Clinical trial NCT03382639
Conditions: Schizophrenia
Keywords: Drug therapy
Sponsor: Neurocrine Biosciences
Start date: 2018-01-04; Completion date: 2021-01-12
Enrollment: 256 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether add-on luvadaxistat is superior to placebo on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS NSFS).

Detailed description:
The drug being tested in this study is called luvadaxistat. Luvadaxistat is being tested to treat negative symptoms in participants who have schizophrenia.

Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups in the double-blind period-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Luvadaxistat 50 mg once daily
* Luvadaxistat 125 mg once daily
* Luvadaxistat 500 mg once daily
* Placebo once daily

Arms: arm 1: Participants received luvadaxistat 50 mg orally once daily (QD) for 12 weeks (Days 1 to 84). arm 2: Participants received luvadaxistat 125 mg orally QD for 12 weeks (Days 1 to 84). arm 3: Participants received luvadaxistat 500 mg orally QD for 12 weeks (Days 1 to 84). arm 4: Participants received placebo (matching luvadaxistat) orally QD for 12 weeks (Days 1 to 84).
Interventions: intervention 1: Luvadaxistat intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-831 tablets. intervention 2: Luvadaxistat placebo-matching tablets.

Protocol documents:
Prot_000.pdf: 
1.0 TITLE PAGENCT0338 
NNN NN2639
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to 
Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose Levels of TAK-831 
in Adjunctive Treatment of Adult Subjects With Negative Symptoms of Schizophrenia
A Study of 3 Doses of TAK-831 as an Adjunctive Treatment for Negative Symptoms of 
Schizophrenia
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge MA 02139
USA
Study Number:
TAK-831-2002
IND Number:
135,176
EudraCT Number:
2017-003471-54 
Compound:
TAK-831
Date:
08 June 2020
Amendment Number:
04
Amendment History: 
Date
Amendment Number
Amendment Type
Region
30 October 2017
Initial Protocol
Not applicable
Global
26 June 2018
Amendment 01
Substantial
Global
19 July 2018
Amendment 02
Substantial
Local (Czech Republic)
13 March 2019
Amendment 03
Substantial
Global
08 June 2020
Amendment 04
Substantial
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.
NCT #: NCT03382639


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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda-sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America Contact
Europe Contact
Serious adverse event and 
pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc 
Fax: +1-224-554-1052
Email: PVSafetyAmericas@tpna.com
Pharmacovigilance
Takeda Development Center Europe, Ltd
Fax: +44-207-242-1820 
Email: eupv@tgrd.com
Medical Monitor
(medical advice on protocol 
and study drug)
 
IQVIA
US: 
Mobile: 
Email:
 
 
IQVIA
Mobile: 
Email: 
Responsible Medical Officer 
(carries overall responsibility 
for the conduct of the study)
 
 
Takeda Development Center Americas, Inc
Office: 
Mobile: 
Email: 
 
 
Takeda Development Center Americas, Inc
Office: 
Mobile:
Email:


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can
be found on the signature page.
Electronic signatures are provided on the last page of this document.
Date
Date
Date
Date


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CONFIDENTIAL
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.

International Council for Harmonisation, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)


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1.3
Protocol Amendment No. 04 Summary of Changes and Rationale
Rationale for Amendment No. 04
This section describes the changes in reference to the protocol incorporating Amendment No. 04. 
The primary reason for this amendment is to describe management of study procedures (eg, 
alternative strategies for collecting data, conducting study visits and distributing investigational 
product) during unexpected, unavoidable circumstances (eg, a widespread disease outbreak or 
natural disaster) such as the coronavirus disease 2019 (COVID-19) pandemic.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
A history of TAK-831-2002 protocol amendments 01 through 03 is provided in Appendix E. 
Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) 
Affected by 
Change
Description
Rationale
Location(s)
1.
Updated medical monitor and responsible medical 
officer contact information and names and titles of 
approval signatories.
To update contact information for 
medical monitors, the responsible 
medical officer, and names and 
titles of signatories who will 
approve this protocol amendment.
Sections:
1.1 Contacts
1.2 Approval
2.
Added guidance regarding rescreening of 
potential subjects who discontinued during 
screening or the single-blind run-in due to 
COVID-19 related factors.
To allow for rescreening of subjects 
who were discontinued during 
screening or single-blind run-in 
period due to COVID-19 outbreak 
related factors. Sponsor made 
decision to ask sites to discontinue 
subjects due to uncertainty related 
to impact of COVID 19 outbreak on 
human activities in communities 
and at study sites. Because these 
subjects may have been qualifiable 
for the study otherwise, sponsor 
agrees for these subjects to be 
rescreened.
Section 6.1 Study 
Design
3.
Added COVID-19-related guidance to criteria for 
discontinuation or withdrawal of a subject.
To ensure that subject 
discontinuations due to COVID-19 
related factors are documented in 
ways that best fit within the 
categories previously supplied.
Section 7.6 Criteria 
for Discontinuation 
or Withdrawal of a 
Subject (Reasons 
number 4 and 11)


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Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) 
Affected by 
Change
Description
Rationale
Location(s)
4.
Added guidance regarding supply of study drug to 
study subjects during unavoidable circumstances 
such as the COVID-19 pandemic.
To provide flexibility for sites to 
provide subjects with drug supply in 
situations where traveling to the site 
or presenting at the site may present 
a risk to health or well-being of 
subjects.
8.2 Study Drug 
Assignment and 
Dispensing 
Procedures
5.
Added section with guidance on alternative 
approaches to executing study procedures and 
collecting study data due to COVID-19 or other 
unavoidable circumstances.
To eliminate apparent hazards to 
participants by providing flexibility 
in administration of study 
procedures during unavoidable 
circumstances such as the COVID-
19 pandemic.
Sections:
9.1.1 Alternative 
Approaches to 
Study Procedures 
and Data Collection 
Due to COVID-19 
or Other 
Unavoidable 
Circumstances,
9.1.10 Efficacy 
Measurements
6.
Corrected a typographical error in guidance for 
female subjects and women of childbearing 
potential for female subjects.
To correct a typographical error.
Section 9.1.17.3
Definitions and 
Procedures for 
Contraception and 
Pregnancy 
Avoidance
7.
Added COVID-19-related guidance for informed 
consent procedures.
To ensure informed consent 
procedures are in accordance with 
all applicable laws and regulations.
Section 9.1.2
Informed Consent 
Procedure
8.
Added COVID-19-related guidance for 
documentation of screen and randomization 
failure.
To ensure that reasons for screen 
failure or randomization failure due 
to COVID-19 related factors are 
documented.
Sections:
9.1.20
Documentation of 
Screen Failure
9.1.21
Documentation of 
Randomization 
Failure.
9.
Added clarification to text regarding 
documentation of pretreatment events 
(PTE)/adverse events (AEs).
Original author of protocol 
inadvertently deleted the 
abbreviation PTE from this text 
which describes how PTE/AE data 
are to be collected in the database. 
This is a typographical error and 
does not indicate a change in 
process.
Section 10.2.1.2
PTE and AE 
Reporting


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Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) 
Affected by 
Change
Description
Rationale
Location(s)
10. Added COVID-related terms to the table of 
Takeda Medically Significant AEs.
To comply with Takeda Global 
Patient Safety Evaluation guidance 
on the medically significant AE list.
Table 10.a Takeda 
Medically 
Significant AEs
11. Updated serious adverse event (SAE) reporting 
guidance.
Text was revised per a new Takeda 
process for SAE reporting that 
includes an acknowledgment of 
receipt for information sent via fax 
or email.
Section 10.2.2
Collection and 
Reporting of SAEs
12. Added guidance for analysis of data impacted by 
COVID-19. 
To provide guidance regarding 
analysis of data impacted by 
COVID-19 in terms of 
completeness or collection 
modality.
Section 13.1.3
Efficacy Analysis
13. Added COVID-19-related guidance for protocol 
deviations.
To further clarify that on occasion 
unexpected circumstances such as 
COVID-19 pandemic will require a 
deviation from protocol-specified 
procedures and investigators should 
consult with sponsor regarding these 
kinds of protocol deviations.
Section 14.3
Protocol Deviations
14. Added guidance in case of a delay in delivery of 
screening laboratory test results due to 
unavoidable circumstances such as the COVID-19 
pandemic
To allow flexibility during
unavoidable circumstances such as 
the COVID-19 pandemic to extend 
the Visit 3 (randomization) window 
for a maximum of 7 days in case of 
a delay in delivery of screening 
laboratory test results needed to 
determine subject eligibility.
Appendix A
Schedule of Study 
Procedures, 
footnote b
15. Extended visit window for final visit (Day 84/End 
of Treatment [ET]). 
To allow flexibility during 
unavoidable circumstances such as 
the COVID-19 pandemic for 
subjects to return to site for final 
visit assessments which are critical 
for the primary endpoint and key 
secondary endpoint analyses.
Appendix A
Schedule of Study 
Procedures, Visit 
Window


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Protocol Amendment 04
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) 
Affected by 
Change
Description
Rationale
Location(s)
16. Added clarification to footnote b in Schedule of 
Study Procedures regarding conduct of final visit 
(Day 84/ET) in unavoidable circumstances such 
as the COVID-19 pandemic.
To emphasize the importance of 
performing the final visit 
(Day 84/ET) in person and the need 
to contact the sponsor or designee to 
discuss individual subject 
circumstances if it may not be 
feasible due to unavoidable 
circumstances such as the 
COVID-19 pandemic.
Appendix A
Schedule of Study 
Procedures, 
footnote b
17. Added footnote describing conduct of study visits 
during unavoidable circumstances such as the 
COVID-19 pandemic.
To eliminate apparent hazards to 
participants by providing flexibility 
in administration of study 
procedures during unavoidable 
circumstances such as the 
COVID-19 pandemic.
Appendix A
Schedule of Study 
Procedures


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 04 Summary of Changes and Rationale .............................5
2.0
STUDY SUMMARY ....................................................................................................15
3.0
STUDY REFERENCE INFORMATION ......................................................................20
3.1
Study-Related Responsibilities.................................................................................20
3.2
Coordinating Investigator.........................................................................................20
3.3
List of Abbreviations ...............................................................................................21
3.4
Corporate Identification...........................................................................................23
4.0
INTRODUCTION.........................................................................................................24
4.1
Background .............................................................................................................24
4.1.1
Study Drug ......................................................................................................24
4.1.2
Schizophrenia ..................................................................................................24
4.1.3
Clinical Background ........................................................................................25
4.2
Rationale for the Proposed Study.............................................................................27
4.3
Benefit/Risk Profile .................................................................................................27
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................29
5.1
Objectives................................................................................................................29
5.1.1
Primary Objective............................................................................................29
5.1.2
Secondary Objectives ......................................................................................29
5.1.3
....................................................................................29
5.2
Endpoints.................................................................................................................30
5.2.1
Primary Endpoint.............................................................................................30
5.2.2
Secondary Endpoints .......................................................................................30
5.2.3
Safety Endpoints..............................................................................................31
5.2.4
.....................................................................................31
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................32
6.1
Study Design ...........................................................................................................32
6.2
Justification for Study Design, Dose, and Endpoints ................................................35
6.2.1
Study Design ...................................................................................................35
6.2.2
Dose ................................................................................................................35
6.2.3
Endpoints ........................................................................................................35
6.2.3.1
Efficacy Endpoints ..................................................................................35


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6.2.3.2
Safety Endpoints......................................................................................37
6.3
Premature Termination or Suspension of Study or Study Site...................................37
6.3.1
Criteria for Premature Termination or Suspension of the Study........................37
6.3.2
Criteria for Premature Termination or Suspension of Study Sites.....................37
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites..............................................................................37
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............38
7.1
Inclusion Criteria .....................................................................................................38
7.2
Exclusion Criteria ....................................................................................................40
7.3
Randomization Criteria............................................................................................43
7.4
Excluded/Allowed Medications, Procedures, and Treatments...................................43
7.5
Diet, Fluid, and Activity Control..............................................................................46
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................46
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................47
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................47
8.1
Study Drug and Materials ........................................................................................48
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................48
8.1.1.1
Study Drug (TAK-831 and Matching Placebo Tablets)............................48
8.1.1.2
Companion Medication............................................................................48
8.1.1.3
Rescue Medication ..................................................................................49
8.1.1.4
Sponsor-Supplied Drug............................................................................49
8.1.2
Storage ............................................................................................................50
8.1.3
Dose and Regimen...........................................................................................50
8.1.4
Overdose .........................................................................................................50
8.2
Study Drug Assignment and Dispensing Procedures ................................................51
8.3
Randomization Code Creation and Storage..............................................................51
8.4
Study Drug Blind Maintenance................................................................................51
8.5
Unblinding Procedure..............................................................................................52
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................52
9.0
STUDY PLAN ..............................................................................................................53
9.1
Study Procedures.....................................................................................................53
9.1.1
Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 or Other Unavoidable Circumstances.............................................54
9.1.2
Informed Consent Procedure............................................................................55
9.1.3
Clinical Trial Subject Database Authorization..................................................56
9.1.4
Demographics, Medical History, and Medication History Procedure................56


