 48 (8 per cohort, up to 6 cohorts)
Planned Number of Sites:
1
CCI
CCI
CCI


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Dose Levels:
Starting dose TAK-831 600 mg (tablet T2 formulation, 
Cohort 1) and 800 mg (suspension formulation, 
Cohort 2) and matching placebo
Route of Administration:
Oral
Duration of Treatment:
One day for SD part (followed by evaluation for 2 
days) and then 14 days for MD part.
Planned Trial Duration:
Approximately 58 days for each cohort: screening 28 days, 
treatment and assessments including follow-up 30 days 
(treatment Days 1 and 3 to 16; assessments Days 1 to 17 for 
non-CSF cohorts or 1 to 19 for CSF cohorts; follow-up: 
Day 30 [±2]). Maximum duration: approximately 348 days 
for 6 cohorts.
Main Criteria for Inclusion for Healthy Subjects:
In order to be eligible for participation, subjects must:

Be a healthy adult male or female not of childbearing potential.

Be aged 18 to 55 years, inclusive, at the time of informed consent and first study drug dose.

Weigh at least 45 kg and has a body mass index between 18.0 and 30.0 kg/m2, inclusive at Screening.
Main Criteria for Exclusion for Healthy Subjects:
The subject must be excluded from participating in the study if the subject:

Has a known hypersensitivity to any component of the formulation of TAK-831.

Has a risk of suicide according to the investigator’s clinical judgment (eg, per Columbia–Suicide Severity Rating 
Scale), or has made a suicide attempt in the previous 6 months.
Additional Exclusion Criteria for Cohort(s) with CSF Collection:
The subject must be excluded from participating in the study if the subject:

Has had CSF collection performed within 30 days before Check-in (Day -1).

Has a known hypersensitivity to the anesthetic or its derivatives used during CSF collection, or any medication 
used to prepare the area of lumbar puncture.

Has significant vertebral deformities (scoliosis or kyphosis) which, in the opinion of the investigator, may 
interfere with lumbar puncture procedure.

Has a history of clinically significant back pain and/or injury.

Has local infection at the puncture site.

Has thrombocytopenia or other suspected bleeding tendencies noted before procedure.

Has developed signs and symptoms of spinal radiculopathy, including lower extremity pain and paresthesia.

Has any focal neurological deficit that might suggest an increase in intracranial pressure.

Has any abnormal finding on ophthalmological assessment/fundoscopy suggestive of raised intracranial pressure 
(ie, optic disc swelling/edema; (uncontrolled) hypertensive retinopathy).

Suffers regularly from moderate to severe headaches requiring analgesics.

Subjects with lower spinal malformations (on physical examination or lumbar spine radiography), local spinal 
infection, or other abnormalities that would exclude lumbar puncture (LP).
Main Criteria for Evaluation and Analyses:
Primary Endpoints
Primary endpoints are the safety parameters of TAK-831 and will be assessed as follows:
1.
Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).


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2.
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at least once postdose.
3.
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least once 
postdose.
4.
Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram (ECG) parameters 
at least once postdose.
Secondary Endpoints 
Secondary endpoints are the plasma PK parameters of TAK-831 and will be measured as follows:
1.
Maximum observed plasma concentration (Cmax) (Day 1). 
2.
Maximum observed steady-state plasma concentration during a dosing interval (Day 16). 
3.
Time of first occurrence of Cmax (Days 1 and 16). 
4.
Area under the plasma concentration-time curve during a dosing interval (Days 1 and 16).
Statistical Considerations:
Safety:
Adverse events will be presented in listings, and TEAEs will be summarized. Individual results of laboratory tests 
(hematology, chemistry, and urinalysis) will be listed and Baseline, postdose, and changes from Baseline to postdose 
laboratory data will be summarized. Individual results of vital signs will be listed and Baseline, postdose, and changes 
from Baseline in vital signs will be summarized. Individual results of quantitative ECG parameters from the 12-lead 
safety ECGs will be listed and Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized. All summaries will be performed by regimen for placebo, each TAK-831 dose level, and TAK-831 
overall. Other safety measures (neurological examination and the ophthalmoscopic assessment of the fundus, physical 
examination findings and suicidality assessments [C-SSRS]) will be presented in data listings. 
PK Measures:
Concentrations of TAK-831 in plasma (all cohorts) and CSF (CSF Cohort[s]) will be summarized by dose, drug 
formulation, and day over each scheduled sampling time using descriptive statistics. Individual plasma concentration 
data versus time will be presented in a data listing. Plasma and CSF PK parameters, including dose-normalized Cmax
and AUCs, will be summarized by dose, drug formulation, and day using descriptive statistics. Changes in the PK 
parameters from Day 1 to Day 16 will be assessed by summarizing the ratio of Day 16 to Day 1 by dose. Dose 
proportionality in plasma PK parameters (Cmax and AUCs) will be assessed graphically for Day 1 and Day 16 plasma 
concentrations. Additional analyses will be included as appropriate.
Biomarker Measures and Exploratory Endpoints:
Sample Size Justification:
The sample size chosen of 8 subjects for all cohorts (6 active:2 placebo) is considered to be sufficient for the 
determination of progression to the next cohort based on the safety and PK data. The sample size was not based on 
statistical power considerations.
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1.1
Protocol Amendment No. 02 Summary of Changes 
Rationale for Amendment No. 02
This document describes the changes in reference to the protocol incorporating Amendment 
No. 02. The primary reason for this amendment is to revise the study procedures to enable cohorts 
that obtain 
 measurements as described in the previous protocol in addition to the 
collection of a baseline CSF sample on Day -1 through a single lumbar puncture and serial CSF 
sampling on Day 16. In addition, the drug supply management has been updated. Clarifications, 
inconsistencies, and minor grammatical, editorial, and formatting changes are included for 
clarification purposes only.
For specific description of text changes and where the changes are located, see Appendix E. 
Changes in Amendment No. 02
1. Updated study design and procedures.
2. Updated clinical study material management.
CCI


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2.0
STUDY SCHEMATIC
Cohorts
(up to 6 as 
needed)
Pretreatment Period
Treatment and Assessments (a)
Study Exit
Follow-
up (b)
Screening
Check-in/ 
Baseline
SD Part
MD Part
Treatment
Evaluation
Non-CSF (or 
CSF cohorts 
that collect 
Day -1 CSF 
samples via a 
single predose 
lumbar 
puncture) 
Days -28 to -3 
Day -2
Day 1 
Days 1 to 2
Days 3 to 
16
Day 17 (non-CSF 
cohort) / Day 19 
(CSF cohort 
where Day -1 
CSF is collected 
via a single 
predose lumbar 
puncture)
Day 30 
(±2)
CSF
Days -28 to -2
Day -1
Day 1
Days 1 to 2
Days 3 to 
16
Day 19
Day 30 
(±2)
                                Confinement                              
CSF=cerebrospinal fluid, MD=multiple dose, PD=pharmacodynamic, PK=pharmacodynamic, SD=single dose.
(a) TAK-831 dosing will be on Day 1 for SD and Days 3 through 16 for MD.
(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 clinic for re-evaluation per investigator’s 
discretion. 


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3.0
SCHEDULE OF STUDY PROCEDURES
Study Day:
Scr-
een-i
ng
Check in / Baseline 
Assessments
Treatment Day
Study 
Exit (a)
Early 
Termina-
tion
(b)
Follow-
up
-28 
to -3
Day -2 (non-CSF or 
CSF cohorts) that 
collect baseline CSF 
samples via a single 
predose lumbar 
puncture or Day -1 
(CSF cohorts)
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16
Day 17 
(non-C
SF) / 
Day 19 
(CSF)
30
(±2) (c)
ADMINISTRATIVE PROCEDURES
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Demographics/ medical 
history
X
Medication history
X
X
Concurrent medical 
conditions
X
X
CLINICAL PROCEDURES/ASSESSMENTS
Full physical 
examination
X
X
X
X
(X)
Height
X
Weight and BMI (d)
X
X
X
(X)
Concomitant 
medications (e)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Neurological 
examination and 
fundoscopy (g)
X
X
Lumbar spine 
radiography (for CSF 
cohorts only) (h) 
X


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Study Day:
Scr-
een-i
ng
Check in / Baseline 
Assessments
Treatment Day
Study 
Exit (a)
Early 
Termina-
tion
(b)
Follow-
up
-28 
to -3
Day -2 (non-CSF or 
CSF cohorts) that 
collect baseline CSF 
samples via a single 
predose lumbar 
puncture or Day -1 
(CSF cohorts)
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16
Day 17 
(non-C
SF) / 
Day 19 
(CSF)
30
(±2) (c)
Safety ECG (i)
X
X
X
X
X
X
X
(X)
C-SSRS (k)
X
X
X
X
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessment 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY PROCEDURES
Clinical laboratory tests 
(l)
X
X
X
X
X
X
(X)
Hepatitis panel (HBsAg 
and anti-HCV)
X
HIV screen
X
FSH (m)
X
hCG (n)
X
X
X
X
(X)
Hormone laboratory 
tests (o)
X
X
X
(X)
Drug screen
X
X
PGx EVALUATIONS
DNA sample collection 
(p)
X
PK EVALUATIONS
PK blood collection (q)
X
X
X
X
X
X
PK CSF collection (r)
X (r)
X (r) X (r)
X
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Study Day:
Scr-
een-i
ng
Check in / Baseline 
Assessments
Treatment Day
Study 
Exit (a)
Early 
Termina-
tion
(b)
Follow-
up
-28 
to -3
Day -2 (non-CSF or 
CSF cohorts) that 
collect baseline CSF 
samples via a single 
predose lumbar 
puncture or Day -1 
(CSF cohorts)
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16
Day 17 
(non-C
SF) / 
Day 19 
(CSF)
30
(±2) (c)
PD/BIOMARKER EVALUATIONS
AE=adverse event, anti-HCV=antibody to hepatitis C virus, BMI=body mass index, C-SSRS=Columbia–Suicide Severity Rating Scale, ECG=electrocardiogram, 
FSH=follicle-stimulating hormone, HbA1c=glycosylated hemoglobin, HBsAg=hepatitis B surface antigen, hCG=human chorionic gonadotropin, HIV=human 
immunodeficiency syndrome, PGx=pharmacogenomics, TSH=thyrotropin.
(a) Study exit for non-CSF cohorts occurs on Day 17 and for CSF cohorts on Day 19.
(b) At Early Termination, perform all procedures per Section 7.6.
(c) The Follow-up Visit will occur by telephone on Day 30 (±2) unless abnormal, clinically significant findings are observed upon discharge. In these cases, subjects 
must be brought back to the clinic for re-evaluation per investigator’s discretion. (X) is for optional procedure.
(d) BMI will be calculated only at Screening.
(e) Record all ongoing medications from Screening and throughout the study.
(f) Vital signs (oral temperature, respiratory rate, pulse, and blood pressure) will be obtained at Screening, Check-in, Day 1, and Days 3 through 16 at predose 
(within 60 minutes before dosing) and at 1, 4, and 12 hours after the morning dose, and Study Exit/Early Termination and as appropriate at the Follow-up Visit. Day 
2 vital signs should be collected approximately 24 hours after the Day 1 dose is administered. Pulse and blood pressure will be measured after 5 minutes supine and 
again at 1 and 3 minutes after standing for all scheduled time points, with exception of Day 1, Day 2, and Day 16 in cohorts where CSF collection is performed using 
an indwelling catheter, when only supine measurements will be taken. 
(g) Only for CSF cohorts: A neurological assessment and eye examination (ophthalmological assessment of the retina, fundoscopy) will be performed on Day -2 
(baseline collection through single lumbar puncture), Day -1 (baseline collection through indwelling catheter) and Day 15. 
(h) Lumbar spine radiography (for CSF cohorts only) if one has not been performed within the past 12 months prior to the screening visit. 
(i) A standard 12-lead ECG (single) will be recorded at Screening, Check-in, Day 1 (predose [within 60 minutes prior to dosing], and at 1.5 hour postdose (morning 
dose), Day 16 (predose [within 60 minutes prior to dosing], and at 1 and 2 hours after morning dose, Day 10 (predose), and Study Exit/Early Termination and as 
appropriate at the Follow-up Visit.
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(k) The C-SSRS (Lifetime/Recent) will be administered at Screening; the C-SSRS (since last visit) will be administered at Check-in and at Study Exit/Early 
Termination.
(l) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening, Check-in, and after a 10-hour fast at predose on Days 1, 
10, and at Study Exit/Early Termination and as appropriate at the Follow-up Visit. 
(m) For women only: A FSH level will be obtained on postmenopausal women at Screening only. 
(n) For women only: Serum hCG will be performed at Screening, Day -1, and Study Exit/Early Termination, and at the Follow-up Visit if the subject is brought back 
to the clinic for re-evaluation.
(o) Hormone laboratory tests (prolactin, growth hormone, cortisol, and TSH) will be collected on Day 1 (before dosing, under fasted conditions and 3 hours 
postdose) and at Study Exit/Early Termination (morning values, under fasted conditions) and as appropriate at the Follow-up Visit.
(p) One blood sample (6 mL) will be collected for DNA analysis before dosing on Day 1.
(q) Blood samples (4 mL) for PK analyses will be collected on Day 1 (within 30 minutes before dosing) and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, hours after the morning 
dose; on Day 10 (predose), Day 13 (predose), and on Day 16 at predose (within 30 minutes before dosing), and at 0.5, 1, 2, 4, 8, 12, 16, and 24 hours after the 
morning dose and at Early Termination. 
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4.0
INTRODUCTION
4.1
Background
Inhibition of D-amino acid oxidase (DAO) has been proposed as a potential for the treatment of 
schizophrenia. DAO is a peroxisomal enzyme active toward neutral D-amino acids, which is 
expressed in both the periphery and the brain. DAO degrades D-amino acids by oxidation. In the 
periphery, this action likely plays a role in the detoxification of D-amino acids from bacterial and 
other sources, as amino acids used for protein synthesis and other metabolic processes are L-amino 
acids. Few D- amino acids are known to play a biological role in humans, but D-serine in the brain 
has been connected to the regulation of glutamatergic neurotransmission [1], and D-serine has 
been shown to be an obligatory co-agonist of N-methyl-D-aspartate (NMDA)-type glutamate 
receptors, binding to the glycine site. Inhibition of DAO elevates endogenous D-serine in the 
cerebellum, increasing Purkinje cell long term depression via activation of δ2 glutamate receptor 
and/or NMDA receptors with subsequent internalization of AMPA 
(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors [2].
Hypofunction of NMDA receptors is considered a possible mechanism in the pathophysiology of 
schizophrenia, which could be mitigated by increasing D-serine levels in the brain [3]. Changes in 
D-serine levels or in the ratio of D-serine to total serine have been reported in the plasma of 
patients with schizophrenia, both naive and under drug treatment [4-7]. 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 DAO sits [8].
Adding to the above evidence of a potential role of DAO in the pathophysiology of schizophrenia, 
a weak inhibitor of DAO, sodium benzoate, demonstrated efficacy in positive, negative, and 
cognitive symptoms in a proof-of-concept study in subjects with schizophrenia [9].
While current medications mitigate positive symptoms of schizophrenia and to some extent the 
negative symptoms, cognitive impairment represents an area of unmet medical need. Moreover, 
cognitive and negative symptoms are associated with functional outcomes to a greater degree than 
positive symptoms and remain an area of focus for the development of novel therapeutics.
4.2
Rationale for the Proposed Study
TAK-831 is a highly selective and potent inhibitor of DAO. TAK-831 was shown to increase 
D-serine levels in the cerebellum of normal rats, and it also demonstrated a positive effect on 
cognition and social interaction in rodent cognition and behavioral models. TAK-831 is under 
development for the treatment of negative symptoms of schizophrenia (NSS) and cognitive 
impairment associated with schizophrenia (CIAS), as well as for cerebellar ataxias such as 
Friedreich ataxia. In addition to safety and tolerability, the current proposed study is aimed at 
providing information on the relationship between concentrations of TAK-831 
 
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4.3
Benefit/Risk Profile
There is no benefit to subjects in this clinical study.
The following risk mitigation measures will be implemented in this study with TAK-831. These 
measures are based on what is known about the mechanism of action of TAK-831, nonclinical 
data, and the 2 phase 1 studies conducted to date. Procedures may be added during the study if 
necessary based on evaluation of any additional clinical or nonclinical safety data.

TAK-831 has been used in a prior single dose (up to 750 mg in oral suspension and 100 mg in 
tablet T1 formulation and 14 days multiple dose (up to 400 mg QD in oral suspension) study in 
healthy subjects (TAK-831-1001) with good safety and tolerability, as well as a single dose 
PET study (TAK-831-1003), and these studies have not resulted in a safety signal that would 
prevent additional studies. Additionally, a T2 tablet formulation is currently under assessment 
in a single dose food effect study (TAK-831-1004) that will contribute additional data to 
inform dose selection during the conduct of this study.

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 PD monitoring (venipuncture may cause bruising), and the placement of 
ECG pads, which may cause some local redness and/or erythema/itching. 

The risk of pain or discomfort at the site of CSF collection and the risk of headache in cohorts 
where CSF will be collected for PK and PD assessment. Severe headaches may require a blood 
patch procedure. There is a small risk of infection with indwelling catheters.

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 C-SSRS will be administered to monitor emergent suicidality.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Trial Objectives
5.1.1
Trial Primary Objective
To evaluate the safety and tolerability of TAK-831 when administered as multiple oral doses at 
escalating dose levels in healthy subjects.
5.1.2
Trial Secondary Objective
To evaluate the PK of TAK-831 when administered as multiple oral doses at escalating dose levels 
in healthy subjects.
5.1.3
Trial Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
Primary endpoints are the safety parameters of TAK-831 and will be assessed as follows:
1. Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE)
2. Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once postdose.
3. Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at 
least once postdose.
4. Percentage of subjects who meet the markedly abnormal criteria for safety ECG parameters at 
least once postdose.
5.2.2
Secondary Endpoints 
Secondary endpoints are the plasma PK parameters of TAK-831 and will be measured as follows:
1. Maximum observed plasma concentration (Cmax) (Day 1). 
2. Maximum observed steady-state plasma concentration during a dosing interval (Day 16). 
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3. Time of first occurrence of Cmax (Days 1 and 16). 
4. Area under the plasma concentration-time curve during a dosing interval (Days 1 and 16). 
5.2.3
Exploratory Endpoints
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
The study is an investigator and subject blinded, sponsor unblinded, placebo-controlled clinical 
study progressively assessing independent cohorts of healthy subjects to continue evaluation of the 
safety, tolerability, and PK of escalating single doses (SD) and multiple doses (MD) of TAK-831, 
as either a suspension or T2 tablet formulation, at levels higher than those achieved in the initial 
single and multiple rising dose (SRD/MRD) Study TAK-831-1001. 
Up to 6 cohorts will be run either singly or in parallel as non- cerebrospinal fluid (CSF) cohorts 
with plasma analysis or CSF cohorts with CSF analysis in addition to plasma analysis to assess 
TAK-831 exposure and 
 levels in the central nervous system (CNS). 
After meeting all the selection criteria, there will be 8 subjects enrolled in each cohort. They will 
be randomized on Day 1 in a 1:3 ratio to receive placebo or TAK-831. 
All cohorts will start with an initial, in-house SD period to include predose PD assessments on 
Day -1, Day 1 TAK-831 dosing, and a 48-hour in-house observation period with full PK 
collections. The SD PK collection and observation phase will be followed by 14 days of in-house 
MD.
In CSF cohorts, lumbar CSF samples will be collected through either a single lumbar puncture or 
an indwelling temporary catheter on 2 separate occasions. In CSF cohorts that use an indwelling 
temporary catheter on both occasions, the first collection will occur on Day 1, and the second on 
Day 16. In CSF cohorts where the pre-dose CSF sample is collected through a single lumbar 
puncture, the first CSF sample will be collected on Day -1 prior to the start of 
 
monitoring and the second collection will be obtained through use of an indwelling temporary 
catheter on Day 16. If an indwelling temporary catheter is being used, it will collect serial CSF 
samples for 24 hours.
Subjects in each cohort will be confined during dosing and be kept in the study unit for 24 hours 
after the last dose for non-CSF cohorts and 48 hours after catheter removal in CSF cohorts. The 
total confinement period in non-CSF cohorts will be 19 days (Day -2 to Day 17), 20 days in CSF 
cohorts where an indwelling temporary catheter is being used on Day 1 and Day 16 (confinement 
from Day -1 to Day 19); and 21 days in CSF cohorts where CSF is collected through a single 
predose lumbar puncture on Day -1 prior to the start of 
 and through an 
indwelling catheter on Day 16 (confinement from Day -2 to Day 19). Follow-up assessments will 
occur on Day 30 (±2) for all cohorts. An exception to these minimum confinement periods will be 
made if a determination is made to evaluate QT/QTc intervals for additional single doses of 
TAK-831 in non-CSF cohorts based on the established tolerated dose range.
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The Study Schematic and Schedule of Study Procedures are provided in Section 2.0 and 
Section 3.0, respectively.
6.2
Dose Escalation
In Cohort 1, the proposed starting dose is TAK-831 600 mg QD, administered as a tablet 
formulation (Formulation T2) and, in Cohort 2, the starting dose is TAK-831 800 mg QD 
administered as a suspension formulation. Cohort 1 and Cohort 2 will run in parallel.
The proposed dose and dose escalation is provided in Table 6.a.
Table 6.a
Proposed Doses and Cohort Dose Escalation
Cohort
Proposed 
Dose, 
(Estimated) 
Formulation
Rationale
1 (with CSF)
600 mg/day 
(QD)
Tablet 
formulation T2
T2 tablet formulation at 600 mg is expected to deliver 
exposures comparable to 400 mg administered as a 
suspension. This exposure level demonstrated 
acceptable safety and tolerability with multiple dosing 
in Study TAK-831-1001;
 
 
2 (with CSF) 
800 mg/day 
(QD)
Suspension 
formulation 
Cohort 2 will be run in parallel with Cohort 1. TAK-831 
750 mg single dose administered as a suspension was 
found to have acceptable tolerability in Study 
TAK-831-1001. The highest multiple dose level in that 
study was 400 mg suspension.
 
 
3
1200 mg/day 
(a) 
Suspension
Evaluate safety, tolerability, PK and PD effects of 
increased doses of TAK-831 administered as a 
suspension as tolerated up to the maximum exposure 
defined below. Once this objective is met, possible 
additional doses and dose regimens (eg, BID, single 
doses), with or without CSF collections and 
 
(in non-CSF cohorts or in CSF cohorts where Day -1 
CSF is being collected through a single lumbar 
puncture), will be examined, pending PK-PD results of 
Cohorts 1 and 2.
4 (with CSF)
100 mg/day 
(a)
Tablet 
formulation T2
5 (with CSF where Day -1 
CSF is collected through 
a single lumbar puncture)
15 mg
Suspension
6
TBD (a)
Tablet 
formulation T2 
or suspension
TBD=to be determined. 
(a) No selected dose will have exposures projected to exceed the study exposure limits or a maximum 2000 mg dose, 
whichever is lower.
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Exposure levels in each cohort will be monitored closely and will not exceed exposures seen at the 
end of a 13-week repeat dose toxicity studies in monkeys (see Section 6.3.2). 
Since, the highest dose tested in single rising dose portion of Study TAK-831-1001 was 750 mg 
administered as a suspension, all dose levels above 750 mg/day will be tested first in SD setting 
before MD in subsequent cohorts.
All decisions concerning dose escalation will be made by Takeda (at a minimum, the clinical 
science representative[s], quantitative clinical pharmacologist, study statistician and 
pharmacovigilance physician) and the principal investigator. The investigator and subjects will 
remain blinded throughout the study, but at the completion of each cohort, specific Takeda 
personnel listed in associated study documentation may be unblinded to analyze data considered 
necessary to determine subsequent doses and cohort management decisions. All data presentations 
prepared for discussions with the investigator and site staff will contain only blinded study data, 
except in the event that formal study unblinding procedures detailed in Protocol Section 8.1.5 have 
been followed and discussion of related data is required.
If agreement regarding a dose escalation decision cannot be reached between the principal 
investigator and Takeda, the study will be stopped.
Based on emerging safety and tolerability and PK data, the planned dose levels may be modified.
All adverse events reported during the Treatment Period, both within and across cohorts, up to the 
time of discharge will be evaluated to assess the need for subject and/or study termination in 
accordance with the prespecified criteria for discontinuation/termination (Section 6.5).
Following assessment of the adverse event data and predefined criteria for study termination, dose 
escalation may be interrupted/stopped if these criteria are met. Based on review of study data as 
outlined above, Takeda, in consultation with the principal investigator, will decide if and how it is 
appropriate for the study to proceed. 
Dose escalation may be interrupted/stopped if:

Exposures in any cohort exceed those observed at the top dose tested in the monkey toxicity 
study, that is, a mean Cmax of 3680 ng/mL or a mean AUC24 of 35,700 hr*ng/mL. 

The exposures reach the plasma exposure plateau in the 2 highest dose cohorts.

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 an increase 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].


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6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design 
In addition to assessing safety, tolerability, and PK of TAK-831, the proposed study is aimed at 
providing information on the relationship between concentrations of TAK-831 and 
 