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9.1.5
Physical Examination Procedure......................................................................57
9.1.6
Weight, Height and BMI..................................................................................57
9.1.7
Vital Sign Procedure........................................................................................57
9.1.8
Documentation of Concomitant Medication.....................................................58
9.1.9
Documentation of Concurrent Medical Conditions...........................................58
9.1.10
Efficacy Measurements....................................................................................58
9.1.10.1
MINI .......................................................................................................59
9.1.10.2
PANSS....................................................................................................59
9.1.10.3
CGI-SCH Scale .......................................................................................59
9.1.10.4
BACS......................................................................................................60
9.1.10.5
BNSS ......................................................................................................60
9.1.10.6
SCoRS.....................................................................................................60
9.1.10.7
CDSS ......................................................................................................60
9.1.10.8
..................................................................................61
9.1.10.9
...............................................................................................61
9.1.10.10
....................................61
9.1.11
Additional Safety Assessments ........................................................................62
9.1.11.1
Modified SAS..........................................................................................62
9.1.11.2
C-SSRS ...................................................................................................62
9.1.12
Order of Psychiatric/Neurological Rating Scales/Assessments.........................63
9.1.13
PK Measurements............................................................................................63
9.1.13.1
PK Sample Collection..............................................................................63
9.1.13.2
Bioanalytical Methods.............................................................................63
9.1.13.3
Population PK .........................................................................................63
9.1.14
................................................................................63
9.1.14.1
ction..................................................................64
9.1.14.2
.................................................................................64
9.1.14.3
..............................................................................64
9.1.15
..........................................................................................64
9.1.15.1
............................................................................65
9.1.16
Procedures for Clinical Laboratory Samples ....................................................65
9.1.16.1
Antipsychotic Plasma Levels ...................................................................68
9.1.17
Contraception and Pregnancy Avoidance Procedure ........................................68
9.1.17.1
Male Subjects and Their Female Partners ................................................68
9.1.17.2
Female Subjects and Their Male Partners ................................................69


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9.1.17.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...............................................................................................69
9.1.18
Pregnancy........................................................................................................71
9.1.19
ECG Procedure................................................................................................71
9.1.20
Documentation of Screen Failure.....................................................................72
9.1.21
Documentation of Randomization Failure........................................................72
9.1.22
Rater Qualification and Certification Process...................................................73
9.1.22.1
Rater Qualifications.................................................................................73
9.1.22.2
Submission of Experience Details............................................................73
9.1.22.3
Rater Training and Qualification Program................................................73
9.1.22.4
Site Changes to Rater Personnel During the Study...................................73
9.1.22.5
Rater Monitoring .....................................................................................73
9.2
Monitoring Subject Treatment Compliance..............................................................74
9.3
Schedule of Observations and Procedures................................................................74
9.3.1
Poststudy Care.................................................................................................75
9.4
Biological Sample Retention and Destruction ..........................................................75
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................75
10.1
Definitions...............................................................................................................75
10.1.1
PTEs................................................................................................................75
10.1.2
AEs .................................................................................................................76
10.1.3
Additional Points to Consider for PTEs and AEs .............................................76
10.1.4
SAEs ...............................................................................................................78
10.1.5
AEs of Special Interest.....................................................................................79
10.1.6
Intensity of PTEs and AEs ...............................................................................79
10.1.7
Assigning Causality of AEs .............................................................................80
10.1.8
Relationship to Study Procedures.....................................................................80
10.1.9
Start Date.........................................................................................................80
10.1.10 Stop Date.........................................................................................................80
10.1.11 Frequency........................................................................................................80
10.1.12 Action Concerning Study Drug........................................................................80
10.1.13 Outcome..........................................................................................................81
10.2
Procedures...............................................................................................................81
10.2.1
Collection and Reporting of AEs .....................................................................81
10.2.1.1
PTE and AE Collection Period.................................................................81
10.2.1.2
PTE and AE Reporting ............................................................................81
10.2.2
Collection and Reporting of SAEs ...................................................................82


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10.2.3
Reporting of Abnormal LFTs...........................................................................83
10.3
Follow-up of SAEs ..................................................................................................83
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...84
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................84
11.1
Data Monitoring Committee ....................................................................................84
12.0
DATA HANDLING AND RECORDKEEPING............................................................84
12.1
eCRFs......................................................................................................................84
12.2
Record Retention .....................................................................................................85
13.0
STATISTICAL METHODS..........................................................................................86
13.1
Statistical and Analytical Plans ................................................................................86
13.1.1
Analysis Sets ...................................................................................................86
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................86
13.1.3
Efficacy Analysis.............................................................................................86
13.1.3.1
Analysis of Primary Efficacy Endpoint....................................................86
13.1.3.2
Analysis of Other Efficacy Endpoints ......................................................87
13.1.4
PK Analysis.....................................................................................................88
13.1.5
PD Analysis.....................................................................................................88
13.1.6
...................................................................................................88
13.1.7
Safety Analysis................................................................................................88
13.1.7.1
AEs .........................................................................................................88
13.1.7.2
Clinical Laboratory Evaluation ................................................................89
13.1.7.3
Vital Signs...............................................................................................89
13.1.7.4
ECGs.......................................................................................................89
13.1.7.5
C-SSRS ...................................................................................................89
13.2
Interim Analysis and Criteria for Early Termination ................................................89
13.3
Determination of Sample Size..................................................................................89
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................90
14.1
Study Site Monitoring Visits....................................................................................90
14.2
Data Monitoring ......................................................................................................90
14.3
Protocol Deviations..................................................................................................90
14.4
Quality Assurance Audits and Regulatory Agency Inspections ................................90
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................91
15.1
IRB and/or IEC Approval ........................................................................................91
15.2
Subject Information, Informed Consent, and Subject Authorization .........................92
15.3
Subject Confidentiality ............................................................................................93


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15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................93
15.4.1
Publication and Disclosure...............................................................................93
15.4.2
Clinical Trial Registration................................................................................94
15.4.3
Clinical Trial Results Disclosure......................................................................94
15.5
Insurance and Compensation for Injury....................................................................94
16.0
REFERENCES..............................................................................................................95
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications and Dietary Products ......................................................44
Table 8.a
Dose and Regimen .............................................................................................50
Table 9.a
Approximate Blood Volume ..............................................................................66
Table 9.b
Clinical Laboratory Tests...................................................................................67
Table 10.a
Takeda Medically Significant AEs.....................................................................79
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................34
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................99
Appendix B
Responsibilities of the Investigator...................................................................103
Appendix C
Elements of the Subject Informed Consent.......................................................105
Appendix D
Investigator Consent to Use of Personal Information........................................108
Appendix E
History of Protocol Amendments 01 through 03...............................................109


TAK-831
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge MA 02139
USA
Compound:
TAK-831
Title of Protocol: A Phase 2, 12-Week, Randomized, 
Double-Blind, Placebo-Controlled, Parallel Study to 
Evaluate Efficacy, Safety, Tolerability, and 
Pharmacokinetics of 3 Dose Levels of TAK-831 in 
Adjunctive Treatment of Adult Subjects With Negative 
Symptoms of Schizophrenia
IND No.:
135,176
EudraCT No.: 
2017-003471-54
Study Number: TAK-831-2002
Phase: 2
Study Design:
This is a randomized, double-blind, parallel, placebo-controlled, phase 2 study to evaluate the efficacy, safety, 
tolerability, and pharmacokinetics (PK) of adjunctive treatment with TAK-831 when administered orally once daily 
(QD) in adult subjects with negative symptoms of schizophrenia. The study will consist of a screening period of up 
to 28 days, a 14-day single-blind placebo run-in period, a 12-week double-blind treatment period, and a safety 
follow-up visit.
Approximately 234 subjects will be enrolled at up to 48 sites in North America and Europe.
At the screening visit (Visit 1), subjects who provide informed consent will proceed with screening procedures. 
Subjects who meet a current diagnosis of schizophrenia, as defined by the Mini International Neuropsychiatric 
Interview (MINI), will then be administered additional psychiatric and neurological rating scale assessments, and 
undergo other screening assessments. Subjects must be currently receiving stable treatment on antipsychotic 
medication at a total daily dose between 2 mg and 6 mg of risperidone equivalents (as outlined in an Antipsychotic 
Dose Equivalency reference supplied to the sites), with no clinically meaningful change in psychotropic medications 
(no increase, ≤25% decrease in dose) for the preceding 2 months before the screening visit. Concomitant treatment 
with a subtherapeutic dose of a second antipsychotic may be permitted with sponsor or designee approval if used as 
a hypnotic, but not if used for refractory positive psychosis symptoms. 
Subjects must have a Brief Negative Symptom Scale (BNSS) total score (12-item, excluding item number 4) ≥28 
and limited Positive and Negative Syndrome Scale (PANSS) symptoms as outlined in the study inclusion criteria, 
and must demonstrate stable BNSS total scores (≤20% change from the screening score) at the single-blind placebo 
run-in visit (Day -14; Visit 2) and baseline visit (Day 1; Visit 3). Subjects with extrapyramidal signs/symptoms or 
depressive symptoms based on study assessments, as outlined in the study entry criteria, will be excluded. 
Confirmation that the subject meets these and other selected entry criteria will be provided by an external subject 
eligibility assessment vendor based on review of data from the screening visit.
The 2-week single-blind placebo run-in period will be used to evaluate compliance with study drug intake and 
stability of the BNSS assessment. At baseline (predose Day 1), subjects who continue to meet all eligibility criteria, 
including placebo run-in drug compliance requirements, will be randomized to 12 weeks of double-blind oral 
treatment with TAK-831 (T2 tablet formulation) or matching placebo.


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Schematic of Study Design
Primary Objective:
The primary objective of this study is to determine whether add-on TAK-831 is superior to placebo on the Positive 
and Negative Syndrome Scale Negative Symptom Factor Score (PANSS NSFS).
Secondary Objectives:

To determine whether add-on TAK-831 is superior to placebo on the BNSS total score.

To determine whether add-on TAK-831 is superior to placebo on the Brief Assessment of Cognition in 
Schizophrenia (BACS) composite cognition score.

To determine whether add-on TAK-831 is superior to placebo on global severity as measured by the Clinical 
Global Impression-Schizophrenia-Severity (CGI-SCH-S) score.

To determine whether add-on TAK-831 is superior to placebo on global improvement as measured by the 
Clinical Global Impression-Schizophrenia-Improvement (CGI-SCH-I) score.

To determine whether add-on TAK-831 is superior to placebo on the Schizophrenia Cognition Rating Scale 
(SCoRS) assessment of cognitive functional outcome.

To determine whether add-on TAK-831 is superior to placebo on the PANSS total score and additional 
subscales and factors.

To assess the safety and tolerability of TAK-831.

To assess the PK of TAK-831.
Subject Population: Male or female subjects, between 18 and 60 years of age, inclusive, with a diagnosis of 
schizophrenia with persistent negative symptoms of schizophrenia.
Number of Subjects:
Approximate number of subjects per treatment group:
TAK-831 50 mg QD: 52
TAK-831 125 mg QD: 52
TAK-831 500 mg QD: 52
Placebo QD: 78
Estimated total: 234 randomized
Number of Sites: 
Approximately 48 sites in North America and Europe


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Dose Levels:
TAK-831 50 mg QD
TAK-831 125 mg QD
TAK-831 500 mg QD
Placebo QD
Route of Administration:
Oral
Duration of Treatment:
12 weeks
Period of Evaluation:
Approximately 20 weeks from screening visit to final 
visit (4 weeks of screening, a 14-day single-blind 
placebo run-in period, 12 weeks of double-blind 
treatment, and 10 to 14 days of follow-up).
Main Criteria for Inclusion:

The subject has a current diagnosis of schizophrenia as defined by the MINI 7.0.2 for Psychotic Disorders for 
the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the general psychiatric 
evaluation.

The subject’s initial diagnosis must be ≥1 year from screening.

The subject is male or female and aged 18 to 60 years, inclusive.

The subject is receiving primary background antipsychotic therapy (other than clozapine) at a total daily dose 
between 2 mg and 6 mg of risperidone equivalents (as outlined in an Antipsychotic Reference document). 
Concomitant treatment with a subtherapeutic dose of a second antipsychotic may be permitted with sponsor or 
designee approval if used to treat specific symptoms such as insomnia, but not if it is used for refractory 
positive psychosis symptoms. 

The subject is treated with a stable regimen of psychotropic medications with no clinically meaningful change 
(no increase in dose, ≤25% decrease in dose for tolerability) in the 2 months prior to the screening visit and no 
dose adjustment is anticipated throughout study participation up to the Day 84/early termination visit.

The subject has a BNSS total score (12-item, excluding number 4) ≥28; stable single-blind placebo run-in and 
baseline BNSS total (12-item, excluding number 4) scores (≤20% change from the screening score).

The subject has no more than moderate-severe (≤5) rating on PANSS positive symptom items P1, P3, P4, P5, 
P6, or unusual thought content (G9), with a maximum of 2 of these items rated “5”; no more than moderate (≤4) 
rating on conceptual disorganization (P2). 

There is evidence that the subject has stable symptomatology ≥3 months prior to the screening visit (eg, no 
hospitalizations for schizophrenia, no emergency room admission due to symptoms of schizophrenia, no 
increase in level of psychiatric care due to worsening of symptoms of schizophrenia).

The subject must have an adult informant who will be able to provide input for completing the study rating 
scales including the PANSS and SCoRS (eg, family member, social worker, caseworker, residential facility 
staff, or nurse who spends ≥4 hours/week with the subject) considered reliable by the investigator.
Main Criteria for Exclusion:

The subject has a lifetime diagnosis of schizoaffective disorder; a lifetime diagnosis of bipolar disorder; or a 
lifetime diagnosis of obsessive compulsive disorder based on the MINI combined with the general psychiatric 
evaluation. As an exception, subjects with a historical prior lifetime diagnosis of schizoaffective disorder may 
be enrolled in the study with sponsor or designee approval provided that the principal investigator can attest that 
the subject’s overall history and current clinical presentation and history is most consistent with schizophrenia, 
not schizoaffective disorder.