 to be explored in both plasma and CSF in healthy subjects in order to support dose 
selection for the follow-up studies planned to evaluate PD effects of TAK-831 in subjects with 
schizophrenia. 
assessments will be conducted in non-CSF cohorts for 
exposure-response analysis of ECG parameters, or in CSF cohorts where the first CSF sample is 
collected through single lumbar puncture prior to the start of 
on Day -1.
6.3.2
Rationale for Dose 
Based on the results of toxicology studies, the monkey is considered the more sensitive species. 
The NOAEL in the 13-week repeat dose study was based on adverse findings of vomiting, 
diarrhea, and loose stool at the top dose of 600 mg/kg/day. Therefore, the next lower dose tested, 
100 mg/kg/day, was assigned the NOAEL for both sexes. This NOAEL was associated with mean 
Cmax values of 1340 and 1270 ng/mL and mean AUC24 values of 7490 and 9190 h*ng/mL for 
males and females, respectively, on Day 91.
As the adverse effects of treatment in the monkey (vomiting, diarrhea, and loose stool) are easily 
monitored in humans, exceeding the NOAEL of 100 mg/kg/day in monkeys may be warranted in 
order to achieve adequate CNS exposures in humans. The targeted maximum exposure in humans 
is that attained in monkeys at 600 mg/kg/day. Dose escalation will be stopped if significant 
vomiting or diarrhea is observed in humans. In monkeys, at 600 mg/kg/day (dosed as 300 mg/kg, 
BID), respective mean Cmax and AUC24 values on Day 91 were 3680 ng/mL and 35,700 h*ng/mL, 
sexes combined.
The highest dose tested in the MRD portion of Study TAK-831-1001 was 400 mg daily of the oral 
suspension formulation for 14 days. At this dose level, there were no significant adverse effects 
reported, and Cmax exposures had reached those of female monkey at the NOAEL dose (Cmax
1270 ng/mL and AUC24 3454 h*ng/mL) (Table 6.b). 
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Table 6.b
Exposure Margins
Species-Study
Dose 
(mg/kg/day or mg)
Cmax
(ng/mL)
AUC24
(h*ng/mL)
Margin (a)
Cmax
AUC24
Rat 13-week
(Day 91)
1000
(NOAEL)
11,000 (M)
26,100 (F)
162,000 (M)
355,000 (F)
8.7 (M)
20.6 (F)
46.9 (M)
102.8 (F)
Monkey 13-week
(Day 91)
100 (50 BID)
(NOAEL)
1340 (M)
1270 (F)
7490 (M)
9190 (F)
1 (M)
1 (F)
2.2 (M)
2.7 (F)
600 (300 BID)
(vomiting, diarrhea)
4650 (M)
2710 (F)
45,500 (M)
25,900 (F)
3.7 (M)
2.1 (F)
13.2 (M)
7.5 (F)
Human MRD
(Day 14)
400 mg QD
(suspension form)
1270 (M)
3454 (M)
-
-
F=female, M=male.
(a) Margins relative to Day 14 exposures in humans administered 400 mg/day.
Based on these data, the proposed doses in the current study are as follows:
Cohort 1 subjects will receive a starting dose of TAK-831 600 mg QD as a T2 tablet formulation, 
which is expected to achieve geometric mean TAK-831 Cmax and AUC24 about 60% and 83%, 
respectively of that of 400 mg suspension formulation under fasted conditions.
In parallel to Cohort 1, Cohort 2 will test the suspension formulation with 800 mg dose. 
Subsequent cohorts will have dose escalated as tolerable. Dose escalation will be stopped 
according to the stopping rules detailed in Section 6.2.
Proposed dose levels as well as dosing intervals for the subsequent cohorts may be adjusted after 
reviewing safety, tolerability, PK, and/or PD data of Cohorts 1 and 2.
6.3.3
Rationale for Endpoints
6.3.3.1
Primary Endpoint
The primary endpoint for this trial is the composite of safety variables to determine the safety and 
tolerability of oral multiple doses of TAK-831, and dose-limiting effects of TAK-831 and are 
common for this type of study.
6.3.3.2
Secondary Endpoint
The secondary endpoints consist of standard plasma PK variables to determine drug exposure at 
each dose to facilitate dose escalation.
6.3.3.3
Exploratory Endpoints
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6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this trial, collecting safety data and collecting blood in all cohorts and CSF samples in one or 
more cohorts for TAK-831 PK and PD are the critical procedures. 
!
At any postdose time point, safety data need should be collected as close to the exact time point 
as possible.
!
At any postdose time point, the blood and/or CSF sample for TAK-831 PK, and PD needs to be 
collected as close to the exact time point as possible.
!
All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
!
The order of priority can be changed during the trial with joint agreement of the investigator 
and the sponsor.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 1 assessment of TAK-831 in healthy subjects. The PK, PD, and safety profiles of 
the compound are still being elucidated. This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of phase 1 dose rising trials. Modifications to the dose, 
dosing regimen, and/or clinical or laboratory procedures currently outlined in Section 6.1 and 6.2
may be required to achieve the trial objectives and to ensure the safety of the trial subjects.
Some alterations from the currently outlined dose and/or dosing regimen may be permitted based 
on newly available data, but the maximum daily dose/exposure detailed in Section 6.3.2, may not 
exceed those currently outlined.
!
Additional cohorts may be added.
!
Repeat of or decrease in the dose of the trial drug administered.
!
Entire cohorts may be omitted.
!
Increase/decrease in the duration of trial drug administration (eg, number of days), including 
evaluation of single doses of TAK-831 on QT/QTc intervals based on the established tolerated 
dose range.
!
Adjustment of the dosing interval, for example, divided doses BID to QD, QD to BID, 3 times 
daily, or vice versa.
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!
A planned PK data review may be eliminated if agreed to by the sponsor and investigator and if 
no further increases in total daily dose occur. 
!
Addition of a PK data review.
!
Instructions to take trial drug with or without food or drink may also be modified based on 
newly available data (ie, food effect is known).
!
The planned CSF sample may be eliminated, if agreed to by the sponsor and the investigator.
The PK/PD sampling scheme currently outlined in the protocol may be modified during the trial 
based on newly available PK or PD data (eg, to obtain data closer to the time of peak plasma 
concentrations).
 
.
Up to an additional 50 mL of blood may be drawn for PK and/or biomarker analyses. This may 
include repeat samples or modified PK/PD time points based on emerging data. The total blood 
volume withdrawn from any single subject will not exceed the maximum allowable volume during 
his/her participation in the entire trial.
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests) currently outlined in the protocol may be modified during the trial based on newly 
available safety, tolerability, PK, or PK/PD data (eg, to obtain data closer to the time of peak 
plasma concentrations). These changes will not increase the number of trial procedures for a given 
subject during his/her participation in the entire trial.
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatine kinase to serum chemistry panel that was 
already drawn).
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the sponsor in 
a letter to the Trial File and forwarded to the investigator for retention. The letter may be 
forwarded to the institutional review board (IRB)/independent ethics committee (IEC) at the 
discretion of the investigator.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.5.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or Follow-up 
Visit/interaction associated with a planned visit (this can be a phone contact), discontinues from 
the trial, or is lost to follow-up (ie, the investigator is unable to contact the subject); or dosing of 
future cohorts is stopped based on the dose escalation rules.
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6.5.3
Definition of Trial Completion
The primary objective of this phase 1 trial is to identify safety and tolerability of multiple rising 
doses. Therefore, it is possible that not all planned doses to be administered, if this objective is 
achieved at lower dose levels in this trial. This is not considered an early termination of the trial, 
but rather an earlier than anticipated achievement of the trial objective(s) or trial completion. 
Therefore, the definition of trial completion follows the same rules as definition of end of trial 
(Section 6.5.2) for the dosing group achieving the primary objective.
6.5.4
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a non–safety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a non–safety-related reason.

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons:

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from nonclinical or clinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.5.5
Criteria for Premature Termination or Suspension of the Trial
6.5.5.1
Criteria for Premature Termination or Suspension of Trial
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound, such that the risk 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 objectives or compromises subject safety.

Meeting study-specific criteria for terminating the study (eg, study meets predefined rule for 
futility or benefit, study meets predefined stopping rules within or between cohorts per 
Section 6.2).

Two or more subjects in any single cohort or across more than 1 cohort experience alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations >5 times the 
upper limit of normal (ULN) in the absence of a concomitant bilirubin increase (see point 
3 below)*. If 2 subjects in 1 dose level after dosing show the following findings in 2 
consecutive measurements within 24 hours:


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
ALT or AST ≥3×ULN, or

ALT or AST ≥2×ULN and ALT or AST ≥5×baseline value, or

Total bilirubin ≥2×ULN or

International normalized ratio (INR) >1.5 or

ALT and/or AST elevations >3×ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) without findings of 
cholestasis or other alternate etiology to explain the elevations (ie, “Hy’s Law cases”).
*Please note that the study may be terminated early before full attainment of these criteria (eg, if 
just 1 subject experiences 1 of these events) if warranted by safety data from the other subjects 
dosed in the study to date.
6.5.6
Criteria for Premature Termination or Suspension of a Site
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement.
6.5.7
Procedures for Premature Termination or Suspension of the Study or a Site
If the sponsor, an IRB, or regulatory authority elects to terminate or suspend the trial or the 
participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or trial suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before the first dose.
7.1
Inclusion Criteria 
Subject eligibility is determined according to the following criteria before entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization before the initiation 
of any study procedures including requesting that a subject fast for any laboratory evaluations. 
3. The subject is a healthy male or female not of childbearing potential adult who is aged 18 to 55 
years, inclusive, at the time of informed consent and first study drug dose.
4. The subject weighs at least 45 kg and has a BMI from 18.0 to 30.0 kg/m2, inclusive at 
Screening. 
5. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 90 days plus 5 half-lives (95 days) after last study drug dose. 
*Definitions and acceptable methods of contraception are defined in Appendix D.
6. A female subject with no childbearing potential, defined as a subject that has been surgically 
sterilized (hysterectomy, tubal ligation, or bilateral oophorectomy) or who is postmenopausal 
(defined as continuous amenorrhea of at least 12 months and FSH >40 IU/L).
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 4 weeks before Screening Visit. 
The 4-week window will be derived from the date of the last trial procedure and/or AE related 
to the trial procedure in the previous trial to the Screening Visit of the current trial.
2. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.
3. The subject has uncontrolled, clinically significant neurological (including seizure disorders), 
cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, 
endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability 
of the subject to participate or potentially confound the study results. It is the responsibility of 
the investigator to assess the clinical significance; however, consultation with the Takeda 
Medical Monitor may be warranted.
4. The subject has a known hypersensitivity to any component of the formulation of TAK-831.


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5. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at 
Screening or Check-in.
6. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse (defined as >3 drinks per day) within 5 year before the Screening visit or is unwilling to 
agree to abstain from alcohol and drugs throughout the study. (1 drink=12 oz. beer=5 oz. 
wine=1.5 oz. liquor.)
7. The subject has taken any excluded medication, supplements, or food products during the time 
periods listed in the Excluded Medications and Dietary Products table listed in Section 7.3.
8. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 35 days after participating in this study; or intending to donate ova during such time 
period.
9. If male, the subject intends to donate sperm during the course of this study or for 90 days plus 
5 half-lives (95 days) after the last dose of study medication.
10. The subject has evidence of current significant cardiovascular, central nervous system, hepatic, 
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, 
asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the 
subject’s medical history, physical examination, or safety laboratory tests giving reasonable 
suspicion of a disease that would contraindicate taking TAK-831, or a similar drug in the same 
class, or that might interfere with the conduct of the study. This includes, but is not limited to, 
peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
11. The subject has a QT interval with Fridericia’s correction method (QTcF) >450 ms (male 
subjects) or >470 ms (female subjects) or PR outside the range of 120 to 220 ms, confirmed 
with 1 repeat testing, at the Screening Visit and Check-in. If repeat testing is required, QTcF 
and PR values should be based on the average of the assessments.
12. The subject has current or recent (within 6 months) gastrointestinal disease that would be 
expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal 
reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] 
occurrence of heartburn, or any surgical intervention).
13. The subject has a history of cancer, except basal cell carcinoma that has been in remission for 
at least 5 years before first dose of study medication.
14. The subject has a positive test result for HBsAg, anti-HCV, or HIV antibody/antigen at 
Screening.
15. The subject has used nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days before 
Check-in. Cotinine test is positive at Screening or Check-in.
16. The subject has poor peripheral venous access.


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17. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 45 days before the first dose 
of study medication.
18. The subject has a Screening or Check-in abnormal (clinically significant) ECG. Entry of any 
subject with an abnormal (not clinically significant) ECG must be approved, and documented 
by signature by the principal investigator or designee.
19. The subject has a supine blood pressure outside 90 to 140 mm Hg for systolic and 50 to 90 mm 
Hg for diastolic, confirmed on repeat testing within a maximum of 30 minutes, at the 
Screening Visit or Check-in.
20. The subject has a resting heart rate outside 40 to 100 beats per minute confirmed on repeat 
testing within a maximum of 30 minutes, at the Screening Visit or Check-in (heart rate from 
the ECG does not apply).
21. The subject has abnormal Screening or Check-in laboratory values, confirmed by repeat 
assessment), that suggest a clinically significant underlying disease or subject with the 
following lab abnormalities: ALT and/or AST >1.5×ULN.
22. The subject has a risk of suicide according to the Investigator’s clinical judgment (eg, per
C-SSRS), or has scored “yes” on item 4 or item 5 of the Suicidal Ideation section of the 
C-SSRS, if this ideation occurred in the past 6 months, or “yes” on any item of the Suicidal 
Behavior section, except for the “Non-Suicidal Self-Injurious Behavior”, if this behavior 
occurred in the past 2 years.
23. The subject has received TAK-831 in a previous clinical study.
7.2.1
Additional Exclusion Criteria for Cohort(s) With CSF Collection
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has had CSF collection performed within 30 days before Check-in.
2. The subject has a known hypersensitivity to the anesthetic or its derivatives used during CSF 
collection, or any medication used to prepare the area of lumbar puncture, or any 
allergy-related indications to medication used for dilation during the eye examination.
3. The subject has significant vertebral deformities (scoliosis or kyphosis), which, in the opinion 
of the investigator, may interfere with lumbar puncture procedure. 
4. The subject has a history of clinically significant back pain and/or injury.
5. The subject has local infection at the puncture site.
6. The subject has thrombocytopenia or other suspected bleeding tendencies noted before
procedure.
7. The subject has developed signs and symptoms of spinal radiculopathy, including lower 
extremity pain and paresthesias.


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8. The subject has any focal neurological deficit that might suggest an increase in intracranial 
pressure.
9. The subject has any abnormal findings on ophthalmological assessment/fundoscopy 
suggestive of raised intracranial pressure (ie, optic disc swelling/edema; (uncontrolled) 
hypertensive retinopathy).
10. Subject suffers regularly from moderate to severe headaches requiring analgesics.
11. Subjects with lower spinal malformations (on physical examination or lumbar spine 
radiography), local spinal infection, or other abnormalities that would exclude lumbar 
puncture (LP).
7.3
Excluded Medications, Supplements, Dietary Products
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until subject is discharged from the unit. 
Table 7.a
Prohibited Medications, Supplements, and Dietary Products
28 Days Before Check-in 
7 Days Before Check-in 
72 Hours Before Check-in 
Prescription medications
OTC medications including aspirin 
or aspirin containing products (a)
Products containing caffeine or 
xanthine
Neutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Vitamin supplements
poppy seeds
Immunization/Vaccines (b)
Foods or beverages containing 
grapefruit or grapefruit juice, star 
fruit or star fruit juice, Seville-type 
(sour) oranges and marmalade, apple, 
orange, or pineapple juices, 
vegetables from the mustard green 
family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled 
meats
Nicotine-containing products
Alcohol containing products
Intake of known OTC 
inhibitors/inducers of CYPs 3A4/5, 
2C9, 2C19, 2D6, 1A2, 2B6, 2E1, and 
2A6 (c) 
CYP=cytochrome P-450, OTC=over-the-counter. 
(a) Occasional use of paracetamol (1 g/day) or other medication as approved by Takeda on a case-by-case basis is 
allowed. Lidocaine and epinephrine or other local anesthetics are not excluded for subjects undergoing lumbar 
puncture. Ibuprofen or acetaminophen may be used for any spinal headaches that may occur as a result of lumbar 
puncture.
(b) Inclusive of but not limited to H1N1 and other flu vaccinations.
(c) Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine.