The subject has a recent (within the last 6 months) occurrence of panic disorder, depressive episode, or other 
comorbid psychiatric conditions currently requiring clinical attention based on the MINI for DSM-5 and the 
general psychiatric evaluation.

The subject has a diagnosis of substance use disorder (with the exception of nicotine dependence) within the 
preceding 6 months based on the MINI for DSM-5 and the general psychiatric evaluation.

The subject is participating in a formal structured nonpharmacological therapeutic treatment program (cognitive 


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remediation, cognitive-behavioral therapy, intensive symptom/vocational rehabilitation) for <3 months prior to 
randomization. In addition, initiation of such nonpharmacological treatment programs is not permitted during 
study participation through the Day 84 visit.

The subject exhibits more than a minimal level of antipsychotic-induced parkinsonism symptoms, as 
documented by a score on the modified Simpson Angus Scale (SAS) (excluding item number 10, Akathisia) >6.

The subject has evidence of depression as measured by a Calgary Depression Scale Score (CDSS) >9.

The subject’s diagnosis of schizophrenia occurred prior to 12 years of age.

The subject has a history of developmental intellectual disability or mental retardation.

Antipsychotic plasma levels for the subject’s primary background antipsychotic are below the minimum 
acceptable concentration criteria per the Antipsychotic Reference document at the screening or placebo run-in 
visits. This criterion is not applicable to subjects on a primary background antipsychotic for which a clinical 
assay is unavailable (ie, not listed in the Antipsychotic Reference document).

The subject is taking concomitant treatment that can impact cognition as determined by the principal 
investigator in consultation with the sponsor or designee.
Main Randomization Criteria:
The subject must continue to meet all of the inclusion criteria and none of the exclusion criteria at the time of the 
baseline visit (Day 1; Visit 3). The subject has completed the single-blind placebo run-in period and has met the 
study drug compliance criteria (75% to 125%) as assessed using the digital compliance technology.
Main Criteria for Evaluation and Analyses:
Baseline is defined as the assessment prior to dosing on Day 1.
Primary Endpoint:

Change from baseline on the PANSS NSFS at Day 84.
Secondary Endpoints:

Change from baseline on the PANSS NSFS at Days 28 and 56.

Change from baseline on the BNSS at Day 84.

Change from baseline on the BACS composite score at Day 84.

Change from baseline on the CGI-SCH-S score at Day 84.

CGI-SCH-I score at Day 84.

Change from baseline on the SCoRS at Day 84.

Change from baseline on the PANSS total score and additional subscales and factors at Day 84.

TAK-831 plasma concentrations.
Safety Endpoints:

Percentage of subjects who experience at least 1 treatment-emergent adverse event.

Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at least once 
postdose.

Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least once 
postdose.

Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram parameters at least 
once postdose.

Percentage of subjects with treatment-emergent suicidal ideation or suicidal behavior as measured using the 
Columbia-Suicide Severity Rating Scale (C-SSRS).
Statistical Considerations:
Primary Efficacy Analysis
The primary endpoint will be analyzed by comparing TAK-831 and placebo over all assessed time points using 
estimates from a mixed model for repeated measures (MMRM) with baseline value as a covariate; pooled site, visit, 


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treatment, and categorical age (randomization factor) as fixed factors; and treatment-by-visit and baseline-by-visit 
interactions. Based on a Missing at Random Assumption, this analysis will be performed using observed case data 
only. The effect at each time point for each treatment is allowed to vary freely and an unstructured covariance 
matrix is assumed. If the model does not converge, other covariance structures (unstructured, compound symmetry, 
2-Toeplitz, etc) will be considered. Additional analyses to address sensitivity to missing data will be specified in the 
statistical analysis plan. 
Multiplicity will be controlled across dose-arms by first testing the 125 mg QD and 500 mg QD dose-arms in 
parallel using Holm’s method to control the overall type I error at the 0.10 level (one-sided), then testing the 50 mg 
QD dose-arm at the 0.10 level if at least 1 of other doses is found to be statistically superior to placebo.
Secondary Efficacy Analyses
Other change from baseline endpoints will be analyzed in the same manner as the primary endpoint, but without 
control for multiple doses. The change from baseline on the CGI-SCH-S at Day 84, and the CGI-SCH-I score at Day 
84 will be analyzed using a Cochran-Mantel-Haenszel test. This analysis will be stratified by age and performed 
using observed cases only.
Interim Analysis
An interim analysis for futility may be performed during the study, allowing for early study termination if the 
probability of success on the primary endpoint fails to meet a pre-specified criterion. The specifics of this analysis 
will be included in an interim analysis plan that will be finalized before interim unblinding.
Sample Size Justification: 
Assuming that the effect size is at least 0.4 for the 125 mg QD and 500 mg QD doses and that at least 85% of the 
234 subjects complete the Day 84 assessment, the study has at least 82% power for at least 1 dose to be statistically-
significant at the 0.10 level with correction for multiple doses.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor (or designee) will perform all study-related activities with the exception of those 
identified in the Clinical Study Supplier template. The vendors identified in the template for 
specific study-related activities will perform these activities in full or in partnership with the 
sponsor.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical 
research, as well as study participation. The signatory coordinating investigator will be required 
to review and sign the clinical study report and, by doing so, agrees that it accurately describes 
the results of the study.


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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
anti-HCV
antibody to hepatitis C virus
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUCt
area under the plasma concentration-time curve from time 0 to time t
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUEC24
area under the effect curve from time 0 to 24 hours
BACS
Brief Assessment of Cognition in Schizophrenia
BMI
body mass index
BNSS
Brief Negative Symptom Scale
CDSS
Calgary Depression Scale Score
CFR
Code of Federal Regulations
CGI-SCH
Clinical Global Impression-Schizophrenia
CGI-SCH-I
Clinical Global Impression-Schizophrenia-Improvement
CGI-SCH-S
Clinical Global Impression-Schizophrenia-Severity
CIAS
cognitive impairment associated with schizophrenia
Cmax
maximum observed plasma concentration
COVID-19
coronavirus disease 2019
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale 
DAO
D-amino acid oxidase
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
EDC
electronic data capture
EIIB
eosinophilic intranuclear inclusion body
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GGT
-glutamyl transferase
GluR2
δ2 glutamate receptor
GPS
Global Positioning System


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HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HPLC
high-performance liquid chromatography
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IQ-PANSS
Informant Questionnaire for the Positive and Negative Syndrome Scale
IRB
institutional review board
IRT
interactive response technology
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
MCP-Mod
Multiple Comparison Procedure Modeling
MDMA
3,4-methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed model for repeated measures
MRD
multiple-rising dose
NMDA
N-methyl-D-aspartate
PANSS
Positive and Negative Syndrome Scale
PANSS NSFS
Positive and Negative Syndrome Scale Negative Symptom Factor Score
PD
pharmacodynamic(s)
PET
positron emission tomography
PK
pharmacokinetic(s)
PT
preferred term
PTE
pretreatment event
QD
once daily
QHS
once daily at bedtime
QTcF
QT interval with Fridericia correction method
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Simpson Angus Scale
SCI-PANSS
Structured Clinical Interview for the Positive and Negative Syndrome Scale
SCoRS
Schizophrenia Cognition Rating Scale
SOC
system organ class
SOP
standard operating procedure
SRD
single-rising dose


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SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
UGT
uridine 5′-diphospho-glucuronosyltransferase
ULN
upper limit of normal
3.4
Corporate Identification 
TDC
Takeda Development Center
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
4.1.1
Study Drug
TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAO), a 
peroxisomal enzyme active toward neutral D-amino acids, being developed by Takeda. DAO is 
involved in D-serine metabolism in the brain and has been connected to the regulation of 
glutamatergic neurotransmission [1]. D-serine is generated from its stereoisomer, L-serine, by 
serine racemase in the brain, and is a potent N-methyl-D-aspartate (NMDA)–type glutamate 
receptor co-agonist and an agonist for the δ2 glutamate receptor (GluR2), which has been 
implicated in synaptic plasticity and long-term depression [2]. The presence of DAO has been 
identified in the cerebellum, brain stem, and other brain regions relevant to the pathophysiology 
of schizophrenia, and numerous studies have verified that endogenous and exogenous D-serine 
potentiate NMDA receptor function in these regions [1,3,4]. TAK-831 inhibition of DAO in the 
liver, kidney, and cerebellum leads to higher D-serine levels in the plasma and cerebellum in 
animal models. As such, TAK-831 has the potential to increase NMDA-dependent glutamatergic 
signaling via its impacts on D-serine–modulated neuronal activity.
4.1.2
Schizophrenia
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and 
behaves. The onset of the disease is usually in late adolescence or early adulthood. Schizophrenia 
affects up to 1% of the population and increases to 10% in individuals having a first-degree 
relative suffering from the disorder (40% to 65% for identical twins) [5-7]. Symptoms of 
schizophrenia can be subdivided into 3 broad classes: positive, negative, and cognitive symptoms 
[8]. Positive symptoms include hallucinations, delusions, and disordered thought and speech, and 
can be summarized as psychosis. Negative symptoms include reduced emotion, reduced ability 
to experience pleasure (anhedonia), lack of motivation, and reduced social interaction. Finally, 
cognitive symptoms include poor information processing, impaired ability to focus on objectives, 
and abnormalities of working memory and learning [8]. Deficits in glutamatergic transmission 
are hypothesized to play an important role in the pathophysiology of the disorder, particularly in 
relation to the genesis of cognitive impairment and negative symptoms, including anhedonia [9].
While currently available antipsychotics are broadly effective for the treatment of positive 
symptoms, the treatment of persistent negative symptoms and cognitive deficits of schizophrenia 
remains a major unmet medical need. These symptom domains are associated with poor 
functional outcomes to a greater degree than positive symptoms with currently available 
treatments [10,11], and there are no approved therapies. Thus, addressing these symptoms 
remains an important area of focus for the development of novel therapeutics.
Inhibition of DAO is a promising target for the treatment of schizophrenia. Hypofunction of 
NMDA receptors is considered a potential mechanism in the pathophysiology of schizophrenia, 
which could be mitigated with increased D-serine levels in the brain [12]. Changes in the 


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D-serine levels or D-serine to total serine ratios have been reported in the plasma of patients with 
schizophrenia both naive to and undergoing drug treatment [13-16]. 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 studies analysis, indicating the 
biological relevance to schizophrenia of the genetic pathway in which DAO is a component [17].
DAO is involved in D-serine metabolism in the brain and has been connected to the regulation of 
glutamatergic neurotransmission [1]. Inhibition of DAO elevates endogenous D-serine in the 
cerebellum, increasing Purkinje cell long-term depression via activation of GluR2 and/or 
NMDA receptors with subsequent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid 
(AMPA) receptor internalization [2].
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 
[18].
4.1.3
Clinical Background
The safety evaluations performed in the TAK-831 early clinical development program 
(Studies TAK-831-1001 and TAK-831-1003) allowed for the initial characterization and 
quantification of the safety profile of TAK-831 in healthy subjects. The first-in-human study 
TAK-831-1001 was designed to assess the pharmacokinetics (PK) of an oral suspension of 
TAK-831 and plasma D-serine levels after single-rising dose (SRD) and multiple-rising dose 
(MRD) administration of TAK-831, as well as the relative bioavailability and effect of food on 
the PK of the T1 tablet formulation of TAK-831. Study TAK-831-1003 was designed to evaluate 
DAO target engagement in the brain, as measured by positron emission tomography (PET), as 
well as assess plasma D-serine levels, TAK-831 plasma concentrations, and the safety of 
TAK-831.
TAK-831 has been administered to a total of 103 healthy subjects in these 2 studies; 74 subjects 
received single doses ranging from 10 to 750 mg and 29 subjects received multiple doses ranging 
from 30 to 400 mg once daily (QD) for up to 13 days. TAK-831 was safe and well tolerated at 
the doses studied in healthy subjects. Headache was the most common treatment-emergent 
adverse event (TEAE) potentially related to study drug. Headaches were mild to moderate in 
intensity and generally self-limiting. The rate of postural dizziness in TAK-831–treated subjects 
did not markedly differ from that observed in placebo-treated subjects. No concerning trends in 
clinical laboratory, electrocardiogram (ECG), or vital sign data were observed. Additional detail 
on the safety and tolerability data from these studies may be found in the current TAK-831 
Investigator’s Brochure.
After both single and multiple dosing with TAK-831 (Study TAK-831-1001), increases in the 
mean area under the effect curve from time 0 to 24 hours (AUEC24) of D-serine were dose 
dependent; changes in D-serine were noticeably higher after multiple QD doses of TAK-831 
400 mg than after multiple QD doses of TAK-831 30, 100, and 200 mg. Single oral doses of 


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TAK-831 temporally increased D-serine plasma concentrations in the PET study 
(TAK-831-1003); the results were similar to those obtained in Study TAK-831-1001.
Since these studies were conducted, dosing in a single-dose PK and food-effect bioavailability 
study with the T2 tablet formulation of TAK-831 has been completed (Study TAK-831-1004). 
Also, a study examining additional escalating multiple (QD) doses of TAK-831 higher than those 
achieved in Study TAK-831-1001 was initiated and is ongoing (Study TAK-831-1005).
Study TAK-831-1004 is a phase 1, randomized, open-label, single-dose, 2-period crossover 
study designed to characterize the PK and effect of food on the bioavailability of TAK-831 
400 mg (administered as 4 × 100 mg oral T2 tablets) in 15 healthy adult subjects. In this study, 
only a single TEAE of mild upper respiratory tract infection was reported, considered by the 
investigator to be unrelated to study drug. One subject met the criteria for orthostatic 
hypotension at a single time point without an accompanying report of a dizziness TEAE. No 
concerning trends in clinical laboratory, ECG, or vital sign data were observed. When the 
TAK-831 T2 tablet formulation was coadministered with a nutritional drink (Ensure Plus), mean 
maximum observed plasma concentration (Cmax) and area under the plasma concentration-time 
curve from time 0 to infinity (AUC∞) values were increased by 35% and 21%, respectively. 
Treatment with a single oral dose of TAK-831 400 mg T2 formulation temporally increased 
D-serine plasma concentrations, similar to the results obtained in Study TAK-831-1001. The 
magnitude and kinetics of the change in D-serine plasma concentrations were similar when the 
drug was administered in either water or nutritional drink.
Study TAK-831-1005 is an ongoing, investigator- and subject-blinded, sponsor-unblinded, 
placebo-controlled study designed to continue evaluation of the safety, tolerability, PK, and 
pharmacodynamics (PD) of escalating multiple (QD) doses of TAK-831 in healthy subjects at 
doses higher than those achieved in Study TAK-831-1001. The following data from this study 
are preliminary, being based on blinded AE data reported by the investigator and blinded safety 
endpoint data. Although not expected, these data are subject to change upon finalization 
following study monitoring, source data verification, and discrepancy query management before
database lock. As of the cut-off date of 18 September 2017, 2 cohorts of 8 subjects each 
(6 TAK-831:2 placebo) have completed dosing with TAK-831 600 mg QD (T2 tablets), 
TAK-831 800 mg QD (oral suspension) or placebo, administered first as a single dose and then 
QD for up to 14 days. In addition to standard safety assessments, subjects underwent catheterized 
cerebrospinal fluid (CSF) collection for a 24-hour period starting before dosing on Day 1 of 
single-dose treatment and on Day 14 of multiple-dose treatment. Nausea and postlumbar 
puncture syndrome were the most commonly reported TEAEs; nausea in the absence of 
postlumbar puncture syndrome was reported by 1 subject in each cohort. All episodes of nausea 
were mild in intensity and self-limiting. Two subjects in each cohort met the criteria for 
orthostatic hypotension on at least 1 assessment; none of these findings were associated with a 
TEAE of dizziness. No concerning trends in clinical laboratory, ECG, or vital sign data were 
observed for these cohorts.
Following QD dosing, mean plasma exposures of TAK-831 were higher (Cmax: 1.3-fold and area 
under the plasma concentration-time curve [AUC]: 1.8-fold) when dosed as an oral suspension 


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than as T2 tablets. Geometric mean Cmax values were 1466 and 1976 ng/mL with 600 mg QD 
(T2 tablets) and 800 mg QD (oral suspension), respectively. Mean steady-state exposures (area 
under the plasma concentration-time curve from time 0 to time t [AUCt]) over the 24-hour 
dosing interval were 4993 and 8853 h*ng/mL for the 600 and 800 mg QD doses, respectively. 
The mean 24-hour PK profile of TAK-831 in CSF was parallel to that in plasma, and observed 
TAK-831 CSF concentrations were well in agreement with the TAK-831 unbound fraction in 
plasma. After both single and multiple dosing with TAK-831 600 mg (T2 tablets) and 800 mg 
(oral suspension), the mean AUEC24 of D-serine in CSF increased notably compared with 
placebo; changes in CSF D-serine concentrations were noticeably higher after multiple (QD) 
doses than after a single dose of TAK-831. The magnitude of the increase in AUEC24 of CSF 
D-serine was similar for both the 600 mg (T2 tablets) and 800 mg (oral suspension) doses, 
suggesting that the maximal PD effect in the CSF was achieved at drug exposures attained with 
both doses.
Overall, the emerging safety data from Studies TAK-831-1004 and TAK-831-1005 are 
consistent with the safety data collected in prior clinical studies and do not alter the risk profile 
of TAK-831.
4.2
Rationale for the Proposed Study
TAK-831 is a highly selective and potent inhibitor of DAO, a peroxisomal enzyme active toward 
neutral D-amino acids. TAK-831 was shown to increase D-serine levels in the cerebellum of 
normal mice and rats, and it also demonstrated a positive effect on social interaction and 
cognition at a broad range of repeated doses in rodent behavioral models. As noted above, 
TAK-831 has been also demonstrated to increase D-serine levels in human CSF. TAK-831 is 
under development for the treatment of the negative symptoms of schizophrenia, cognitive 
impairment associated with schizophrenia (CIAS), and cerebellar ataxia. The current phase 2 
study is being conducted to assess the efficacy and safety of adjunctive administration of 
TAK-831 in the treatment of negative symptoms and cognition in symptomatically stable 
outpatients with chronic schizophrenia on stable antipsychotic and other psychotropic 
medications.
4.3
Benefit/Risk Profile
The current study is designed to evaluate the efficacy, safety, PD, and PK of 3 dose levels of 
TAK-831 oral T2 tablets in the adjunctive treatment of adult subjects with schizophrenia for up 
to 84 days. The proposed doses of TAK-831 have been selected based on the available PK, brain 
target occupancy (PET), CSF D-serine, and safety data for TAK-831 in healthy subjects (see 
Section 6.2.2). The safety data from healthy subjects cannot be directly generalized to subjects 
with schizophrenia. However, no safety signal has manifested that would prevent additional 
studies in healthy subjects or subjects with schizophrenia. A placebo-controlled study is standard 
in the evaluation of novel therapeutics for neuropsychiatric disorders; as TAK-831 is being 
administered as an add-on to standard therapy in stable subjects in this study, the risk of subjects 
experiencing an exacerbation of their underlying condition is minimized.


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The risk mitigation measures that will be implemented in the current study are described below. 
These measures are based on what is known about the mechanism of action of TAK-831, the 
available nonclinical data, the available phase 1 clinical data, and general considerations in the 
development of new chemical entities for central nervous system disorders. Procedures may be 
added during the study if necessary based on evaluation of any additional clinical or nonclinical 
safety data.

The exposures associated with the TAK-831 dosing regimens selected for this study have 
been evaluated in prior studies in healthy subjects and have not resulted in a safety signal that 
would prevent additional studies.

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.

Subjects with a risk of suicide according to the investigator’s clinical judgment (or as 
assessed by the Columbia-Suicide Severity Rating Scale [C-SSRS]), or who have made a 
suicide attempt in the previous 12 months, will be excluded from this study. The C-SSRS 
will be administered at prescribed intervals to monitor emergent suicidality. Subjects should 
be monitored for any signs of suicidal ideation or behaviors, and appropriate psychiatric 
interventions or other precautions should be instituted, if warranted.

Eosinophilic intranuclear inclusion bodies (EIIBs) were observed in the proximal tubule 
epithelium of the kidneys at doses of ≥10 mg/kg/day in rats. The EIIBs were not 
accompanied by apparent necrosis, inflammation, or impaired renal function and were not 
considered adverse. Similar findings have been reported in the literature and are considered 
to be species-specific to the rat [19]. Elevated creatinine levels were not reported in the 
TAK-831 clinical studies summarized above; creatinine will continue to be measured in the 
clinical studies.

Postural hypotension and dizziness were observed in prior TAK-831 studies in healthy 
subjects. However, the incidence of dizziness in subjects treated with TAK-831 and placebo 
was similar. Subjects will be informed of these findings and possible ways to mitigate this 
risk, and orthostatic vital sign assessments will be monitored periodically at study visits.

Study procedure–specific risks include issues relating to blood collection for safety
assessment/PK monitoring (venipuncture may cause discomfort at the site of puncture; 
bruising and swelling; and rarely, infection or faintness from the procedure), and the 
placement of ECG pads, which may cause some local redness and/or erythema/itching. The 
PD assessments planned for the study, aside from those requiring a blood draw, are 
noninvasive and are associated with minimal risk.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this study is to determine whether add-on TAK-831 is superior to 
placebo on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS 
NSFS).
5.1.2
Secondary Objectives 

To determine whether add-on TAK-831 is superior to placebo on the Brief Negative 
Symptom Scale (BNSS) total score.

To determine whether add-on TAK-831 is superior to placebo on the Brief Assessment of 
Cognition in Schizophrenia (BACS) composite cognition score.

To determine whether add-on TAK-831 is superior to placebo on global severity as measured 
by the Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) score.

To determine whether add-on TAK-831 is superior to placebo on global improvement as 
measured by the Clinical Global Impression-Schizophrenia-Improvement (CGI-SCH-I) 
score.

To determine whether add-on TAK-831 is superior to placebo on the Schizophrenia 
Cognition Rating Scale (SCoRS) assessment of cognitive functional outcome.

To determine whether add-on TAK-831 is superior to placebo on the Positive and Negative 
Syndrome Scale (PANSS) total score and additional subscales and factors.

To assess the safety and tolerability of TAK-831.

To assess the PK of TAK-831.
5.1.3
 
 
 
 
 


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
 
 
 
 
 
 
 
 
5.2
Endpoints
Baseline is defined as the assessment prior to dosing on Day 1 for all assessments other than the 
 where baseline is defined as the Day -14 assessment.
5.2.1
Primary Endpoint 

Change from baseline on the PANSS NSFS at Day 84.
5.2.2
Secondary Endpoints

Change from baseline on the PANSS NSFS at Days 28 and 56.

Change from baseline on the BNSS at Day 84.

Change from baseline on the BACS composite score at Day 84.

Change from baseline on the CGI-SCH-S score at Day 84.

CGI-SCH-I score at Day 84.

Change from baseline on the SCoRS at Day 84.

Change from baseline on the PANSS total score and additional subscales and factors at 
Day 84.


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
TAK-831 plasma concentrations.
5.2.3
Safety Endpoints

Percentage of subjects who experience at least 1 TEAE.

Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once postdose.

Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements 
at least once postdose.

Percentage of subjects who meet the markedly abnormal criteria for safety ECG parameters 
at least once postdose.

Percentage of subjects with treatment-emergent suicidal ideation or suicidal behavior as 
measured using the C-SSRS.
5.2.4
 
 
 
 
 
 
 


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, double-blind, parallel, placebo-controlled, phase 2 study to evaluate the 
efficacy, safety, tolerability, and PK of adjunctive treatment with TAK-831 when administered 
orally QD in adult subjects with negative symptoms of schizophrenia. The study will consist of a 
screening period of up to 28 days, a 14-day single-blind placebo run-in period, a 12-week 
double-blind treatment period, and a safety follow-up visit.
Approximately 234 subjects will be enrolled at approximately 48 sites in North America and 
Europe.
At the screening visit (Visit 1), subjects who provide informed consent will proceed with 
screening procedures. Subjects who meet a current diagnosis of schizophrenia, as defined by the 
Mini International Neuropsychiatric Interview (MINI), will then be administered additional 
psychiatric and neurological rating scale assessments as specified in Section 9.1.12, and undergo 
other screening assessments. Subjects must be currently receiving stable treatment on 1 
antipsychotic medication at a total daily dose between 2 mg and 6 mg of risperidone equivalents 
(as outlined in an Antipsychotic Dose Equivalency reference supplied to the sites), with no 
clinically meaningful change in psychotropic medications (no increase, ≤25% decrease in dose) 
for the preceding 2 months before the screening visit and no dose adjustment is anticipated 
throughout study participation up to the Day 84/early termination visit. Concomitant treatment 
with a subtherapeutic dose of a second antipsychotic may be permitted with sponsor or designee 
approval if used as a hypnotic, but not if used for refractory positive psychosis symptoms. 
Subjects must have a BNSS total score (12-item, excluding item number 4) ≥28 and limited 
PANSS symptoms as outlined in the study inclusion criteria, and must demonstrate stable BNSS 
total scores (≤20% change from the screening score) at the single-blind placebo run-in visit 
(Day -14; Visit 2) and baseline visit (Day 1; Visit 3). Subjects with extrapyramidal 
signs/symptoms or depressive symptoms based on study assessments, as outlined in the study 
entry criteria, will be excluded.
During the screening period (Days -42 to -15), subjects will visit the clinic and receive full 
medical, neurological, and psychiatric examinations as well as be familiarized with study 
procedures. Additional screening procedures include diagnostic assessments, safety assessments, 
and other clinical assessments, as outlined in Appendix A. An adult informant capable of 
providing information about the subject’s symptoms and function for the PANSS and SCoRS 
must attend the screening or placebo run-in visit for evaluation by site staff and to provide 
written informed consent for informant study participation. Alternatively, a site staff member 


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may also go to the informant’s location to obtain informed consent and, if a qualified rater, 
obtain the informant interview; or the informant interview may be conducted by phone if the site 
staff is not a rater. If the informant is unavailable for an in-person interview at the screening
visit, the initial informed consent may be obtained in a telephone discussion (as permitted by 
local ethics and regulatory policy) so that the informant information may be included in the 
screening assessments requiring informant input.
Subject eligibility for the study will be confirmed by a centralized vendor that will also provide 
rater qualification, training, and ongoing rater quality monitoring throughout the conduct of the 
study. For the screening visit, the centralized vendor will review documentation and recordings 
of the diagnostic and selected symptom assessment interviews as well as collected information 
addressing key study entry criteria. The study site must receive documentation of approval of 
subject eligibility before the subject can be enrolled into the single-blind run-in period.
The 2-week single-blind placebo run-in period (Days -14 to -1) will be used to evaluate 
compliance with study drug intake and stability of BNSS scores. During this period, all subjects 
will receive placebo tablets that appear identical to the study drug to be used during the 
randomized double-blind treatment period. Note: If the scheduling of the Day 1 visit is delayed 
for any reason, the subject should be instructed to continue treatment with run-in medication 
until the Day 1 visit is rescheduled.
At baseline (predose Day 1; Visit 3), subjects who continue to meet all eligibility criteria, 
including placebo run-in drug compliance requirements, will be randomized via an interactive 
response technology (IRT) system to 1 of the following 4 treatments: TAK-831 50 mg QD, 
TAK-831 125 mg QD TAK-831 500 mg QD, and placebo QD. Randomization will be followed 
by a 12-week double-blind treatment period (Days 1 to 84), during which subjects will undergo 
assessments as outlined in Appendix A. Efforts will be made to perform cognition testing at 
approximately the same time of day throughout the double-blind treatment period (postbaseline 
assessments must be administered ±2 hours from the time of baseline assessment 
administration). A safety follow-up visit (between Days 94 and 98; Visit 11) will be scheduled 
for all subjects 10 to 14 days after the last dose of study drug. This study also includes 
 
 
 These assessments 
will be included in a subset of study sites and subjects.
Subjects will be instructed to take 5 tablets QD during the single-blind placebo run-in and 
double-blind treatment periods, during which time study drug compliance will be monitored with 
a mobile technology system. Subjects will be instructed to take their study drug with water or 
milk and to avoid drinking juices 1 hour before and 1 hour after taking study drug.
Subjects who have been screened but have exceeded the 28-day screening period may proceed to 
the placebo run-in visit after a discussion with the sponsor/designee to obtain approval and to 
determine whether any screening procedures should be repeated before that study visit.