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Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Subjects in each cohort will be confined during dosing and be kept in the study unit for 24 hours 
after the last dose for non-CSF cohorts and 48 hours after catheter removal in CSF cohorts. 
The total confinement period in non-CSF cohorts will be 19 days (Day -2 to Day 17), 20 days in 
CSF cohorts where an indwelling temporary catheter is being used on Day 1 and Day 16 
(confinement from Day -1 to Day 19), and 21 days in CSF cohorts where CSF is collected through 
a single predose lumbar puncture on Day -1 and through an indwelling catheter on Day 16 
(confinement from Day -2 to Day 19). Follow-up assessments will occur on Day 30 (±2) for all 
cohorts. (See Section 3.0). An exception to these minimum confinement periods will be made if a 
determination is made to evaluate QT/QTc intervals for additional single doses of TAK-831 in 
non-CSF cohorts based on the established tolerated dose range.
During the confinement period, subjects will be given a menu that will include 3 meals and an 
evening snack, each containing approximately 30% fat (relative to the total calories). The meals 
served on dosing and PK assessment days (Days 1 and 16) should be identical; no breakfast will be 
served; also on these days, record whether the meals were fully consumed (100%), or if not, record 
the percentage consumed (0, 25%, 50%, 75%). The study menu should be recorded and submitted 
to the study file with a copy provided to the sponsor before the start of the study (for PK days 
only). 
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence 
followed by the study procedure and then the meal.
TAK-831 (as a tablet or suspension formulation) or placebo will be administered in the morning 
(QD on Day 1 and Days 3 through 16 in Cohorts 1 and 2) after a fast of at least 10 hours; subjects 
will be instructed to fast for an additional 4 hours on Days 1, 3, and 16 and 2 hours for all other 
dose administration days. For cohorts with T2 formulation tablets, dose administration will be 
followed by a 240 mL of water. For cohorts with suspension formulation, dose administration will 
be followed by two rinses of 80 mL of water each (total volume of rinse water=160mL). All 
subjects may then consume water ad libitum with the exception of 1 hour before and 1 hour after 
drug administration. Subjects do not have to fast when no dosing is scheduled or for additional 
doses administered on the same day if TAK-831 is administered more than once per day. 
7.4.2
Activity
Subjects will remain upright (seated, standing, or ambulatory) for 4 hours following the dose 
administration, except as necessitated by the occurrence of an AE or study procedures (eg, 
obtaining 12-lead ECG).


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Subjects will refrain from strenuous and/or unaccustomed exercise throughout the entire course of 
the study, from Check-in through Study Exit/Early Termination.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories.
1. 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.
a.
Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 10.2.8.5), if the following circumstances occur at any 
time during study medication treatment:
–
ALT or AST >8×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 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%).
b. Subject discontinuation should be considered if there is a marked prolongation of the QTcF 
interval during treatment with the study drug, especially if the measurements are confirmed 
from more than 1 ECG. The thresholds for marked corrected QT (QTc) interval increases 
are considered to be >500 ms on any given QTcF measurement or >60 ms over baseline 
QTc and should be discussed with Takeda.
2. Significant protocol deviation. The discovery postrandomization 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.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) 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 because of 
an AE).


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5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 6.5.5. 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. In addition, efforts should be made to perform all procedures 
scheduled for the Early Termination Visit. Discontinued or withdrawn subjects may be replaced to 
ensure that a minimum of 6 subjects are completed for each cohort. This will be examined by the 
team on a case-by-case basis.
7.7
Subject Replacement
Subjects may be replaced on a case-by-case basis at the discretion of the sponsor.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
Details regarding the active drug and placebo in tablet dosage form and the extemporaneous 
preparation can be found in the IB and compounding manual respectively. Clinical study drug will 
be packaged to support enrollment and replacement subjects as required. When a replacement 
subject is required, the sponsor needs to be contacted prior to dosing.
8.1.1
Clinical Study Drug Labeling
Clinical study drug will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Clinical study drug must be stored in a secure, limited-access location and remained in the original 
container until dispensed. The storage condition and temperature excursion information can be 
found in the compounding manual. Receipt and dispensing of study drug must be recorded by 
authorized personnel at the trial site.
8.1.3
Clinical Study Drug Blinding
This is an investigator and subject blinded, sponsor-open study. The investigator and subjects are 
blinded to treatment assignment. The unblinded study drug supply will be provided to an 
unblinded pharmacist or other qualified trial site personnel who will blind the trial supplies.
Treatment identity (name and strength or potency) will be included on the study drug container 
label; randomization code/disclosure envelopes or lists will be provided as per site procedure.
8.1.4
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
The investigational drug blind is maintained through a randomization schedule held by the 
randomization personnel.
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. The 
investigator should perform all study assessments and causality evaluation, if possible, before 
unblinding. In the event of a medical emergency, if possible, the medical monitor or designee 
should be contacted before the investigational drug blind is broken to discuss the need for 
unblinding. The sponsor must be notified as soon as possible if the investigational drug blind is 
broken.


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Individual code break envelopes will be provided for all subjects to the investigator or designee by 
the sponsor or designee. Each sealed envelope containing the randomization code and treatment 
will be kept in a medication storage room, which is locked with restricted access. If opened, the 
name of the person who opened it, the date and time of opening and the reason for opening must be 
written on the envelope. A similar mechanism may be substituted for envelopes (eg, scratch-off 
cards).
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical study drug received 
from the sponsor or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the study. For the study site, the sponsor personnel or designee will 
provide appropriate documentation that must be completed for clinical study drug accountability, 
return, and destruction.


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9.0
STUDY PROCEDURES
The following sections describe the study procedures and data to be collected as indicated in the 
Schedule of Study Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject entering into the study and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations. PGx informed consent is a component of the overall study informed consent. The 
requirements of informed consent are described in Section 13.2.
When subjects have performed screening assessments before study, the data from Screening using 
a generic screening consent form can be used in this study for those who were subsequently 
enrolled, as long as the procedure was performed within the protocol screening to enrollment 
window.
The sampling of whole blood for PGx analysis is mandatory; every subject must sign informed 
consent to participate in the study. A separate optional informed consent may be required for PGx.
9.1.1.1
Assignment of Screening and Randomization Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only 1 screening number. Screening numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event.
Subjects who qualify for the study will be assigned a 4-digit randomization sequence number 
starting with X001 in the order in which they are enrolled into their respective Cohort X, and ended 
with X008. For example, for Cohort 2, the randomization numbers will be 2001 to 2008. The 
number will be assigned by the clinic site personnel in sequential order beginning and ending with 
the numbers specified for each cohort. The 4-digit randomization number will dictate which 
treatment will be assigned to each subject based on the randomization schedules distributed only to 
the authorized personnel (eg, pharmacist). Once a randomization number is assigned to a subject, it 
can never be reassigned to another subject. A single subject cannot be assigned more than 1 
randomization number.
For a subject's replacement, the randomization number will be X9XX, where X's are the same as 
those for the original subject. For example, the replacement number for Subject 3005 will be 3905. 
The replacement will be given the same drug as that for the original subject.


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9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned a randomization number in ascending numerical order at the 
study site. The randomization number encodes the subject assignment to either the TAK-831 or the 
placebo arm of the study, according to the randomization schedule generated before the study by 
the sponsor’s Statistics Department or designee. Each participant will be dispensed blinded study 
treatment, labeled with his/her unique randomization number, throughout the study. If a subject is 
discontinued before the first dose on Day 1, the replacement subject will have the same 
randomization number as the discontinued subject.
9.1.2
Inclusion and Exclusion
Each subject is assessed through randomization, according to the eligibility criteria provided in 
Section 7.0.
9.1.3
Medical History/Demography
Qualified site personnel are to collect subject significant medical history and concurrent medical 
condition per the site’s standard of care and appropriate clinical judgment as well as subject 
demographics.
9.1.4
Medication History/Concomitant Medications
Medications are defined as prescription and over-the-counter drugs, vitamin supplements, 
nutraceuticals, and oral herbal preparations. Qualified site personnel are to review subject 
medication use.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
Qualified site personnel will conduct full physical examinations.
A comprehensive clinical neurological assessment (with a focus on cerebellar signs), will be 
performed on all subjects (except on CSF collection days in CSF cohorts) as indicated in the 
Section 3.0 Schedule of Study Procedures.
The neurological examination will include: 1. Mental status, 2. Cranial nerves I – XII; 3. Motor 
(muscle bulk; tone; power; reflexes); 4. Sensory (pain; temperature, light touch and 
proprioception); 5. Cerebellar function: a) Gait; b) Walk heel-toe in a straight line; c) Romberg’s 
test; d) Intention tremor; e) Assess tone at shoulder, elbow and wrist; f) Test for 
dysdiadochokinesis by rapid alternating movements of hands; g) Test for dysmetria by finger-nose 
test and heel-shin test; h) Assess eye movements for nystagmus; i) Assess speech for staccato 
cerebellar speech; j) Assess for titubation.
For the eye examination: a baseline (Day -2 for single lumbar puncture, Day -1 for indwelling 
catheter, and Day 15) ophthalmological assessment of the retina (fundoscopy), as well as a repeat 
assessment before performing the lumbar puncture for CSF collection.


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Any abnormal finding on a pretreatment physical examination assessment must be assessed as Not 
Clinically Significant (NCS) or Clinically Significant (CS) by the investigator and recorded in the 
source document and eCRF. All CS findings/changes will be recorded as a pretreatment event or 
concurrent medical condition in the source document and on the appropriate eCRF described in 
Section 10.0.
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately before the first dose of the investigational drug on Day 1 in 
each cohort must be assessed as NCS or CS by the investigator and recorded in the source 
document and eCRF. Any CS change or new diagnosis as a result of a CS change, as determined 
by the investigator, will be recorded as an AE in source documentation and on the AE eCRF 
described in Section 10.0.
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.
9.2.3
BMI
BMI equals a person's weight in kilograms divided by height in meters squared (BMI=kg/m2). 
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 round down and 0.5 to 0.9 round up.
9.2.4
Vital Signs
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a supine position for at least 5 minutes before having vital sign 
measurements obtained. Vital signs will include heart rate, respiration rate, and systolic and 
diastolic blood pressure. The same method (eg, same size cuff, manual or automated) must be used 
for all measurements for each individual subject and should be the same for all subjects.
9.2.5
ECGs
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bra.
Subjects should be resting in a supine position for at least 5 minutes before each ECG 
measurement.
QTcF will be used to calculate QT intervals in this study.


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9.2.5.1
Safety ECG
Standard 12-lead ECG (singlet) will be recorded. When an ECG is scheduled at the same time as 
blood draws, or vital signs then the ECG will take priority followed by vital signs and then the 
blood draw. Vitals will be collected within approximately 0.5 hour before the scheduled timepoint. 
The blood draw will be then performed as closely as possible to the ECG. If an ECG coincides 
with a meal or CSF collection, ECG will take precedence followed by CSF collection and then the 
meal.
All stationary 12-lead ECG machines will be supplied by the site. Subjects should be resting in a 
supine position for at least 5 minutes prior to each ECG measurement. Should technical difficulties 
occur during recording of the ECG, a reasonable attempt should be made to repeat the ECG shortly 
after the failed attempt.
Before each Treatment Period/cohort, a predose ECG will be obtained within approximately 
1 hour before dosing TAK-831. This measurement will be used as the baseline. The principal 
investigator should arrange to have a study cardiologist available as needed to review ECG 
tracings with abnormalities.
If a subject demonstrates an increase in QTcF interval ≥40 msec compared with a predose baseline 
measurement, the ECG will be repeated within 30 minutes. The average value of the QTcF interval 
from the 2 ECGs will represent the value at that time point. If the average QTcF interval increase 
from Baseline for any postdose time point is ≥40 msec, the subject will continue to be monitored 
by repeat 12-lead ECGs every 60 minutes for at least 4 hours or until the QTcF is within 40 msec of 
the baseline value. If prolongation of the QTcF interval ≥40 msec persists, a consultation with a 
study cardiologist may be appropriate and the sponsor should be notified.
If the QTcF interval is #500 msec on repeat measurements, the sponsor should be notified and the 
ECGs should be reviewed by a cardiologist. The subject should be monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted, the 
subject should be immediately transferred to an acute care setting for definitive therapy. 
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: heart rate, PR-interval, QRS-duration, 
QT-interval, QTcF interval, and the interpretation of the ECG profile by the principal investigator.
9.2.5.2
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9.2.6
C-SSRS
Suicidality will be assessed by the use of the C-SSRS [10,11]. The C-SSRS was developed by 
researchers at Columbia University as a tool to help systematically assess suicidal ideation and 
behavior in subjects during participation in a clinical trial of centrally-acting drugs. The C-SSRS is 
composed of 3 questions addressing suicidal behavior and 5 questions addressing suicidal 
ideation, with subquestions assessing the severity. The Screening/Baseline C-SSRS (Lifetime) 
will be administered at Screening for all subjects, by the principal investigator or a trained 
designee.
9.2.7
Study Drug Administration
This is an investigator and subject blinded study; therefore, TAK-831 or matching placebo will be 
administered orally on Day 1 and Days 3 through 16 in a blinded fashion.
9.2.7.1
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study medication, appropriate mouth and/or hand checks will 
be performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the eCRFs. An inventory of the 
study medication supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate logistics 
at the site.
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9.2.8
AE Monitoring
AE monitoring begins following signing of informed consent. Changes in subject health status 
from baseline assessment to trial drug administration should be captured in the subject’s medical 
history. A complete description of AE collections and procedures is provided in Section 10.0.
9.2.9
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken on the days stipulated in the Schedule of Study Procedures (Section 3.0).
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells) with absolute differential
Coagulation panel (PT/INR, aPTT) for CSF cohort 
subjects
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cell/high-power field, white blood cell/high-power field, and casts.
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN total bilirubin will be 
fractionated
Protein (total)