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Subjects who do not meet symptom or medication stability criteria (or other entry criteria that 
may be met by the subject at a future time) may be considered for rescreening with the approval 
of the sponsor or designee. Subjects who were in screening or the single-blind run-in period at 
the time that COVID-19 related factors resulted in discontinuation may also be rescreened with 
approval.
In the event that a subject prematurely discontinues the study, an early termination visit must be 
conducted, at which time all the assessments scheduled for the final visit will be performed.
An interim analysis for futility may be performed during the study, allowing for early study 
termination if the probability of success on the primary endpoint fails to meet a prespecified 
criterion. The specifics of this analysis will be included in an interim analysis plan that will be 
finalized before interim unblinding. 
The end of the study is defined as the date the last subject completes the safety follow-up visit 
(Visit 11).
A schematic of the study design is included as Figure 6.a. A schedule of study procedures is 
provided in Appendix A.
Figure 6.a
Schematic of Study Design
DB: double-blind; F/U: follow-up; QD: once daily.
Sites should see subjects at the study site to conduct the study procedures. In unavoidable 
circumstances (eg, a widespread disease outbreak or natural disaster) that impact the study site’s 
ability to conduct study procedures according to the Schedule of Procedures (Appendix A), 
contingency measures may be implemented. Restrictions of human activities or institution 
activities placed by hospitals, local, state and national governments may prevent conduct of 
study procedures according to the Schedule of Procedures. Alternative approaches to study 
procedures and data collection for the current study are described in Section 9.1.1.


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6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
A multicenter, double-blind, placebo-controlled, parallel design is the standard approach for 
assessing clinical efficacy in neuropsychiatric disorders. To evaluate efficacy in treating negative 
and cognitive symptoms, subjects who have stable psychiatric symptomatology and psychotropic 
medications are chosen to control for potential confounding effects of fluctuating psychosis or 
other symptoms independent of the investigational treatment. The presence of other disorders or 
AEs that can mimic negative symptoms or impact treatment response is also excluded to 
minimize any potential negative impact on efficacy detection. Hence, subjects who participate in 
the study will be receiving stable antipsychotic and other psychotropic medication therapy, and 
subjects will be excluded if presenting with clinically relevant symptoms of depression, 
excessive positive symptoms, specific comorbid disorders, or extrapyramidal side effects.
6.2.2
Dose
The effects of 3 dose levels of TAK-831 or placebo will be evaluated in the current study. The 
proposed doses of TAK-831 (50, 125, and 500 mg QD) have been selected based on the 
SRD/MRD PK data (Studies TAK-831-1001 and TAK-831-1005), food-effect PK data 
(Study TAK-831-1004), brain target occupancy (PET) data (Study TAK-831-1003), CSF 
D-serine data (Study TAK-831-1005), and safety data from all clinical studies after oral 
administration of TAK-831 in healthy subjects. D-serine levels in CSF and plasma after 
administration of TAK-831 600 mg QD (oral T2 tablets) and 800 mg QD (oral suspension) 
increased similarly, suggesting that 600 mg QD produced levels of D-serine approaching 
maximal DAO inhibition in the brain. The planned 500 mg QD dose is expected to result in CSF 
D-serine level increases near the plateau that are maintained over 24 hours with QD dosing. 
Preliminary PK/PD modeling analyses showed that the high-dose regimen (500 mg QD) resulted 
in steady-state exposures associated with mean peak target occupancy near the maximum 
(>90%) and provided mean target occupancy ≥50% over 16 hours, whereas the low-dose 
regimen (50 mg QD) produced daily exposures associated with a peak target occupancy of ≥50% 
of all subjects. The middle dose (125 mg QD) produced daily exposures associated with a peak 
target occupancy between 50% and the maximum. All 3 doses selected for the current study are 
predicted to demonstrate PD effects based on nonclinical efficacy models. The planned dose 
regimens are expected to deliver mean exposures within the range previously studied in Studies 
TAK-831-1001 and TAK-831-1005 that were found to be well tolerated in healthy subjects.
6.2.3
Endpoints
6.2.3.1
Efficacy Endpoints
Established, validated efficacy measures will be utilized to assess relevant schizophrenia 
symptom domains (negative, positive, general symptoms, global improvement, cognitive 
impairment, functional capacity, and quality of life).


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6.2.3.1.1
PANSS
The PANSS is a reliable, validated comprehensive evaluation scale of the severity of various 
symptoms of schizophrenia and is commonly employed in clinical studies involving 
antipsychotics [20,21]. The subscales of the PANSS and the 5-factor model of the PANSS are 
commonly employed to explore different symptom domains of schizophrenia [22]. Change from 
baseline in the PANSS NSFS is the primary endpoint of the current study. In addition, the 
secondary endpoints will include the PANSS total score and additional subscales and factors.
6.2.3.1.2
Clinical Global Impression-Schizophrenia
The Clinical Global Impression-Schizophrenia (CGI-SCH) scale [23] is an adapted version of the 
CGI scale [24] that is designed to assess global severity of illness and change in schizophrenia 
patients over time. The assessment consists of 2 subscales, the CGI-SCH-S and the CGI-SCH-I, 
which assess severity and improvement of illness, respectively. The CGI-S and CGI-I are 
validated measures that have been shown to corroborate efficacy, as measured by the PANSS 
[21,24,25]. The CGI-I score and change from baseline in CGI-S score are included as secondary 
endpoints in the current study.
6.2.3.1.3
BNSS
The BNSS is a 13-item instrument designed for use in clinical trials and other studies that 
measures 5 domains of negative symptoms: blunted affect, alogia, asociality, anhedonia, and 
avolition [26]. Examination of the correlations between other instruments supports the 
discriminant validity (ie, low correlations with other instruments measuring positive symptoms) 
and convergent validity (ie, high correlations with other instruments measuring negative 
symptoms). The BNSS has been demonstrated to have a 2-factor structure similar to other 
negative symptom scales, consisting of a diminished expressivity subscale and a motivation and 
pleasure subscale [27]. This feature will support examination of effects on these clinically 
important subsyndromes of negative symptoms. Change from baseline in BNSS total score is 
included as a secondary endpoint in the current study.
6.2.3.1.4
BACS
Cognitive symptoms of schizophrenia will be assessed as a secondary endpoint using the BACS, 
which is a reliable and sensitive measure of cognitive function in schizophrenia [28]. The BACS 
assesses 6 domains of cognitive function found to be consistently impaired in schizophrenia: 
verbal memory, working memory, motor speed, attention, executive functions, and verbal 
fluency. The BACS is specifically designed to measure treatment-related improvements in 
cognition and includes alternate forms. The BACS has high test-retest reliability and is sensitive 
to cognitive dysfunction in schizophrenia. The selection of the BACS was informed by the 
results of a schizophrenia clinical trial with a weak DAO inhibitor, sodium benzoate [18], which 
demonstrated beneficial effects on similar cognitive tasks.


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6.2.3.1.5
SCoRS
The SCoRS is an interview-based measure of cognitive functioning that was developed to 
specifically assess aspects of cognitive functioning found in each of the 7 cognitive domains 
assessed by the MATRICS primary outcome measure for clinical trials of new medications to 
improve cognition in schizophrenia [29]. The psychometrics and performance of the SCoRS 
were evaluated with a number of other cognition-focused functional endpoints and found to have 
good test-retest reliability and the highest feasibility of the interview-based assessments [30]. 
The SCoRS has also been found acceptable as a functional coprimary measure in a phase 3 
program by regulators for approval of an indication for cognition in schizophrenia [31].
6.2.3.2
Safety Endpoints
The secondary endpoint of safety will be evaluated by TEAE assessment, clinical laboratory 
tests, physical examinations, ECGs, vital signs, and suicidality assessment with C-SSRS.
The C-SSRS is a well-established 3-part scale that measures suicidal ideation (eg, subject 
endorses thoughts about a wish to be dead or has other thoughts of suicide), intensity of ideation 
(frequency, duration, controllability, deterrents, and reasons for ideation), and suicidal behavior 
(actual, interrupted, and aborted attempts at suicide) [32].
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one 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 drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by the investigational site during the 
course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to the first dose of study drug 
in the single-blind placebo run-in period.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, 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 prior to the 
initiation of any study procedures.
3. The subject has a current diagnosis of schizophrenia as defined by the MINI 7.0.2 for 
Psychotic Disorders for the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) and the general psychiatric evaluation.
4. The subject is male or female and aged 18 to 60 years, inclusive.
5. The subject weighs at least 45 kg and has a body mass index (BMI) between 18 to 
40.5 kg/m2, inclusive. 
6. The subject’s initial diagnosis must be ≥1 year from screening.
7. A female subject is eligible to participate if she is of (a) nonchildbearing potential or 
(b) childbearing potential and, if sexually active with a nonsterilized* male partner, agrees to 
use an acceptable effective method of contraception* from signing of informed consent 
throughout the duration of the study and for 35 days after the last dose. Female subjects of 
childbearing potential must also have a negative pregnancy test at the screening, single-blind 
placebo run-in, and baseline visits. Male subjects are not required to use barrier contraception 
in this study.
*Definitions of acceptable effective methods of contraception are defined in 
Section 9.1.17, and reporting responsibilities are defined in Section 9.1.18.
8. The subject is receiving primary background antipsychotic therapy (other than clozapine) at a 
total daily dose between 2 mg and 6 mg of risperidone equivalents (as outlined in an 
Antipsychotic Reference document supplied to the sites). Concomitant treatment with a 
subtherapeutic dose of a second antipsychotic may be permitted with sponsor or designee 
approval if used to treat specific symptoms, such as insomnia (for example, quetiapine 100 
mg or its equivalent once daily at bedtime) or anxiety (for example, quetiapine 25-50 mg or 
its equivalent as needed for anxiety), but not if it is used for refractory positive psychosis 
symptoms. Under this exception, the total daily dose of the second antipsychotic will not 
have to be included in the calculation of the 6 mg/day risperidone-equivalent limit. 
Recognizing that some prescribers use higher doses of quetiapine as a hypnotic, subjects 
taking up to 200 mg quetiapine or its equivalent as a hypnotic may be enrolled after 


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discussion with and approval from the sponsor or designee. Under this circumstance, the 
dosage above 100 mg quetiapine equivalent must be included in the calculation of the 6 
mg/day risperidone-equivalent limit.
9. The subject is treated with a stable regimen of psychotropic medications with no clinically 
meaningful change (no increase in dose, <25% decrease in dose for tolerability) in the 
prescribed dose for 2 months before the screening visit, and no dose adjustment is anticipated 
throughout study participation up to the Day 84/early termination visit. As an exception, 
prohibited medications that are used as hypnotics or anxiolytics may be replaced with 
permitted medications as medically appropriate with approval from the sponsor or designee. 
Recognizing that physicians outside of the study may be managing the subject’s background 
antipsychotic and other psychotropic medications, changes in background medication dosing 
that exceed this limit during the conduct of the study should be discussed with the sponsor or 
designee to determine subject disposition (based on consideration of safety and the study 
scientific objectives).
10. The subject has a BNSS total score (12-item, excluding number 4) ≥28; stable single-blind 
placebo run-in and baseline BNSS total (12-item, excluding number 4) scores (≤20% change 
from the screening score).
11. The subject has no more than moderate-severe (≤5) rating on PANSS positive symptom 
items P1, P3, P4, P5, P6, or unusual thought content (G9), with a maximum of 2 of these 
items rated “5”; no more than moderate (≤4) rating on conceptual disorganization (P2). 
12. There is evidence that the subject has stable symptomatology ≥3 months prior to the 
screening visit (eg, no hospitalizations for schizophrenia, no emergency room admission due 
to symptoms of schizophrenia, no increase in level of psychiatric care due to worsening of 
symptoms of schizophrenia).
13. The subject must have an adult informant who will be able to provide input for completing 
study rating scales, including the PANSS and SCoRS (for example, a family member, social 
worker, caseworker, residential facility staff, or nurse) who spends ≥4 hours/week with the 
subject and is considered reliable by the investigator. The informant must be able and willing 
to provide written informed consent and to participate in at least 1 in-person interview 
(during the screening period in the clinic, at Visit 2, or via site staff conducting informed 
consent at the informant’s location), then be able to provide continuing input by attending 
each clinical assessment visit or via participating in a telephone interview for other study 
visits that include the PANSS or SCoRS endpoints. Informant participation at the screening 
visit is preferred, if possible. If the informant is unavailable for an in-person interview at the 
screening visit, the initial informed consent may be obtained in a telephone discussion (as 
permitted by local ethics and regulatory policy) so that the informant information may be 
included in the screening assessments requiring informant input.