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9.2.9.2
Diagnostic Screening
Serum/Blood
Serum diagnostic evaluations will include the following tests:
Alcohol
Hepatitis Screen (HBsAg, HCV antibody)
hCG (female subjects only)
HIV
FSH (female subjects only)
Urine
A urine drug screen will include the following tests: 
Amphetamines
Cotinine
Barbiturates
3,4-methylenedioxy-methamphetamine (MDMA)
Benzodiazepines
Methadone/Metabolite
Buprenorphine/Metabolite
Opiates
Cannabinoids
Oxycodone/Oxymorphone
Cocaine/Metabolites.
Phencyclidine
9.3
PK, PD, and PGx, Samples
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
(a) Only in selected cohort(s).
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9.3.1
PK Measurements 
The PK parameters of TAK-831 will be derived using noncompartmental analysis methods and 
will be determined from the concentration-time data for all evaluable subjects. Actual sampling 
times, rather than scheduled sampling times, will be used in all PK computations involving 
sampling times for plasma PK parameters. 
9.3.1.1
PK Sample Collection
PK blood and CSF samples for TAK-831 concentrations will be collected as specified in the 
Schedule of Trial Procedures (See Section 3.0).
The actual date and time of each PK (blood and CSF) sample collection as well as the date and 
time of study drug dosing for the most recent dose will be recorded accurately in the eCRF.
Instructions for sample processing and shipment are provided in the laboratory manual.
9.3.1.2
PK Sample Analysis
Plasma and CSF concentrations of TAK-831 will be measured by a validated HPLC with tandem 
mass spectrometry assay.
Part of the archival plasma and CSF samples will be used for potential analysis of unknown 
metabolite characterization, if appropriate.
9.3.2
PD Measurements
9.3.2.1
PD Sample Collection
Blood
The actual time of sample collection, time since last dose was administered, and time since last 
meal will be recorded on the source document and eCRF.
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Instructions for sample processing and shipment are provided in the laboratory manual.
CSF
9.3.2.2
PD Sample Analysis
9.3.3
PGx Measurements 
The sampling of whole blood for PGx and genotyping analysis is mandatory; every subject must 
sign informed consent in order to participate in this study. DNA samples will be used to evaluate 
drug metabolic enzyme and transporter polymorphisms. Also, 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 hypothesis-generating 
exploratory research and diagnostic development on stored samples.
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 by Takeda or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Takeda. “Stored samples” are defined as samples 
that are double 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 investigational drug or related drug.
9.3.4
Total Blood Volume
Approximately 380 mL of total blood volume will be collected.
9.3.5
Confinement
Subjects in each cohort will be confined during dosing and be kept in the study unit for 24 hours 
after the last dose for non-CSF cohorts and 48 hours after catheter removal in CSF cohorts. 
The total confinement period in non-CSF cohorts will be 19 days (Day -2 to Day 17), 20 days in 
CSF cohorts where an indwelling temporary catheter is being used on Day 1 and Day 16 
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(confinement from Day -1 to Day 19); and 21 days in CSF cohorts where CSF is collected through 
a single predose lumbar puncture on Day -1 and through an indwelling catheter on Day 16 
(confinement from Day -2 to Day 19). Follow-up assessments will occur on Day 30 (±2) for all 
cohorts. An exception to these minimum confinement periods will be made if a determination is 
made to evaluate QT/QTc intervals for additional single doses of TAK-831 in non-CSF cohorts 
based on the established tolerated dose range.


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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
a study procedure. However, if the subject experiences a worsening or complication of such a 


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


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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.2.8.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
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AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
No AEs of special interest have been identified for TAK-831.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, that is, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
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10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn: a study medication is stopped because of the particular AE.

Dose not changed: the particular AE did not require stopping a study medication.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a study medication was stopped for a reason other than the particular AE, for 
example, the study has been terminated, the subject died, dosing with study medication had not
yet started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced: the dose was reduced because of the particular AE.

Dose increased: the dose was increased because of the particular AE.

Drug interrupted: the dose was interrupted due to the particular AE.
10.2.7 Outcome 

Recovered/resolved: subject returned to first assessment status with respect to the AE.

Recovering/resolving: the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved: there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “not recovered/not 
resolved.”

Recovered/resolved with sequelae: the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal: an AE that is considered as the cause of death.

Unknown: the course of the AE cannot be followed up because of hospital change or residence 
change at the end of the subject’s participation in the study.


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10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up phone call on Day 30 (±2 days), approximately 15 days after the last dose of 
investigational product. For subjects who discontinue before the administration of study 
medication, AEs will be followed until the subject discontinues study participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE before the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin before the first exposure to 
investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/intensity.

Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
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A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs 
No AEs of special interest have been identified for TAK-831.
10.2.8.5 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.9 must also be 


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performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9). 
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before unblinding of treatment 
assignments. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives.
A blinded targeted data review will be conducted before the database lock for the entire study. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods.
For analyses where baseline and/or change from baseline will be evaluated, the baseline is defined 
as the last available results prior to first dose of study drug except for 
 parameters. For 
 parameters, the baseline is defined as the average of the 3 measurements (average of 
triplicate measurements) on Day -1 at time points that are matched with those on Day 1.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety set will include all randomized subjects who receive at least 1 dose of study medication. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
11.1.1.2 PK Set
The PK set will include all randomized subjects who receive at least one dose of study medication and 
who have any available plasma concentration data.
11.1.1.3 PD Set
The PD set will consist of all subjects who receive at least 1 dose of study drug and have at least 1 
postdose PD result.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in the 
PK and PD analyses; however, data for all subjects will be presented in the data listings.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for subjects in the safety set by 
pooled placebo, each TAK-831 dose level, summary statistics (number of subjects, mean, SD, 
median, minimum, and maximum) will be presented for continuous variables (age, weight, and 
BMI), and the number and percentage of subjects within each category will be presented for 
categorical variables (sex, ethnicity, and race).
Individual subject demographic and baseline characteristic data will be listed. Demographic 
variables of screen failure subjects and reasons for screen failures will be summarized overall for 
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subjects who are screened but not enrolled in the study. Individual demographic characteristics, 
date of informed consent, and reason for screen failure will be listed.
11.1.3 PK Analysis
Concentrations of TAK-831 in plasma (all cohorts) and CSF (CSF Cohort[s]) will be summarized 
by dose, drug formulation, and day over each scheduled sampling time using descriptive statistics. 
Individual plasma concentration data versus time will be presented in a data listing. 
PK parameters of TAK-831 will be derived using noncompartmental analysis methods. The PK 
parameters of TAK-831 will be determined from the concentration-time data for all evaluable 
subjects. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. Plasma and CSF PK parameters, including 
dose-normalized Cmax and AUCs, will be summarized by dose, drug formulation, and day using 
descriptive statistics. Changes in the PK parameters from Day 1 to Day 16 will be assessed by 
summarizing the ratio of Day 16 to Day 1 by dose and drug formulation. Dose proportionality in 
plasma PK parameters (Cmax and AUCs) will be assessed graphically for Day 1 and Day 16 plasma 
concentrations for each formulation. Additional analyses will be included if appropriate.
11.1.4 PD Analysis
11.1.5 Safety Analysis
The safety set will be used for all summaries of safety parameters. Summaries will be presented by 
pooled placebo, each TAK-831 dose level, drug formulation, TAK-831 overall, and overall.
11.1.5.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). TEAEs with onset occurring within 30 days 
(onset date – last date of dose +1≤30) after study drug administration will be included in the 
summary tables. All AEs will be in the listings. TEAEs will be summarized by SOC and PT. The 
following summary tables will be included in the report: summary of TEAEs and drug-related 
AEs, relationship of AEs to study drug (related vs not related), severity of AEs, and related AEs. 
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Data listings will be provided for all AEs including TEAEs, AEs leading to study drug 
discontinuation, and SAEs.
11.1.5.2 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal criteria will be summarized and provided in the data listings. 
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized. All 
clinical laboratory data will be provided in the data listings.
11.1.5.3 Vital Signs
Individual results of vital signs that meet Takeda’s markedly abnormal criteria will be summarized 
and provided in the data listings. Baseline, postdose, and changes from Baseline in vital sign 
measurements will be summarized. All vital sign data will be provided in the data listings.
11.1.5.4 ECGs
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria will be summarized and provided in the data listings. 
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized. Shift tables will be generated to show the investigator’s ECG interpretations at each 
postdose collection by the interpretation at Baseline. All ECG data will be provided in the data 
listings.
11.1.5.5 Other Safety Parameters
Physical and neurological examination findings and suicidality assessments (C-SSRS) will be 
presented in data listings.
11.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned. As described in Section 6.2, specific Takeda personnel 
listed in associated study documentation may be unblinded to analyze data considered necessary to 
determine subsequent doses and cohort management decisions during the conduct of the study. In 
addition, sponsor may perform preliminary analysis to inform dose selection for future 
development.
11.3
Determination of Sample Size
The sample size chosen of 8 subjects for all Cohorts (6 active:2 placebo) is considered to be 
sufficient for evaluation of safety, tolerability, and PK of each cohort to determine the dose for the 
next cohort. The sample size was not based on statistical power considerations.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, trial drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration, the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator guarantees access for quality assurance auditors 
to all study documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki are 
addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a Federal 
Wide Assurance Number or comparable number assigned by the Department of Health and 
Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time before analysis. Notify 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, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s 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, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 


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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical 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 investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
SAE and pregnancy reporting
PPD


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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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14.1.3 Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
14.1.4 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
anti-HCV
antibody to hepatitis C virus
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC24
area under the plasma concentration-time curve from 0 to 24 hours
AUCτ
area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the length 
of the dosing interval
BID
twice daily
BMI
body mass index
Cav,ss
average plasma concentration at steady state
CFR
Code of Federal Regulations
CIAS
cognitive impairment associated with schizophrenia
Cmax
maximum observed plasma concentration
Cmax CSF
maximum observed CSF concentration
CNS
central nervous system
CS
clinically significant
CSF
cerebrospinal fluid
C-SSRS
Columbia–Suicide Severity Rating Scale 
DAO
D-amino acid oxidase
ECG
electrocardiogram
eCRF
electronic case report form
Emax
maximum drug-induced effect
FDA
Food and Drug Administration
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
institutional review board


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LFT
liver function test
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple rising dose
NCS
not clinically significant
NMDA
N-methyl-D-aspartate
NOAEL
no-observed-adverse-effect level
NSS
negative symptoms of schizophrenia
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetic
PT
preferred term
QD
once daily
QTc
corrected QT (interval)
QTcF
QT interval with Frederica correction method
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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


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


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16.0
REFERENCES
1. Verrall L, Burnet PW, Betts JF, Harrison PJ. The neurobiology of D-amino acid oxidase and its 
involvement in schizophrenia. Mol Psychiatry 2010;15(2):122-37.
2. Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, et al. D-serine 
regulates cerebellar LTD and motor coordination through the delta2 glutamate receptor. Nat 
Neurosci 2011;14(5):603-11.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights 
from 108 schizophrenia-associated genetic loci. Nature 2014;511(7510):421-7.
9. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of 
benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino 
acid oxidase inhibitor. JAMA Psychiatry 2013;70(12):1267-75.
10. Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. Columbia-suicide severity 
rating scale (C-SSRS). Columbia University. Updated 14 January 09. Accessed 01 May 2012. 
Available at: http://www.cssrs.columbia.edu/docs/C-SSRS_1_14_09_Since_Last_Visit.pdf.
11. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43.


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


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


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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 


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


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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 
(5 half-lives PLUS 30 days) after the last dose of study drug. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study drug will be discontinued and the investigator will 
offer the subject the choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for (5 half-lives 
PLUS 90 days) after the last dose of study drug. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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


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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for (5 half-lives 
PLUS 90 days, which for TAK-831 is 95 days) after last dose of study drug, nonsterilized** male 
subjects who are sexually active with a female partner of childbearing potential* must use barrier 
contraception (eg, condom with or without spermicidal cream or jelly). In addition, they must be 
advised not to donate sperm during this period. Females partners of childbearing potential who are 
partners of male subjects are also advised to use additional contraception as shown in the list 
containing highly effective/effective contraception below.
In studies with no risk of fetotoxicity/teratogenicity/genotoxicity: male subjects are not required to 
use barrier contraception.
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for (5 half-lives 
PLUS 30 days, which for TAK-831 is 35 days) after last dose of study drug, female subjects of 
childbearing potential* who are sexually active with a nonsterilized male partner** must use a 
highly effective/effective method of contraception (from the list below). 
For studies in which teratogenicity/genotoxicity/embryotoxicity has been demonstrated (IMP or 
comparator or background medication), or there is a lack of adequate reproductive toxicity data, 
female subjects should be instructed to use two highly effective methods of contraception/one 
highly effective and one effective method (from the list below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, that is, fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, tubal ligation, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in younger 
women (eg, those <45 years old) or women who are not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
** Sterilized men should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.


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The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are excluded, the 
only acceptable methods of contraception are: 

Non-hormonal methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
the entire period of the study, from 1 month before the first dose until 5 half lives PLUS 
30 days after last dose.

Hormonal methods: hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method (evaluate on compound-by-compound and protocol –
by-protocol basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral †.

Intravaginal † (eg, ring).

Transdermal †.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation1 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has been 
on contraceptive for 3 months;

Oral †.

Injectable.

Implantable.


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5. If genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the investigational 
drug, comparator, background therapy or standard of care medications effective methods of 
contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
6. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
7. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
8. During the course of the study, regular serum hCG pregnancy tests will be performed only for 
women of childbearing potential and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom) in male subjects with pregnant partners.
c) Assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
9.
In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative serum hCG pregnancy test specify time before receiving any dose 


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of study medication. In addition, subjects must also have a negative serum hCG pregnancy test 
specify time before receiving first dose of investigational drug as close as possible and before 
first dose of investigational drug, preferably on the same day.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (ie, condom) in males with pregnant partners.

assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
Pregnancy
Women of childbearing potential will not be included in this study.
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for (5 half-lives PLUS 90 days) after the last dose, 
should also be recorded following authorization from the subject’s partner. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female partner of a male subject agrees to the primary care physician being informed, the 
investigator should notify the primary care physician that the female partner of the subject was 
participating in a clinical study at the time she became pregnant and provide details of the study 
drug the subject received (blinded or unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) will be followed up to final outcome, using the pregnancy 
form. Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted. 


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Appendix E
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 02 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Updated study design and procedures.
The primary change occurs in Section 6.1 Trial Design
Initial 
wording:
The study is a double-blind, placebo-controlled clinical study progressively 
assessing independent cohorts of healthy subjects to continue evaluation of the 
safety, tolerability, PK, and PD of escalating single doses (SD) and multiple doses 
(MD) of TAK-831, as either a suspension or T2 tablet formulation, at levels higher 
than those achieved in the initial single and multiple rising dose (SRD/MRD) Study 
TAK-831-1001. 
….
In all CSF cohorts, serial lumbar CSF samples will be collected through an 
indwelling temporary catheter on 2 separate occasions: the first from Day 1 through 
Day 2, and the second from Day 16 through Day 17, for 24 hours each.
….
Subjects in each cohort will be confined during dosing and be kept in the study unit 
for 24 hours after the last dose for non-CSF cohorts and 48 hours after catheter 
removal in CSF cohorts. The total confinement period in non-CSF cohorts will be 
19 days (Day -2 to Day 17) and 20 days in CSF cohorts (Day -1 to Day 19). 
Follow-up assessments will occur on Day 30 (±2) for all cohorts. An exception to 
these minimum confinement periods will be made if a determination is made to 
evaluate QT/QTc intervals for additional single doses of TAK-831 in non-CSF 
cohorts based on the established tolerated dose range.
Amended or 
new wording:
The study is a double-blindan investigator and subject blinded, sponsor 
unblinded, placebo-controlled clinical study progressively assessing independent 
cohorts of healthy subjects to continue evaluation of the safety, tolerability, and 
PK, and PD of escalating single doses (SD) and multiple doses (MD) of TAK-831, 
as either a suspension or T2 tablet formulation, at levels higher than those achieved 
in the initial single and multiple rising dose (SRD/MRD) Study TAK-831-1001. 
….
In all CSF cohorts, serial lumbar CSF samples will be collected through either a 
single lumbar puncture or an indwelling temporary catheter on 2 separate 
occasions. In CSF cohorts that use an indwelling temporary catheter on both 
occasions, the first fromcollection will occur on Day 1 through Day 2, and the 
second fromon Day 16. In CSF cohorts where the predose CSF sample is 
collected through a single lumbar puncture, the first CSF sample will be 
collected on Day -1 prior to the start of 
 monitoring and the 
CCI


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second collection will be obtained through use of an indwelling temporary 
catheter on Day 17,16. If an indwelling temporary catheter is being used, it 
will collect serial CSF samples for 24 hours each.
….
Subjects in each cohort will be confined during dosing and be kept in the study unit 
for 24 hours after the last dose for non-CSF cohorts and 48 hours after catheter 
removal in CSF cohorts. The total confinement period in non-CSF cohorts will be 
19 days (Day -2 to Day 17) and 20 days in CSF cohorts (Day -1 to Day 19)., 20 
days in CSF cohorts where an indwelling temporary catheter is being used on 
Day 1 and Day 16 (confinement from Day -1 to Day 19); and 21 days in CSF 
cohorts where CSF is collected through a single predose lumbar puncture on 
Day -1 prior to the start of 
 measurements and through an 
indwelling catheter on Day 16 (confinement from Day -2 to Day 19). Follow-up 
assessments will occur on Day 30 (±2) for all cohorts. An exception to these 
minimum confinement periods will be made if a determination is made to evaluate 
QT/QTc intervals for additional single doses of TAK-831 in non-CSF cohorts 
based on the established tolerated dose range.
The following sections also contain this change:
Title Page
1.0 STUDY SUMMARY
2.0 STUDY SCHEMATIC
3.0 SCHEDULE OF STUDY PROCEDURES
5.1.3 Trial Exploratory Objectives #4
5.2.3 Exploratory Endpoints #3, 4, 5, and 6
6.2 Dose Escalation
Table 6.a Proposed Doses and Cohort Dose Escalation
6.3.1 Rationale of Trial Design
6.3.3.3 Exploratory Endpoints
7.1 Inclusion Criteria
7.2 Exclusion Criteria
7.2.1 Additional Exclusion Criteria for Cohort(s) With CSF Collection
7.4.1 Diet and Fluid
9.2.1 Full Physical Examination
9.2.5.2
CCI
CCI


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9.2.7 Study Drug Administration
9.3.2.1 PD Sample Collection
9.3.2 PD Measurements
9.3.5 Confinement
11.1 Statistical and Analytical Plans
11.2 Interim Analysis and Criteria for Early Termination
Rationale for Change: Allow combination of CSF measurements at baseline and 
 
monitoring, clarifications, and corrections/editorial changes.
Change 2: Updated clinical study material management.
The primary change occurs in Section 8.0 CLINICAL STUDY MATERIAL MANAGEMENT.
Initial 
wording:
8.1 Clinical Study Drug
Clinical study drug will be packaged to support enrollment.
8.1.1 Clinical Study Drug Labeling
Clinical study drug will be affixed with a clinical label in accordance with 
regulatory requirements.
8.1.2 Clinical Study Drug Inventory and Storage
Clinical study drug must be stored in a secure, limited-access location under the 
storage conditions specified on the label. Inventory (receipt and dispensing) of 
study drug must be recorded by an authorized person at the study site.
8.1.3 Clinical Study Drug Blinding
This is an investigator and subject blinded, sponsor unblinded study. The study
drug blind is maintained through a randomization schedule held by the 
randomization personnel. Investigational drug will be dispensed in a manner so as 
to minimize the possibility of identification of different doses and placebo through 
appearance. Further details will be provided in the Pharmacy Manual.
8.1.4 Randomization Code Creation and Storage
Takeda Analytical Sciences Department or designee will generate the 
randomization schedule. All randomization information will be stored in a secured 
area, accessible only by authorized personnel. 
8.1.5 Clinical Trial Blind Maintenance/Unblinding Procedure
….
The investigational drug blind shall not be broken by the investigator unless 
information concerning the investigational drug is necessary for the medical 
CCI


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treatment of the subject. All study assessments and causality should be performed, 
if possible, before unblinding. In the event of a medical emergency, if possible, the 
medical monitor or designee should be contacted before the investigational drug 
blind is broken to discuss the need for unblinding. The sponsor must be notified as 
soon as possible if the investigational drug blind is broken.
Individual code break envelopes will be provided for all subjects by the sponsor or 
designee. Each sealed envelope containing the randomization code and treatment 
will be kept in a medication storage room, which is locked with restricted access. If 
opened, the name of the person who opened it, the date and time of opening and the 
reason for opening must be written on the envelope. A similar mechanism may be 
substituted for envelopes (eg, scratch-off cards).
Amended or 
new wording: ….
8.1 Clinical Study Drug
Details regarding the active drug and placebo in tablet dosage form and the 
extemporaneous preparation can be found in the IB and compounding 
manual respectively. Clinical study drug will be packaged to support enrollment 
and replacement subjects as required. When a replacement subject is 
required, the sponsor needs to be contacted prior to dosing.
8.1.1 Clinical Study Drug Labeling
Clinical study drug will be affixed with a clinical label in accordance with 
regulatory requirements.
8.1.2 Clinical Study Drug Inventory and Storage
Clinical study drug must be stored in a secure, limited-access location underand 
remained in the original container until dispensed. The storage conditions 
specified oncondition and temperature excursion information can be found in 
the label. Inventory (receiptcompounding manual. Receipt and dispensing of 
study drug must be recorded by anauthorized personpersonnel at the studytrial 
site.
8.1.3 Clinical Study Drug Blinding
This is an investigator and subject blinded, sponsor-open study. The investigator 
and subjects are blinded to treatment assignment. The unblinded study. The 
study drug supply will be provided to an unblinded pharmacist or other 
qualified trial site personnel who will blind is maintained through athe trial 
supplies. Treatment identity (name and strength or potency) will be included 
on the study drug container label; randomization schedule held by the 
randomization personnel. Investigational drug will be dispensed in a manner 
socode/disclosure envelopes or lists will be provided as to minimize the
possibility of identification of different doses and placebo through appearance. 


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Further details will be provided in the Pharmacy Manualper site procedure.
8.1.4 Randomization Code Creation and Storage
Takeda Analytical Sciences DepartmentRandomization personnel of the 
sponsor or designee will generate the randomization schedule. All randomization 
information will be stored in a secured area, accessible only by authorized 
personnel. 
8.1.5 Clinical Trial Blind Maintenance/Unblinding Procedure
….
The investigational drug blind shall not be broken by the investigator unless 
information concerning the investigational drug is necessary for the medical 
treatment of the subject. AllThe investigator should perform all study 
assessments and causality should be performedevaluation, if possible, before 
unblinding. In the event of a medical emergency, if possible, the medical monitor 
or designee should be contacted before the investigational drug blind is broken to 
discuss the need for unblinding. The sponsor must be notified as soon as possible if 
the investigational drug blind is broken.
Individual code break envelopes will be provided for all subjects to the 
investigator or designee by the sponsor or designee. Each sealed envelope 
containing the randomization code and treatment will be kept in a medication 
storage room, which is locked with restricted access. If opened, the name of the 
person who opened it, the date and time of opening and the reason for opening must 
be written on the envelope. A similar mechanism may be substituted for envelopes 
(eg, scratch-off cards).
….
Rationale for Change: Clarification of procedure.


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Investigator and Subjects Blinded, Sponsor Unblinded, Placebo-
Controlled, Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating 
Multiple Doses of TAK-831 in Healthy Subjects
NCT Number: NCT03224325
SAP Approve Date: 27 September 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-831-1005
A Randomized, Investigator and Subjects Blinded, Sponsor Unblinded, Placebo-Controlled, 
Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Multiple 
Doses of TAK-831 in Healthy Subjects
Phase 1, TAK-831-1005, Multiple Rising Dose
PHASE 1
Version: Amendment 1
Date: 27 September 2018
Prepared by:
Based on:
Protocol Version: Amendment 21
Protocol Date: 19 March 2018
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
SUMMARY OF CHANGES...........................................................................................7
5.0
OBJECTIVES .................................................................................................................8
5.1
Primary Objectives ....................................................................................................8
5.2
Secondary Objectives.................................................................................................8
5.3
Additional Objectives ................................................................................................8
5.4
Study Design .............................................................................................................8
6.0
ANALYSIS ENDPOINTS.............................................................................................10
6.1
Primary Endpoints ...................................................................................................10
6.2
Secondary Endpoints ...............................................................................................10
6.3
Additional Endpoints ...............................................................................................10
7.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
8.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
8.1
General Principles....................................................................................................13
8.1.1
Study Definitions ...............................................................................................13
8.1.2
Definition of Study Days....................................................................................13
8.1.3
Definition of Study Visit Windows ....................................................................13
8.1.4
Conventions for Missing Adverse Event Dates...................................................13
8.1.5
Conventions for Missing Concomitant Medication Dates...................................13
8.1.6
Conventions for Missing Data............................................................................13
8.2
Analysis Sets ...........................................................................................................14
8.3
Disposition of Subjects ............................................................................................14
8.4
Demographic and Other Baseline Characteristics.....................................................15
8.5
Medical History and Concurrent Medical Conditions...............................................15
8.6
Medication History and Concomitant Medications...................................................15
8.7
Study Drug Exposure and Compliance.....................................................................15
8.8
Efficacy Analysis.....................................................................................................16
8.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................16
8.9.1
Pharmacokinetic Analysis ..................................................................................16
8.9.2
Pharmacodynamic Analysis ...............................................................................17
8.10
Other Outcomes.......................................................................................................18


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8.11
Safety Analysis........................................................................................................19
8.11.1 Adverse Events ..................................................................................................19
8.11.2 Clinical Laboratory Evaluations .........................................................................20
8.11.3 Vital Signs .........................................................................................................21
8.11.4 12-Lead ECGs ...................................................................................................21
8.11.5
......................................................................................................22
8.11.6 Other Observations Related to Safety.................................................................22
8.12
Interim Analysis ......................................................................................................22
8.13
Changes in the Statistical Analysis Plan...................................................................22
9.0
REFERENCES..............................................................................................................23
LIST OF IN-TEXT FIGURES
Figure 5.a
Schematics of Study Design.................................................................................9
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................24
Appendix B
Criteria for Abnormal Changes from Baseline of Vital Signs..............................25
Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes...............26
Appendix D
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters....................27
Appendix E
Detailed Description of Amendment to Text ......................................................28
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3.0
LIST OF ABBREVIATIONS
%CV
coefficient of variation
λz
terminal disposition phase rate constant
AE
adverse event
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC
Area under the concentration-time curve from time 0 to infinity 
AUC24
area under the plasma drug concentration-time curve from time 0 to 24hours postdose
AUC24,CSF
area under the CSF drug concentration-time curve from time 0 to 24hours postdose
AUCτ
area under the plasma drug concentration-time curve during a dosing interval
AUCτ,CSF
area under the CSF drug concentration-time curve during a dosing interval
AUCt
area under the plasma drug concentration-time curve from time 0 to time t on Day 1
AUCt,CSF
area under the CSF drug concentration-time curve from time 0 to time t on Day 1
AUEC24
area under the plasma effect-time curve from time 0 to 24 hours postdose
AUEC24, CSF
area under the CSF effect-time curve from time 0 to 24 hours postdose
BLQ
below the limit of quantification
BMI
body mass index
Cav,ss
average plasma drug concentration during a dosing interval, at steady state
Cav,ss,CSF
average CSF drug concentration during a dosing interval, at steady state
C-SSRS
Columbia-Suicide Severity Rating Scale
CI
confidence interval
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
Cmax,CSF
maximum observed CSF concentration
Cmax,ss
maximum observed plasma concentration during a dosing interval, at steady state
Cmax,ss,CSF
maximum observed CSF concentration during a dosing interval, at steady state
CNS
central nervous system
CSF
cerebrospinal fluid
CV
conventional units
ECG
Electrocardiogram
eCRF
electronic case report form
Emax
maximum observed effect
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple-rising dose
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PT
preferred term
PTE
pretreatment event
QD
once daily