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7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. A female subject who is lactating or pregnant (positive prerandomization serum pregnancy 
test) or plans to become pregnant during the study.
2. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality (other 
than the disease being studied), which may impact the ability of the subject to participate or 
potentially confound the study results.
3. The subject has a lifetime diagnosis of schizoaffective disorder; a lifetime diagnosis of 
bipolar disorder; or a lifetime diagnosis of obsessive compulsive disorder based on the MINI 
combined with the general psychiatric evaluation. As an exception, subjects with a historical 
prior lifetime diagnosis of schizoaffective disorder may be enrolled in the study with sponsor 
or designee approval provided that the principal investigator can attest that the subject’s 
overall history and current clinical presentation and history is most consistent with 
schizophrenia, not schizoaffective disorder.
4. The subject has a recent (within the last 6 months) occurrence of panic disorder, depressive 
episode, or other comorbid psychiatric conditions currently requiring clinical attention based 
on the MINI for DSM-5 and the general psychiatric evaluation.
5. The subject has a diagnosis of substance use disorder (with the exception of nicotine 
dependence) within the preceding 6 months based on the MINI for DSM-5 and the general 
psychiatric evaluation.
6. The subject has any other medical or psychiatric condition or cognitive impairment that, in 
the opinion of the investigator, may interfere with study conduct or clinical assessments.
7. The subject is participating in a formal structured nonpharmacological psychosocial 
therapeutic treatment program (cognitive remediation, cognitive-behavioral therapy, 
intensive symptom/vocational rehabilitation) for a duration of <3 months before 
randomization. In addition, initiation of such nonpharmacological treatment programs is not 
permitted during study participation through the Day 84 visit. Recognizing that physicians 
outside of the study may be managing the subject’s psychosocial treatment, changes to this 
type of treatment during the conduct of the study should be discussed with the sponsor (or 
designee) to determine subject disposition.
8. The subject has a positive drug screen for disallowed substances, including amphetamines, 
barbiturates, cocaine, marijuana, methadone, methamphetamine, 3,4-
methylenedioxymethamphetamine (MDMA), phencyclidine, or nonprescribed 
benzodiazepines or opiates.
Note: Subjects testing positive for marijuana at screening may be eligible for participation in 
the study provided that the principal investigator’s clinical assessment indicates that the 
subject is not a regular user of marijuana, and after discussion with and approval from the 
sponsor or designee. Under this circumstance, a local urine dipstick drug screen must be 


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performed at the placebo run-in and Day 1 visits and verified to be negative prior to 
conducting any other study procedures at these visits. If the subject is confirmed to be 
eligible for randomization at the Day 1 visit, the central laboratory urine drug screen will be 
performed at all study visits to confirm that the subject is complying with restrictions on 
substances of abuse. Any positive urine drug screens during conduct of the study must be 
discussed with the sponsor or designee to determine the subject’s disposition.
9. The subject exhibits more than a minimal level of antipsychotic-induced parkinsonism 
symptoms, as documented by a score on the modified SAS (excluding item number 10, 
Akathisia) >6.
10. The subject has evidence of depression as measured by a Calgary Depression Scale Score 
(CDSS) >9.
11. The subject is considered by the investigator to be at imminent risk of suicide or injury to 
self, others, or property, or the subject has attempted suicide within the past year prior to 
screening. Subjects who have positive answers on item number 4 or 5 on the C-SSRS (based 
on the past year) prior to randomization are excluded.
12. The subject has a history of brain trauma associated with loss of consciousness 
for >15 minutes.
13. The subject’s diagnosis of schizophrenia occurred prior to 12 years of age.
14. The subject has received electroconvulsive therapy within 6 months (180 days) before 
screening.
15. The subject has a history of developmental intellectual disability or mental retardation.
16. Antipsychotic plasma levels for the subject’s primary background antipsychotic are below 
the minimum acceptable concentration criteria per the Antipsychotic Reference document at 
the screening or placebo run-in visits. This criterion is not applicable to subjects on a primary 
background antipsychotic for which a clinical assay is unavailable (ie, per the Antipsychotic 
Reference document). Screening antipsychotic plasma levels that do not meet the criteria 
listed in the Antipsychotic Reference document should be repeated as soon as possible if, in 
the judgment of the investigator, the subject may actually be adherent to their medication 
regimen. Please see Section 9.1.16.1 and the Antipsychotic Reference document for specific 
procedures to follow and for determination of subject eligibility in this circumstance.
17. The subject is treatment resistant. Treatment resistance is defined as prior nonresponse of 
positive symptoms of schizophrenia to 2 courses of treatment with antipsychotics of different 
chemical classes for at least 4 weeks, each at doses considered to be effective. 
18. Use of disallowed concomitant medications as documented in Section 7.4 that cannot be 
discontinued during the screening period (as medically appropriate). Note that disallowed 
psychotropic medications may not be discontinued during screening because of the 
psychotropic medication stability requirements for the study. Subjects taking disallowed 
psychotropic medications should not be considered for participation in the study (except 
those explicitly addressed in Sections 7.4 and 8.1.1).


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19. The subjects is taking concomitant treatment that can impact cognition as determined by the 
principal investigator in consultation with the sponsor or designee, including (but not limited 
to) the following: anticholinergics (exception: up to 2 mg benztropine/day or equivalent for 
treatment of extrapyramidal motor symptoms with sponsor or designee approval; must not be 
taken within 8 hours of any cognition assessment), stimulants, tricyclic antidepressants, 
anticonvulsants (exception for pregabalin and gabapentin), and lithium.
20. The subject has received TAK-831 in a previous clinical study; or has previously or is 
currently participating in this study; has received treatment with other experimental therapies 
within the preceding 60 days or <5 half-lives prior to randomization, whichever is longer; has 
participated in 2 or more clinical studies within 12 months prior to screening; or has 
participated in a clinical study for a psychiatric condition that is exclusionary per this 
protocol.
21. The subject is known by history or subject reporting to be currently infected or to have been 
infected with human immunodeficiency virus (HIV).
22. The subject has a known hypersensitivity to any component of the formulation of TAK-831 
or to the practice pills (ie, small candies) used during the compliance monitoring device 
training.
23. The subject has a history of cancer. As an exception, subjects may be enrolled if they have a 
history of treated basal cell carcinoma, stage I squamous cell skin cancer, or in situ cervical 
cancer that has been in remission for ≥5 years prior to first dose of study drug.
24. Subjects with evidence or history of current clinically significant cardiovascular disease, 
including uncontrolled hypertension (supine diastolic blood pressure >95 mm Hg and/or 
supine systolic blood pressure >160 mm Hg, with or without treatment), symptomatic 
ischemic heart disease, uncompensated heart failure or recent (past 12 months) acute 
myocardial infarction or bypass surgery. Controlled essential hypertension and nonclinically 
significant sinus bradycardia and sinus tachycardia will not be considered significant medical 
illnesses and would not exclude a subject from the study.
25. The subject has a QT interval with Fridericia correction method (QTcF) >450 msec (males) 
or >470 msec (females), confirmed with 1 repeat testing, at screening or Day 1, or the subject 
has long QT syndrome or is under the treatment with Class 1A (eg, quinidine, procainamide) 
or Class 3 (eg, amiodarone, sotalol) antiarrhythmic drugs.
26. The subject has type 1 diabetes that requires insulin for their treatment; has type 2 diabetes 
that is poorly controlled; has had changes to their diabetic treatment regimen within 30 days 
before screening; or has had hospitalizations for diabetes and/or diabetes-related conditions 
in the past 6 months before screening. As an exception, subjects who have consistently 
demonstrated the ability to adhere to their insulin and dietary regimens for an extended 
period of time in addition to demonstrating stable control of type 2 diabetes mellitus for an 
extended period of time may be considered for enrollment after discussion with the sponsor 
or designee.


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27. The subject has 1 or more laboratory values outside the normal range that are considered by 
the investigator to be clinically significant at the screening visit.
28. The subject has any of the following at the screening visit: a serum creatinine value >1.5 × 
upper limit of normal (ULN); a serum total bilirubin value >1.5 × ULN; a serum alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) value >2 × ULN. As an 
exception, subjects with Gilbert syndrome may be considered for enrollment after discussion 
with the sponsor or designee if the direct bilirubin is within the normal range. Subjects with a 
positive hepatitis B surface antigen (HBsAg) test result, or known or suspected active 
hepatitis C infection are also excluded.
29. The subject does not have a stable residence or is homeless.
7.3
Randomization Criteria
1. The subject must continue to meet all of the inclusion criteria and none of the exclusion 
criteria at the time of the baseline visit (Day 1; Visit 3). 
2. The subject has completed the single-blind placebo run-in period and has met the study drug 
compliance criteria (75% to 125%) as assessed using the digital compliance technology. As 
an exception, subjects who are in a residential setting that incorporates directly observed 
medication administration who meet this criterion (but not via the digital compliance 
technology) may be eligible for randomization with site documentation and approval of the 
sponsor or designee.
NOTE: Before enrollment into the single-blind run-in period, the site must confirm that 
approval has been received from the study sponsor or designee, and from the central 
eligibility vendor. The sponsor or designee approval will also serve as approval of subject 
randomization provided that the subject meets the specified randomization criteria at the 
baseline visit.
7.4
Excluded/Allowed Medications, Procedures, and Treatments
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
Subjects who require treatment with one or more of the specified medications should be 
excluded or discontinued (as appropriate) from the study. If a subject is prescribed treatment 
with a prohibited medication during the conduct of the study, the investigator should contact the 
sponsor or designee to review the relevant clinical information and medication treatment to 
determine subject disposition.
Excluded agents (prescription or nonprescription) or dietary products are listed in Table 7.a. 
Items with an ‘X’ indicate restrictions on either chronic or episodic use. Drug classes without an 
‘X’ in these columns indicate no restrictions. This table encompasses the most commonly used 
medications; however, it is not a comprehensive list. Additional detailed guidance on 


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excluded/allowed medications may be provided in separate reference documentation provided to 
study sites.
Table 7.a
Excluded Medications and Dietary Products
Drug Class
Disallowed (X) During the Study
(sections without [X] indicate no restriction unless noted in Comments)
Chronic Use
Episodic Use
Comments or Exceptions
Any investigational drug
X
X
<60 days before screening or 5 half-lives –
whichever is longer
Narcotic analgesics
X
Episodic use permitted if prescribed, must 
not be taken within 8 hours. of any study 
efficacy assessment.
Anorexiants (eg, phentermine, benzphetamine, 
phendimetrazine, methamphetamine, 
amphetamine, stimulants, sibutramine, Belviq 
(lorcaserin), Qsymia (phentermine/topiramate)
X
X
Must be discontinued for ≥30 days prior to 
screening
Antiarrhythmics of 1C class, quinidine
X
X
Antibiotics
X
Anticholinergics
X
X
Exception: The maximum permitted dose of 
chronic anticholinergic treatment is 2 
mg/day benztropine or equivalent; episodic 
use of anticholinergics must adhere to 
requirements outlined in Section 8.1.1.3.
Antithrombic agents and anticoagulants 
(excluding warfarin, which is excluded)
X
Antidepressants (excluding tricyclic 
antidepressants, MAOIs, and reversible 
Inhibitors of MAO [RIMAs])
X
Tricyclic antidepressants, MAOIs, and 
RIMAs are excluded, and subjects taking 
them should not be considered for 
participation in the study, as their 
discontinuation could lead to symptom 
instability.
Chronic treatment with SSRIs, SNRIs, and 
other antidepressants not listed above is 
permitted if they are prescribed at a stable 
dose for ≥2 months before screening and 
throughout study treatment.
Antihistamines
X
X
Except nonsedating antihistamines including 
loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine, and 
fexofenadine, or country-specific equivalent. 
Note that antihistamines used for 
anticholinergic properties are addressed 
separately in the relevant section above.
Antihypertensives
Clonidine NOT allowed.
Antipsoriatic agents
X
X
Topical agents are allowed.