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Rac(AUC)
accumulation ratio based on AUC
Rac(Cmax)
accumulation ratio based on Cmax
Rac(AUC, CSF)
accumulation ratio based on CSF AUC 
Rac(Cmax, CSF)
accumulation ratio based on CSF Cmax
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
International System of Units
SOC
system organ class
SRD
single-rising dose
TEAE
treatment emergent adverse event
t1/2z
terminal disposition phase half-life
tmax
Time of first occurrence of Cmax
tmax,CSF
time of first occurrence of Cmax in CSF
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
WHODrug
World Health Organization Drug Dictionary


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4.0
SUMMARY OF CHANGES
This section describes the changes made about the SAP incorporating Amendment No. 1. 
Detailed description of amendments to the text is presented in Appendix E.
1.
2.
3. Approver changes
Justification: SAP signatories changed in accordance with personal changes.
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5.0
OBJECTIVES
5.1
Primary Objectives
To evaluate the safety and tolerability of TAK-831 when administered as multiple oral doses at 
escalating dose levels in healthy subjects.
5.2
Secondary Objectives
To evaluate the PK of TAK-831 when administered as multiple oral doses at escalating dose 
levels in healthy subjects.
5.3
Additional Objectives
5.4
Study Design
The study is a investigator and subject blinded, sponsor-unblinded, placebo-controlled clinical 
study progressively assessing independent cohorts of healthy subjects to continue evaluation of 
the safety, tolerability, PK of escalating single doses (SD) and multiple doses (MD) of TAK-831, 
as either a suspension or T2 tablet formulation, at levels higher than those achieved in the initial 
single and multiple rising dose (SRD/MRD) Study TAK-831-1001. 
Up to 6 cohorts will be run either singly or in parallel as non- cerebrospinal fluid (CSF) cohorts 
with plasma analysis or CSF cohorts with CSF analysis in addition to plasma analysis to assess 
TAK-831 exposure and 
levels in the central nervous system (CNS). 
After meeting all the selection criteria, there will be 8 subjects enrolled in each cohort. They will 
be randomized on Day 1 in a ratio of 1:3 to receive placebo or TAK-831. 
All cohorts will start with an initial, in-house SD period to include predose PD assessments on 
Day -1, Day 1 TAK-831 dosing, and a 48-hour in-house observation period with full PK/PD
collections. The SD PK/PD collection and observation phase will be followed by 14 days of in-
house MD.
In CSF cohorts, lumbar CSF samples will be collected through either a single lumbar puncture or 
an indwelling temporary catheter on 2 separate occasions. In CSF cohorts that use an indwelling 
temporary catheter on both occasions, the first collection will occur on Day 1, and the second on
Day 16. In CSF cohorts where the predose CSF sample is collected through a single lumbar 
puncture, the first CSF sample will be collected on Day -1 prior to the start of 
 
CCI
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monitoring and the second collection will be obtained through use of an indwelling temporary
catheter on Day 16. If an indwelling temporary catheter is being used, it will collect serial CSF 
samples for 24 hours.
Subjects in each cohort will be confined during dosing and be kept in the study unit for 24 hours 
after the last dose for non-CSF cohorts and 48 hours after catheter removal in CSF cohorts. The 
total confinement period in non-CSF cohorts will be 19 days (Day -2 to Day 17), 20 days in CSF 
cohorts where an indwelling temporary catheter is being used on Day 1 and Day 16 (confinement 
from Day -1 to Day 19); and 21 days in CSF cohorts where CSF is collected through a single 
predose lumbar puncture on Day -1 prior to the start of 
 measurements and through 
an indwelling catheter on Day 16 (confinement from Day -2 to Day 19). Follow-up assessments 
will occur on Day 30 (±2) for all cohorts. An exception to these minimum confinement periods 
will be made if a determination is made to evaluate QT/QTc intervals for additional single doses 
of TAK-831 in non-CSF cohorts based on the established tolerated dose range.
A schematic of the study design is presented in Figure 5.a.
Figure 5.a
Schematics of Study Design 
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6.0
ANALYSIS ENDPOINTS
6.1
Primary Endpoints
Primary endpoints for the study include:
∀
Percentage of subjects who experience at least 1 treatment emergent adverse event (TEAE).
∀
Percentage of subjects who meet the markedly abnormal criteria for clinical safety laboratory 
tests at least once postdose.
∀
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements 
at least once post dose.
∀
Percentage of subjects who meet the markedly abnormal criteria for 12-lead safety 
electrocardiogram (ECG) parameters at least once post dose.
6.2
Secondary Endpoints
Plasma PK Parameters of TAK-831:
1. Maximum observed plasma concentration (Cmax) (Day 1). 
2. Maximum observed steady-state plasma concentration during a dosing interval (Day 16). 
3. Time of first occurrence of Cmax (Days 1 and 16). 
4. Area under the plasma concentration-time curve during a dosing interval (Days 1 and 16).
6.3
Additional Endpoints
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7.0
DETERMINATION OF SAMPLE SIZE
The sample size chosen of 8 subjects for all Cohorts (6 active : 2 placebo) is considered to be 
sufficient for evaluation of safety, tolerability, and PK of each cohort to determine the dose for 
the next cohort. The sample size was not based on statistical power considerations.


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8.0
METHODS OF ANALYSIS AND PRESENTATION
8.1
General Principles 
All study-related raw and derived data for randomized subjects will be presented in listings by 
cohort. Randomized subjects are the subjects who are enrolled and received a randomization 
number.
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percent of subjects for each category, where appropriate.
Unless otherwise stated, baseline is defined as the last observed value before the first dose of 
study medication.
As applicable, summaries will be presented by pooled placebo, each combination of TAK-831 
dose level /formulation, TAK-831 overall and overall. 
All data analyses and figures will be generated using SAS System® Version 9.2 or higher.
8.1.1
Study Definitions
There are no study-specific definitions.
8.1.2
Definition of Study Days
Study day will be calculated relative to the date of the first dose of the study drug in each study 
part. Study days prior to the first dose of study drug in each study part will be calculated as: 
{date of assessment/event – date of first dose of study drug of the subject}. Study days on or 
after the first dose of study drug will be calculated as: {date of assessment/event – date of first 
dose of study drug of the subject + 1}.
8.1.3
Definition of Study Visit Windows
There will be no visit windows.
8.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.
8.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.
8.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 


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Plasma or CSF concentrations that are below the limit of quantification (BLQ) will be treated as 
zero in the summarization of concentration values and derivation of PK parameters. These values 
will be flagged in the data listings and deviations from this convention may be considered on a 
case-by-case basis as deemed appropriate.
8.2
Analysis Sets
Safety Set
The Safety Set will include all randomized subjects who receive at least 1 dose of study drug in a 
given part of the study. Subjects in this set will be used for demographic and safety summaries.
Pharmacokinetic Set
The PK set will include all randomized subjects with at least 1 measurable concentration for 
TAK-831. All subjects with valid PK parameter estimates will be included in the summaries and 
analyses for that parameter.
Pharmacodynamic Set
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in 
the PK and PD analyses; however, data for all subjects will be presented in the data listings.
8.3
Disposition of Subjects
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data.
Summaries will be presented by pooled placebo, each combination of TAK-831 dose 
level/formulation, TAK-831 overall and overall. 
Disposition of all randomized subjects will be tabulated for each part of the study: 
∀
All subjects received at least one dose of study drug (denominator).
∀
Subjects who completed the study.
∀
Subjects who prematurely discontinued study.
Primary reasons for discontinuation of study, as entered on the electronic case report form
(eCRF), will be tabulated. Reasons for discontinuation include adverse event, significant 
protocol deviation, lost to follow-up, withdrawal by subject, study termination, and other. The 
date of first dose, date of last dose, duration of treatment and the reason for premature 
discontinuation of study drug/study visit will be presented for each subject in listings. 
Disposition of screen failure subjects will be summarized descriptively. Primary reasons for 
failure will be summarized and will be presented in a data listing.
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8.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized using the Safety Set. Summaries
will be presented by pooled placebo, each combination of TAK-831 dose level and formulation, 
TAK-831 overall and overall.
Summary statistics will be presented for continuous variables (age, height, weight, and body 
mass index [BMI]). The number and percentage subjects within each category will be presented 
for categorical variables (for example, gender, race, etc.). Individual subject demographic and 
baseline characteristic data will be listed.
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized overall for subjects who are screened but not enrolled in the study.
8.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 18 or higher) coding system. 
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Ongoing conditions are considered 
concurrent medical conditions.
All medical history and concurrent medical condition data will be listed by site (study center) 
and subject number. The listing will contain subject identifier, treatment, system organ class 
(SOC), preferred term (PT), whether there was any medical history or concurrent condition, and,
if yes, a detail of the medical history or concurrent condition. No inferential statistics will be 
presented.
8.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medications are recorded on 
the eCRF and include any medications, other than study drug, taken at any time between 
informed consent and the end of the study. 
All medication history and concomitant medications will be listed by site (study center) and 
subject number. The listings will contain subject identifier, treatment, World Health 
Organization Drug Dictionary (WHODrug) preferred medication name, dose, unit, frequency, 
route, start date, stop date, whether the medication was ongoing, and reason for use. No 
inferential statistics will be presented. 
Medication history and concomitant medications will be coded using the WHODrug Version 
01March 2017 or higher.
8.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all 
subjects. Meal consumptions and timing will be reported in the data listing as well. Summaries 


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of PK data will be provided by dose and formulation group. No other summary statistics for the 
extent of exposure to study drug or compliance calculations will be performed for this study.
8.8
Efficacy Analysis
Not applicable.
8.9
Pharmacokinetic/Pharmacodynamic Analysis
8.9.1
Pharmacokinetic Analysis
All PK summaries and analyses will be based on the PK set. PK parameters of TAK-831 will be 
derived using non-compartmental analysis methods. The PK parameters of TAK-831 will be 
determined from the concentration-time data for all evaluable subjects. Actual sampling times, 
rather than scheduled sampling times, will be used in all computations involving sampling times.
Serial blood samples for determination of TAK-831 concentrations will be collected on Day 1 
(within 30 minutes before dosing) and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, hours after the morning dose; 
on Day 10 (predose), Day 13 (predose), and on Day 16 at predose (within 30 minutes before 
dosing), and at 0.5, 1, 2, 4, 8, 12, 16, and 24 hours after the morning dose and at Early 
Termination. 
In CSF cohorts, serial CSF samples will be collected On Day 1 and/or Day 16 at predose (within 
30 minutes before dosing) and at 1, 4, 8, 12, and 24 hours after the morning dose.
The following pharmacokinetic parameters will be calculated for plasma (Day -1, Day 1 and 
Day 16) and CSF (Days 1 and/or 16) concentrations of TAK-831 when appropriate:
Symbol/Term
Definition 
AUCτ /AUCτ, CSF
Area under the concentration-time curve during a dosing interval.
AUCt /AUCt, CSF
Area under the concentration-time curve from time 0 to time t. (Day 1 only)
AUC∞
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (Day 1 only)
Rac(AUC) / Rac(AUC, CSF)
Accumulation ratio based on AUCτ. 
Rac(Cmax) / Rac(Cmax, CSF)
Accumulation factor based on Cmax.
Cav,ss /Cav,ss, CSF
Average concentration during a dosing interval, at steady state.
Cmax /Cmax, CSF
Maximum observed concentration on Day 1 and Day 16.
CL/F
Apparent clearance after extravascular administration, calculated as =Dose/AUC∞after a 
single dose. Plasma only. (Day 1 only)
λz
Terminal disposition phase rate constant. Plasma only.
t1/2z
Terminal disposition phase half-life. Plasma only.
tmax/ tmax, CSF
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration. 
Plasma only. (Day 1 only)


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Descriptive statistics (N, arithmetic mean, SD, %CV, median, minimum, and maximum) will be 
used to summarize the plasma and CSF PK parameters for TAK-831, including dose-normalized 
Cmax and AUCs, by dose and formulation. In addition, geometric mean will be computed for Cmax
and AUCs, including those dose-normalized Cmax and AUCs. Individual plasma PK parameters
will be presented in a data listing.
Dose proportionality in plasma and CSF PK parameters (Cmax and AUCs as well as dose-
normalized Cmax and AUCs) will be assessed graphically using box-plots for Day 1 and Day 16 
plasma and CSF PK parameters for each formulation. Other figures needed for PK data are 
described in Clinical pharmacology Analysis Plan for this study.
Additional analyses will be included if appropriate.
8.9.2
Pharmacodynamic Analysis
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8.10
Other Outcomes
Not applicable.
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8.11
Safety Analysis
Safety analyses include AEs, clinical laboratory parameters, vital sign parameters, 12-lead ECG 
results, and other safety parameters. The Safety Set will be used for all summaries of safety 
parameters. The safety endpoints will be presented by pooled placebo, each TAK-831 dose level, 
TAK-831 overall, and overall.
8.11.1 Adverse Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. PTE and AE verbatim terms will be coded by SOC and PT using MedDRA (version 
20.0 or later).
TEAEs will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occur after the first dose of study drug and up to 30 days (onset 
date – last date of dose + 1 ≤30) after the last dose of study drug or early termination.
TEAEs are recorded in the eCRF as being related or not related to study drug and study 
procedure. TEAEs that are recorded as related to study drug and/or study procedure will be 
summarized separately. TEAEs will also be presented by intensity/severity (mild, moderate, and 
severe). Serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to 
death will also be summarized using SOC and PT. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
In general, AEs will be tabulated at the following levels: overall summary (subjects with at least 
1 AE in any dose or regimen), the MedDRA SOC, and the MedDRA PT. The tables will include 
the number and percentage (N[%]) of subjects. The following summary tables will be generated 
for each study part: 

Overview of Treatment-Emergent Adverse Events.

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.

Treatment-Emergent Adverse Events by Preferred Term.


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
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term.

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.

Drug-Related Treatment-Emergent Adverse Events by Preferred Term.

Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.

Pretreatment Adverse Events by System Organ Class and Preferred Term.
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
liver function abnormalities, SAEs, and AEs that resulted in death. AEs happened after 30 days 
post the last dose of the study drug will be listed as well.
8.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. Refer to Protocol Section 
9.2.9.1 and 9.2.9.2 as well as the schedule of the events for a list of all clinical laboratory tests.
All laboratory test parameters will be displayed in individual subject data listings in both SI units 
and conventional (CV) units. For test results not in SI units, the conversion to SI units will be 
done in the derived SDTM and ADaM datasets using the known conversion factors. If necessary, 
SI units from the central laboratory may be converted to Takeda’s preferred SI units in the 
derived SDTM and ADaM datasets. All summaries and analyses will be based on the values 
using these preferred SI units.
Only observations within 7 days of the last dose of study drug will be included in the tables. No 
inferential statistics will be presented unless otherwise stated.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values will be presented. Study baseline will be used for change from 
baseline. Note that “character” urinalysis tests will only be listed.
Laboratory MAVs, identified by the criteria defined in Appendix A, will be tabulated. If a 
subject has a MAV for a particular laboratory test, all visits for that subject for that parameter 
will be listed. The number and percentage of subjects with at least 1 postdose markedly abnormal 
laboratory test result will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Listings of all clinical safety laboratory data will be provided in Appendix 16.2 and will be 
presented in both SI and CV units. Laboratory data outside of the normal reference range will be 


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indicated in the listings. In addition, MAVs will be flagged. The listing will include site number, 
subject identifier, age, gender, treatment group, study visit, and sample collection date.
8.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Only observations within 7 days of the study drug will be included in 
the tables.
Vital sign MAVs, identified by the criteria defined in Appendix B, will be tabulated. If a subject 
has a MAV for a particular vital signs parameter, all visits for that subject for that parameter will 
be listed. The number and percentage of subjects with at least 1 postdose markedly abnormal 
vital signs measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Orthostatic hypotension, identified by the criteria defined in Appendix C, will be calculated at 
every time point where standing and supine measurements are available using the formula: 
standing vital measurement – supine vital measurement. The mapping of the subjects who meet 
the criteria for orthostatic hypotension will be listed by study visit as a table. All orthostatic 
hypotension observations, including ones at unscheduled visits, will be included in the subject 
mappings.
Listings of all vital signs data will be provided in Appendix 16.2. Vital sign MAVs will be 
flagged in the listings. The listing will include site number, subject identifier, age, gender, 
treatment group, study visit, and sample collection date.
8.11.4 12-Lead ECGs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters, 
including heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc interval 
(Fredericia’s and Bazett’s corrections), will be presented for baseline, each post-baseline visit, 
and change from baseline to each post-baseline visit. Only the scheduled measurements will be 
included in the summary. Only observations within 7 days of the study drug will be included in 
the tables. No inferential statistics will be presented.
ECG MAVs, identified by the criteria defined in Appendix D, will be tabulated. If a subject has a 
MAV for a particular 12-lead ECG parameter, all visits for that subject for that parameter will be 
listed. The number and percentage of subjects with at least 1 postdose markedly abnormal 12-
lead ECG measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant) is collected by eCRF at baseline and at each scheduled post-baseline visit. 
Shifts in ECG interpretation will be presented as cross-tabulations (baseline versus each post-


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baseline visit) of numbers of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant interpretations with missing, if applicable, and total categories by 
regimen.
Listings of all 12-lead ECG data will be provided in Appendix 16.2. MAVs will be flagged in the 
listings. The listing will include site number, subject identifier, age, gender, treatment group, 
study visit, and sample collection date.
8.11.5
8.11.6 Other Observations Related to Safety
Follow-up phone calls, DNA sample collections, physical and neurological examination and 
suicidality assessments (C-SSRS) will be presented in data listings.
8.12
Interim Analysis
This is an investigator-subject blinded, sponsor unblinded study. No formal interim analysis is 
planned. 
8.13
Changes in the Statistical Analysis Plan 
Not Applicable.
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9.0
REFERENCES
1. A Phase 1, Randomized, Investigator and Subjects Blinded, Sponsor Unblinded, Placebo-
Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple 
Doses of TAK-831 in Healthy Subjects, Takeda Development Center Europe, Ltd., Protocol 
No. TAK-831-1005, Amendment No.2, dated 19 March 2018.
2. Garnett C, Bonate PL, Dang Q, Ferber G, et.al. (2018) Scientific white paper on 
concentration-QTc modeling. J. Pharmacokinet Pharmacodyn. 45, 383-397.


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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
CPK
Both
--
>5x ULN
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CPK=creatine phosphokinase, GGT=-glutamyl 
transferase, LLN=lower limit of normal, ULN=upper limit of normal.


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


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Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes
Parameter
Criteria
Orthostatic Hypotension
(Orthostatic Systolic Blood Pressure < -20 mm Hg OR
Orthostatic Diastolic Blood Pressure < -10 mm Hg) AND Heart 
Rate Increase > 20 beats/min
Note: Orthostatic measurement = standing vital measurement – supine vital measurement.


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Appendix D
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcB Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and 
≥450 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤80 milliseconds
≥180 milliseconds


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Appendix E
Detailed Description of Amendment to Text
This section describes changes about SAP incorporating Amendment No. 1.
Page 2 Section 1.1 Approval Signatures
Existing Text
Approvals:
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Revised Text
Approvals:
Rational for Amendment
SAP signatories updated in accordance with personnel changes.
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Page 8, Section 5.3 Additional Objectives:
Existing Text:
…4. To explore the effect of a single oral dose of TAK-831 on the QT/QTc interval in non-CSF 
cohorts.
Revised Text:
… 4. To explore the effect of a single oral dose of TAK-831 on the QT/QTc interval in non-CSF 
cohorts (or in CSF cohorts that collect baseline CSF samples via a single pre-dose lumbar 
puncture on Day -1 prior to 
 measurements).
Rational for Amendment
For the last 2 dosing Cohorts 5 and 6, The serial CSF samples are not to be collected on Day 1 to 
allow 
 monitoring in the CSF cohorts where, and the first single baseline CSF sample 
is to be collected instead through a single lumbar puncture on Day -1 based on the protocol 
Amendment 2. The analysis of CSF samples is revised in the SAP to reflect this study change.
Page 8 Section 5.4 Study Design
Existing Text:
The study is an investigator and subject blinded, sponsor-unblinded, placebo-controlled clinical 
study progressively assessing independent cohorts of healthy subjects to continue evaluation of 
the safety, tolerability, PK, and PD of escalating single doses (SD) and multiple doses (MD) of 
TAK-831…
Revised Text:
The study is an investigator and subject blinded, sponsor-unblinded, placebo-controlled clinical 
study progressively assessing independent cohorts of healthy subjects to continue evaluation of 
the safety, tolerability and PK of escalating single doses (SD) and multiple doses (MD) of TAK-
831…
Rational for Amendment:
Based on a few changes in the protocol amendment which was for clarification and correction.
Page 8-9, Section 5.4 Study Design:
Existing Text:
… In all CSF cohorts, serial lumbar CSF samples will be collected through an indwelling 
temporary catheter on 2 separate occasions: the first from Day 1 through Day 2, and the second 
from Day 16 through Day 17, for 24 hours each.
Revised Text:
In CSF cohorts, lumbar CSF samples will be collected through either a single lumbar 
puncture or an indwelling temporary catheter on 2 separate occasions. In CSF cohorts that use 
an indwelling temporary catheter on both occasions, the first collection will occur on Day 1, 
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and the second on Day 16. In CSF cohorts where the predose CSF sample is collected 
through a single lumbar puncture, the first CSF sample will be collected on Day -1 prior to 
the start of 
 monitoring and the second collection will be obtained through use 
of an indwelling temporary catheter on Day 16. If an indwelling temporary catheter is 
being used, it will collect serial CSF samples for 24 hours.
Rational for Amendment:
Allow combination of CSF measurements at baseline and 
 monitoring, clarifications, 
and corrections/editorial changes.
Page 9 Section 5.4 Study Design:
Existing Text:
The total confinement period in non-CSF cohorts will be 19 days (Day -2 to Day 17) and 20 days 
in CSF cohorts (Day -1 to Day 19).
Revised Text:
The total confinement period in non-CSF cohorts will be 19 days (Day -2 to Day 17), 20 days in 
CSF cohorts where an indwelling temporary catheter is being used on Day 1 and Day 16 
(confinement from Day -1 to Day 19); and 21 days in CSF cohorts where CSF is collected 
through a single predose lumbar puncture on Day -1 prior to the start of 
 
measurements and through an indwelling catheter on Day 16 (confinement from Day -2 to 
Day 19).
Rational for Amendment:
Allow combination of CSF measurements at baseline and 
 monitoring, clarifications, 
and corrections/editorial changes.
Page 9, Figure 5.a Schematics of Study Design
Existing Text:
Cohorts
(up to 6 as 
needed)
Pretreatment Period
Treatment and Assessments (a)
Study 
Exit
Follow-up 
(b)
Screening
Check-in/ 
Baseline
SD Part
MD Part
Treatment
Evaluation
Non-CSF 
Days -28 to -3 
Day -2
Day 1 
Days 1 to 2
Days 3 to 16
Day 17
Day 30 (±2)
CSF
Days -28 to -2
Day -1
Day 1
Days 1 to 2
Days 3 to 16
Day 19
Day 30 (±2)
                                 Confinement                              
CSF=cerebrospinal fluid, MD=multiple dose, PD=pharmacodynamic, PK=pharmacodynamic, SD=single dose.
(a) TAK-831 dosing will be on Day 1 for SD and Days 3 through 16 for MD.
(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 clinic for re-evaluation per investigator’s 
discretion. 
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Revised Text:
Rational for Amendment:
Allow combination of CSF measurements at baseline and 
 monitoring, clarifications, 
and corrections/editorial changes.
Page 11 Section 6.3 Additional Endpoints
Existing Text:
Revised Text:
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Rational for Amendment:
Allow combination of CSF measurements at baseline and 
 monitoring, clarifications, 
and corrections/editorial changes.
Page 16 Section 8.9.1 Pharmacokinetic Analysis
Existing Text:
In CSF cohorts, serial CSF samples will be collected On Day 1 and Day 16 at predose (within 30 
minutes before dosing) and at 1, 4, 8, 12, and 24 hours after the morning dose.
The following pharmacokinetic parameters will be calculated for plasma (Day -1, Day 1 and Day 
16) and CSF (Days 1 and 16) concentrations of TAK-831
Revised Text:
In CSF cohorts, serial CSF samples will be collected On Day 1 and/or Day 16 at predose (within 
30 minutes before dosing) and at 1, 4, 8, 12, and 24 hours after the morning dose.
The following pharmacokinetic parameters will be calculated for plasma (Day -1, Day 1 and Day 
16) and CSF (Days 1 and/or 16) concentrations of TAK-831 when appropriate
Rational for Amendment:
Allow combination of CSF measurements at baseline and 
 monitoring, clarifications, 
and corrections/editorial changes.
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Page 17 Section 8.9.2 Pharmacodynamic Analysis
Existing Text:
Revised Text:
Rational for Amendment:
Page 18 Section 8.9.2 Pharmacodynamic Analysis:
Existing Text:
Revised Text:
Rational for Amendment:
Editorial change due to the change in study design.
Page 22 Section 8.11.5 
Exiting Text:
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Revised Text:
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Rational for Amendment:
Based on the recent scientific white paper on concentration-QTc modeling published by Garnett 
et. al, (published online 5 December 2017)2, a pre-specified and dedicated modeling analysis is 
recommended. Therefore, the concentration-QTc analysis will be performed outside of the 
current SAP and results will be reported separately for regulatory purposes.
Page 23 Section 9.0 References
Existing Text:
1. A Phase 1, Randomized, Investigator and Subjects Blinded, Sponsor Unblinded, Placebo-
Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple 
Doses of TAK-831 in Healthy Subjects, Takeda Development Center Europe, Ltd., Protocol 
No. TAK-831-1005, Amendment No.1, dated 15 August 2017.
Revised Text:
1. A Phase 1, Randomized, Investigator and Subjects Blinded, Sponsor Unblinded, Placebo-
Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple 
Doses of TAK-831 in Healthy Subjects, Takeda Development Center Europe, Ltd., Protocol 
No. TAK-831-1005, Amendment No.2, dated 19 March 2018.
2. Garnett C, Bonate PL, Dang Q, Ferber G, et.al. (2018) Scientific white paper on 
concentration-QTc modeling. J. Pharmacokinet Pharmacodyn. 45, 383-397.
Rational for Amendment:
Adding more references for the changes.
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