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Table 7.a
Excluded Medications and Dietary Products
Drug Class
Disallowed (X) During the Study
(sections without [X] indicate no restriction unless noted in Comments)
Chronic Use
Episodic Use
Comments or Exceptions
Antipsychotics
X
Clozapine is excluded; all other treatments 
must adhere to requirements outlined in the 
study entry criteria and Section 8.1.1.2.
Subjects being treated with low-dose 
clozapine (up to 100 mg/day) for anxiety or 
insomnia before screening may be switched 
to a permitted medication during screening, 
as clinically appropriate, with sponsor or 
designee approval. 
Episodic use: As an exception, occasional 
use of an additional episodic dose of the 
background antipsychotic may be permitted 
with sponsor or designee approval (see 
Section 8.1.1.3). 
Herbal remedies, which are psychoactive (eg, St 
John’s wort, kava, valerian, ginkgo biloba, 
melatonin)
X
X
Must be discontinued ≥7 days prior to 
Visit 2.
Sedative hypnotics 
Barbiturates are excluded. Chronic treatment 
with BZs is allowed up to 3 mg/day 
lorazepam or equivalent (BZ equivalence 
standards will be provided in a site reference 
document). Episodic use of BZs must adhere 
to requirements outlined in Section 8.1.1.3. 
Note that hypnotics are excluded from the 2-
month stability requirement for other 
psychotropic medications.
Insulin
X
X
As an exception, subjects with type 2 
diabetes treated with insulin who have 
consistently demonstrated the ability to 
adhere to their insulin and dietary regimens 
for an extended period of time in addition to 
demonstrating stable control of type 2 
diabetes mellitus for an extended period of 
time may be considered for enrollment after 
discussion with the sponsor/designee.
Lithium 
X
X
Steroids:
Systemic oral or injectable
X
X
As an exception, treatment with local 
steroid injections for orthopedic conditions 
may be permitted with sponsor or designee 
approval.
Topical
Inhalant
Stimulants
X
X
Must be discontinued for ≥30 days prior to 
screening.
BZ: benzodiazepine; MAOI: monoamine oxidase inhibitor; RIMA: reversible inhibitor of monoamine oxidase type A, SSRI: 
selective serotonin reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitor.


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7.5
Diet, Fluid, and Activity Control
Study subjects will be instructed to take their study drug with water or milk. Subjects should 
avoid drinking juices 1 hour before and 1 hour after taking study drug.
7.6
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.20.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or 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 PTE or AE.

Liver Function Test (LFT) Abnormalities:
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status), if any of the following circumstances occur at any time during 
study drug treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for >2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5.
2. Important protocol deviation. The discovery post-randomization 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 study site and multiple attempts to contact 
the subject were unsuccessful. Attempts to contact the subject must be documented.
4. Withdrawal by subject. 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 due to 
an AE should not be recorded in the “voluntary withdrawal” category). If a subject chooses 
to withdraw from study participation due to personal concerns related to the COVID-19 
pandemic (other than a COVID-19-related AE), this should be specified as the reason for 
subject withdrawal in the eCRF.
5. Study termination. The sponsor, IRB/IEC, or regulatory agency terminates the study.


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6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.18.
7. Unsatisfactory therapeutic response. The investigator has determined that the subject is not 
benefitting from study treatment and continued participation would pose an unacceptable risk 
to the subject.
8. Noncompliance with study drug during the double-blind treatment period. Noncompliance 
with study drug includes subjects who are <75% compliant between visits, as assessed via 
the digital compliance technology. As an exception, this criterion may be assessed via site-
recorded compliance documentation for subjects who are in a residential setting that 
incorporates directly observed medication administration with approval of the sponsor or 
designee, as described for the placebo run-in period in Section 7.3. If these criteria for 
noncompliance are met on more than 1 occasion during the study, the subject will be 
considered significantly out of compliance and the site investigator will need to discuss the 
subject’s continuation in the study with the sponsor or designee. Based upon the assessment 
of the investigator and sponsor or designee, an out-of-compliance subject may be withdrawn 
from the study.
9. Throughout the study, signs of suicidal risk will be assessed by C-SSRS and the 
investigator’s clinical judgment. If the subject has a significant risk of suicide according to 
the investigator’s clinical judgment, the subject will be withdrawn from the study.
10. Symptomatic deterioration: Any subject from the study who experiences a clinically 
significant psychotic episode, relapse in positive symptoms, or overall worsening of illness 
that poses an unacceptable risk to the subject based on the judgment of the investigator 
should be discontinued from study participation, and the event documented as an AE.
11. Other: The reason for discontinuation should be entered into the eCRF including unavoidable 
circumstances such as the COVID-19 pandemic.
7.7
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 7.6. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the early termination visit.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.


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8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Study Drug (TAK-831 and Matching Placebo Tablets)
TAK-831 will be supplied as matching tablet dosage forms in 10, 25, and 100 mg and placebo. 
Each TAK-831 tablet strength and the placebo tablets will be bottled in a 60-count round high-
density polyethylene bottle with a child-resistant cap.
8.1.1.2
Companion Medication
Subjects must be on a stable ongoing oral or depot maintenance antipsychotic (other than 
clozapine) monotherapy regimen and on stable ongoing treatment with any nonprohibited 
concomitant psychotropic medications for ≥2 months prior to the single-blind placebo run-in 
visit and throughout the double-blind treatment period. Subjects must be treated with a primary 
background antipsychotic at a total daily dose between 2 mg and 6 mg of risperidone 
equivalents. A reference document listing the dose equivalency of currently marketed 
antipsychotics will be provided to study investigators. Subjects may also be treated with other 
nonprohibited psychotropic medications including antidepressants, anxiolytics, and hypnotics 
with a stable treatment regimen for ≥2 months prior to the single-blind placebo run-in visit and 
throughout study participation up to the Day 84/early termination visit.
All efforts should be made to maintain background nonprohibited psychotropic medications at 
consistent doses throughout the double-blind treatment period. Allowable exceptions to this rule 
include the following:
1. Primary background antipsychotic medication: Minor adjustments (no increase, ≤25% 
decrease) to manage drug-specific tolerability issues with sponsor or designee approval if 
required to support the subject’s continued participation in the study. Recognizing that 
physicians outside of the study may be managing the subject’s background antipsychotic and 
other psychotropic medications, changes in background medication dosing that exceed this 
limit should be discussed with the sponsor or designee to determine subject disposition. The 
evaluation will include assessment of whether the change in dosing poses a risk to clinical 
stability of the subject’s condition as well as the potential for impact on subject safety or the 
scientific objectives of the study.
2. Other background psychotropic medications: Minor adjustments (≤25% increase or decrease) 
with sponsor or designee approval if required to support the subject’s continued participation 
in the study. Recognizing that physicians outside of the study may be managing the subject’s 
background antipsychotic and other psychotropic medications, changes in background 
medication dosing that exceed this limit should be discussed with the sponsor or designee to 
determine subject disposition. The evaluation will include assessment of whether the change 
in dosing poses a risk to clinical stability of the subject’s condition as well as the potential for 
impact on subject safety or the scientific objectives of the study.


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3. Concomitant treatment with a subtherapeutic dose of a second antipsychotic may be 
permitted with sponsor or designee approval if used as a hypnotic, but not if it is used for 
refractory psychotic symptoms. Under this exception, if the total nightly dose of the second 
antipsychotic is ≤100 mg of quetiapine or its equivalent, the total daily dose of the second 
antipsychotic will not have to be included in calculation of the 6 mg/day risperidone-
equivalent limit. If a subject is taking up to 200 mg quetiapine or its equivalent as a hypnotic 
(the maximum allowed under this exception), the dosage above 100 mg quetiapine equivalent 
must be included in the calculation of the 6 mg/day risperidone-equivalent limit.
4. Prohibited medications that are used as hypnotics or anxiolytics may be substituted with 
nonbenzodiazepine hypnotics (eg, zolpidem up to 10 mg/day, zaleplon up to 20 mg/day, 
eszopiclone up to 3 mg/day, or zopiclone 7.5 mg/day) within their respective recommended 
dose ranges.
8.1.1.3
Rescue Medication
The guidelines below refer to use of medications that are not part of the subject’s routine 
ongoing background psychotropic companion medication regimen.
1. Treatment of insomnia as needed with benzodiazepine and nonbenzodiazepine hypnotics (eg, 
zolpidem up to 10 mg/day, zaleplon up to 20 mg/day, eszopiclone up to 3 mg/day, or 
zopiclone 7.5 mg/day) is permitted within their respective recommended dose ranges.
2. Treatment of anxiety or agitation as needed with up to 2 mg/day lorazepam (or the equivalent 
dose of another benzodiazepine) is permitted up to 3 times per week but cannot be taken 
within 8 hours of the administration of study assessments.
3. Treatment of extrapyramidal motor symptoms as needed with up to 2 mg/day benztropine (or 
the equivalent dose of another anticholinergic) is permitted up to 2 times per week but cannot 
be taken within 8 hours of the administration of study assessments.
4. The occasional use of an additional dose of the background antipsychotic medication, as 
occurs during standard of care treatment, may be permitted with sponsor or designee 
approval.
8.1.1.4
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:

TAK-831 10 mg T2 tablets.

TAK-831 25 mg T2 tablets.

TAK-831 100 mg T2 tablets.

Matching placebo tablets.


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8.1.2
Storage
Please refer to clinical labels for local storage conditions.
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature 
log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
For the single-blind placebo run-in period, the first dose of study drug (placebo) will be 
administered to subjects by the investigator or investigator’s designee in the clinic on Day -14 
(Visit 2) as subjects are familiarized with the compliance monitoring technology. Subjects will 
be instructed to take study drug orally each morning during the remainder of this period.
For the double-blind treatment period, the first dose of study drug (TAK-831 or placebo) will be 
administered to subjects by the investigator or investigator’s designee in the clinic on Day 1 
(Visit 3) after completion the Day 1 study procedures. Subjects will also take study drug at the 
clinic on the morning of Day 28 (Visit 6). For all other dosing days during this period, subjects 
will be instructed to take study drug orally each morning. Note: While morning dosing is the 
preferred approach for subjects in this study, exceptions may be granted with sponsor/designee 
approval based on individual subject contingencies and will not be considered protocol 
deviations.
Subjects should be advised to be consistent in the study drug dosing time throughout the duration 
of the study.
The dose and tablet count that will be provided to each treatment group are described in 
Table 8.a.
Table 8.a
Dose and Regimen
Treatment Group
Dosage
Treatment Description
Placebo Run-in Period
Placebo QD
5 oral placebo tablets
A
Placebo QD
5 oral placebo tablets
B
TAK-831 50 mg QD
5 oral TAK-831 10 mg T2 tablets
C
TAK-831 125 mg QD
5 oral TAK-831 25 mg T2 tablets
D
TAK-831 500 mg QD
5 oral TAK-831 100 mg T2 tablets
QD: once daily.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.


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All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE eCRFs according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, supportive measures should be employed as dictated by the 
subject’s clinical status and additional clinical monitoring should be initiated.
8.2
Study Drug Assignment and Dispensing Procedures
At screening, the investigator or designee will access the IRT to obtain the subject identification 
(ID) number (subject number). The investigator or designee will utilize the IRT to initiate the 
Placebo Run-in treatment on Day -14 and to randomize the subject to study drug treatment on 
Day 1. During these contacts, the investigator or designee will provide the necessary subject 
identifying information, including the subject ID number assigned at screening. The medication 
ID number of the study drug to be dispensed will then be provided by the IRT. If sponsor-
supplied drug (TAK-831 or placebo) is lost or damaged, the site can request a replacement from 
the IRT. (Refer to IRT manual provided separately).
At subsequent drug-dispensing visits, the investigator or designee will again access IRT to 
request additional study drug for the subject. The medication ID number of the study drug to be 
dispensed will be provided by the IRT.
On occasion, in unavoidable circumstances such as the COVID-19 pandemic that may impact the 
ability to conduct on-site visits, in order to reduce the risk of spreading infection and protect the 
safety of subjects, study drug can be shipped directly from study sites to subjects’ residences 
using the process known as Direct to Patient shipment. Additional drug supply may also be 
provided to subjects (either at an in-person visit or delivered to subject’s residence) to cover 
extended periods between on-site visits. Any additional resupply must be reviewed and approved 
in advance by the sponsor or designee. 
8.3
Randomization Code Creation and Storage
All randomization information will be stored in a secured area, accessible only by authorized 
personnel.
The randomization will be stratified by age at screening (<35 and ≥35 years of age). The 
allocation ratio will be 2:2:2:3 to the 3 TAK-831 arms and placebo arm respectively.
8.4
Study Drug Blind Maintenance 
The study drug blind will be maintained using the IRT. The investigator must not disclose the 
details of study drug (ie, placebo run-in) to subjects until the study has been completed.


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8.5
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. All study assessments and 
causality assessment should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the sponsor or designee should be contacted before the study 
drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the study drug blind can be obtained by the investigator or emergency 
personnel, by accessing the IRT.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, 
time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
If any site personnel are unblinded during the double-blind treatment period, study drug must be 
stopped immediately and the subject must be withdrawn from the study.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. or before destruction at the site according to the site’s internal standard operating 
procedure (SOP).
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug, the investigator or designee must maintain records of 
all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the study drug is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by recording in IRT. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to the following:

Continuously monitoring expiration dates if provided to the investigator. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed with, at a minimum, the medication ID and lot number for 
each dose.

Verifying that all containers used are documented accurately on the log.


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
Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
Current inventory of all study drug will be recorded in the IRT. The following information will 
be recorded at a minimum:

Protocol number.

Subject ID number.

Name of investigator, site number.

Description of sponsor-supplied drugs.

Date and amount dispensed.

Date and amount returned.

Name of the person making each IRT transaction.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
In the event of expiry date extension of supplies already at the study site, supplies may be 
relabeled with the new expiry date at that site. In such cases, Takeda or designee will prepare 
additional labels, certificates of analyses, and all necessary documentation for completion of the 
relabeling procedure at the sites.
At appropriate intervals before site closure, a representative from the sponsor or designee will 
perform clinical study material accountability and reconciliation before clinical study materials 
are returned to the sponsor or designee for destruction. The investigator will retain a copy of the 
documentation regarding clinical study material accountability, return, and/or destruction, and 
originals will be sent to the sponsor or designee.
9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures to be performed and data to be collected. 
For each procedure, subjects are to be assessed by the same investigator or site personnel 
whenever possible. The Schedule of Study Procedures is located in Appendix A.


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9.1.1
Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 or Other Unavoidable Circumstances
In unavoidable circumstances (eg, a widespread disease outbreak or natural disaster) that impact 
the study site’s ability to conduct study procedures according to the Schedule of Procedures 
(Appendix A), contingency measures may be implemented. In acknowledgement of study site, 
hospital, local, state and national restrictions established in response to circumstances like 
COVID-19, the following measures are being taken for the current study:

For subjects impacted while in the double-blind period, all attempts should be made to 
perform the assessments with the subject present at the site using the visit windows. 
Exceptions may be granted for alternative approaches to study procedures and data 
collection through approval by the sponsor or designee. Such instances must be 
documented in the study records and may include the following:
–
Sites must contact the sponsor or designee to discuss individual subject and site 
circumstances to obtain approval for use of alternative approaches to study 
procedures and data collection due to COVID-19 or other unavoidable circumstances.
–
Sites may seek approval from the sponsor or designee to continue subjects in the 
study despite departures from the Schedule of Procedures. The principal investigator 
is expected to evaluate the impact to the safety of the study participants and site 
personnel for subjects to continue. In evaluating such requests, the sponsor or 
designee will give the highest priority to the safety and welfare of the subjects. 
Subjects must be willing and able to continue taking study medication and remain 
compliant with the protocol. 
–
Other than the final visit, alternative methods for conducting subject visits (eg, video 
conferencing, telephone visits, or in-home study visits conducted by study site 
personnel or designated clinical personnel, contingent upon local regulations) may be 
used per approval by the sponsor or designee:

Under these circumstances, collection of certain study assessments may be 
omitted and visit windows may be extended. 

When approval is given for a subject to miss an in-person study visit, a study site 
physician will speak directly with the subject by telephone or other medium (e.g. 
a computer-based video communication) during each visit window to assess 
subject safety and overall clinical status. 

The study site physician or other qualified site personnel should conduct the 
following assessments within specified-visit window timeframes: AE 
assessments, documentation of concomitant medication, administration of 
C-SSRS, and an assessment of clinical symptoms.

Other study assessments may be collected using an alternative method as feasible, 
and may involve audio or video recording where allowed by local regulation. In 
some cases, audio and/or video recording of subject interviews may not be 


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possible and thus will deviate from the planned rater monitoring plan. This will be 
documented in the study records.

In some instances sites may need to split visits or sites may only be able to 
perform a few procedures on site and some procedures may need to be performed 
remotely. Sites should inform sponsor or designee when this occurs.

Sites may seek approval to extend a visit window in order to conduct an on-site 
visit. Assessments that cannot be completed during the protocol-specified window 
or within the visit window granted by the sponsor or designee will be considered 
missing data and such departures will be recorded in the study records. 

There will be no interval longer than 8 weeks between visits at which clinical 
laboratory tests are performed and vital signs are measured. Should this 8 week 
interval be reached for a particular subject, the site should reach out to the sponsor 
or designee to discuss withdrawal of the subject.
–
Study site personnel may dispense additional investigational medicinal product to 
subjects at a visit to allow for potentially longer intervals between visits than 
originally planned per protocol, or investigational medicinal product may be supplied 
to subjects via delivery by site personnel or by courier.
–
The final visit should be performed in person. When it is not possible for the subject 
to come to the study site and the protocol specified visit window cannot be extended 
further, the preferred alternative for the final visit is for qualified study site personnel 
or designated clinical personnel to go to the subject’s residence and conduct the 
protocol-specified procedures in that location. Assessments collected at a subject’s 
residence should comply with applicable local regulations. If neither option is 
available with sponsor or designee approval, sites may conduct final visit procedures 
remotely as is feasible.
All subject discontinuations and alternative approaches to study procedures (ie, procedures not 
conducted per the Schedule of Procedures) due to the COVID-19 pandemic must be documented 
in the study records as related to COVID-19. Data collected using alternative methods may be 
handled differently in the final data analyses. This will be documented in the statistical analysis 
plan (SAP). 
9.1.2
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for 
laboratory evaluations.
 


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The provision of informed consent to participate in remote study visits due to COVID-19 will be 
provided separately. A separate informed consent in regions where remote data verification is 
permitted per local regulations will also be obtained before implementation.
The Subject Database Authorization will be a component of the overall study informed consent 
(see Section 9.1.3) in some countries where this process is permitted by local regulations and 
ethics standards.
A unique subject ID number will be assigned to each subject at the time that informed consent is 
obtained/explained; this subject ID number will be used throughout the study.
In addition, as a requirement for entry into this study, subjects are required to have an informant. 
Informants will be required to sign a separate Designated Study Partner consent form.
When subjects have completed screening assessments prior to the study under a generic 
screening consent form, the data from this screening can be used in this study for those subjects 
who were subsequently enrolled, as long as the screening procedures were performed within the 
protocol-defined screening window.
9.1.3
Clinical Trial Subject Database Authorization
Clinical trial subject registries seek to reduce subjects from enrolling into multiple clinical trials 
by identifying potential duplicates before enrollment. This study will utilize 1 or more subject 
registry databases in some countries where they are available. At the time of providing the 
informed consent for the study, the investigator or designee will explain to the subject the IRB-
approved Subject Database Authorization and witness the signature.
During screening, site staff who have received training and login information to access the 
registry will enter the subject ID number and authorized subject identifiers on the registry 
website. An immediate report detailing matches is generated and should be printed for source 
documentation. The report will specify either (1) no potential matches found, (2) a potential 
match was found with a subject participating in another study within 30 days, and/or (3) the 
subject potentially matches with a subject who has prescreened/screened at another site. 
9.1.4
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic ethnicity 
(United States sites only), race as described by the subject, education, work status, tobacco use, 
reproductive status, alcohol consumption, and caffeine consumption of the subject at screening.
Medical and psychiatric history to be obtained will include determining whether the subject has 
any significant conditions or diseases relevant to the condition/disease under study that stopped 
at or prior to informed consent, specifically psychiatric history, including number of previous 
hospitalizations (lifetime and in past year), duration of each hospitalization (in the past year), and 
date of initial diagnosis of schizophrenia. Ongoing medical or psychiatric conditions are 
considered concurrent medical conditions (see Section 9.1.9).


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Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent.
9.1.5
Physical Examination Procedure
A baseline physical examination (defined as the last assessment prior to first dose of study drug) 
will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes and 
(11) other.
All subsequent physical examinations should assess clinically significant changes from baseline.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as 
not clinically significant or clinically significant by the investigator and recorded in the source 
document and eCRF. All clinically significant findings/changes will be recorded as a PTE or 
concurrent medical condition in the source document and on the appropriate eCRF as described 
in Section 10.0 or Section 9.1.9.
9.1.6
Weight, Height and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms with 1 decimal place. For assessment of entry criteria at screening, BMI 
should be derived as follows:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters 
can be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2.
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. If BMI is used as a study entry criterion, this determination 
must be made after rounding.
9.1.7
Vital Sign Procedure
Vital signs will include body temperature, blood pressure (systolic and diastolic), and pulse 
(bpm). Supine blood pressure, and pulse will be collected at a subset of study visits as outlined in 
the Schedule of Study Procedures (Appendix A). All other vital signs assessments will be 
collected in a sitting position.
Body temperature will be measured with an oral (temperature taken at floor of the mouth), 
tympanic, or infra-axillary thermometer. The same method (eg, oral, tympanic, or infra-axillary) 
must be used for all subsequent measurements for each individual subject and should be the 
same for all subjects.


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Subjects should rest in the specified position for at least 5 minutes prior to blood pressure and 
pulse measurements. 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. It is also 
recommended that the same arm be used for all blood pressure measurements for each individual 
subject.
Pulse should be recorded separately and should not be derived from the ECG.
9.1.8
Documentation of Concomitant Medication
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. This includes the subject’s background antipsychotic medication 
(which will be recorded on a specific antipsychotic medication eCRF) as well as the other stable 
background medications in the subject’s treatment regimen. At each study visit, subjects will be
asked whether they have taken any medication other than the study drug (used from signing of 
informed consent through the end of the study), and all medications including vitamin 
supplements, over-the-counter medications, and oral herbal preparations, must be recorded in the 
eCRF.
9.1.9
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the screening and single-blind placebo run-in visits, 
according the judgment of the investigator. The condition (ie, diagnosis) should be described.
9.1.10
Efficacy Measurements 
All assessments will be performed per the Schedule of Study Procedures (Appendix A). Clinical 
interviews will be video recorded for the MINI, PANSS, and BNSS and may be recorded for 
other measures at the discretion of the sponsor. The purpose of these recordings is to assess 
subject eligibility during the screening period and to provide feedback on interview technique 
and accuracy of ratings to raters throughout the study for endpoint quality assurance. To 
accommodate local cultural considerations in the schizophrenia population with regard to video 
recording versus audio recording, individual subject exceptions for video recording (record audio 
only instead) may be considered for sites that have already demonstrated high-quality subject 
interviews and ratings. Exceptions to proceed with only an audio recording will be made only 
after assessment of these factors, discussion of the subject and clinical contingencies between the 
investigator and the sponsor or designee, and receipt of documented approval from the sponsor 
or designee. 
Note: in unavoidable circumstances such as the COVID-19 pandemic, it may be necessary to 
administer clinical interviews and assessments using alternative approaches (please refer to 
Section 9.1.1). In some cases, audio/or video recording of subject interviews may not be possible
This will be documented in the study records.


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9.1.10.1
MINI
The MINI is a short structured diagnostic interview developed jointly by psychiatrists and 
clinicians in the United States and Europe for DSM-5 and International Classification of 
Diseases 10th Revision psychiatric disorders. With an administration time of approximately 
15 minutes, the MINI was designed to meet the need for a short but accurate structured 
psychiatric interview for multicenter clinical trials and epidemiology studies. Validation and 
reliability studies have been performed comparing the MINI to the Structured Clinical Interview 
for DSM-IV, Patient Edition and the Composite International Diagnostic Interview. The results 
of these studies showed that the MINI has acceptably high validation and reliability scores, but 
can be administered in a much shorter period of time (mean 18.7±11.6 minutes, median 
15 minutes) than the above-referenced instruments [33-35].
The assessment of the criterion for schizophrenia will be standardized using the MINI Version 
7.0.2 for DSM-5. The MINI will also be used to evaluate the presence of comorbid psychiatric 
disorders in order to assess the appropriateness of the subject for inclusion. Administration of the 
MINI will be video recorded (for exceptions, see Section 9.1.10) to facilitate review by third 
party independent expert clinicians.
9.1.10.2
PANSS
The PANSS is a reliable, validated comprehensive evaluation scale of the severity of various 
symptoms of schizophrenia and is commonly employed in clinical studies involving 
antipsychotics [20,21]. The Structured Clinical Interview for the Positive and Negative 
Syndrome Scale (SCI-PANSS) must be used to support the rating of each item and in accordance 
with guidelines provided by the sponsor (or designee). The Informant Questionnaire for the 
Positive and Negative Syndrome Scale (IQ-PANSS) must be used to collect information from 
the informant.
For all study visits, including the screening visit, administration of the PANSS will be recorded 
to facilitate review by third party independent expert clinicians (see Section 9.1.22.5) and may be 
used for exploratory analyses. Relevant data from each recorded PANSS administration, 
including scores on each of the 30 PANSS Items, CGI scores for the visit, and supporting 
information (including corroborating informant data for the past week) may be submitted along 
with the recording file to third party clinicians. Additional instructions will be provided during 
rater training and documented in the rater training manual.
The PANSS total score is derived from the summation of each item. The total time to administer 
the PANSS is approximately 45 minutes. PANSS raters will be required to have suitable 
experience and training (as deemed by the sponsor or designee) to be eligible to rate subjects 
within the study.
9.1.10.3
CGI-SCH Scale
The CGI-SCH scale is an adapted version of the CGI scale that is designed to assess global 
illness status in patients with schizophrenia [23]. The assessment consist of 2 subscales, the CGI-


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SCH-S and the CGI-SCH-I, which assess global severity of illness and change in the clinical 
condition over time, respectively, on a 7-point scale.
9.1.10.4
BACS
The BACS is a cognition assessment battery that assesses 6 domains of cognitive function found 
to be consistently impaired in schizophrenia: verbal memory, working memory, motor speed, 
attention, executive functions, and verbal fluency [28]. It takes approximately 30 minutes to 
complete and is devised for easy administration and scoring by nonpsychologists. It is 
specifically designed to measure treatment-related improvements in cognition and includes 
alternate forms.
9.1.10.5
BNSS
The BNSS is a13-item instrument designed for use in clinical trials and other studies that 
measures 5 domains of negative symptoms: blunted affect, alogia, asociality, anhedonia, and 
avolition [26]. Examination of the correlations between other instruments supports the 
discriminant validity (ie, low correlations with other instruments measuring positive symptoms) 
and convergent validity (ie, high correlations with other instruments measuring negative 
symptoms). Similar to the procedures for the PANSS assessment noted in Section 9.1.10.2, 
administration of the BNSS will be video recorded (for exceptions, see Section 9.1.10) for all 
study visits including the screening visit to facilitate review by third party independent expert 
clinicians.
9.1.10.6
SCoRS
The SCoRS is an interview-based measure of cognitive functioning that was developed to 
specifically assess aspects of cognitive functioning found in each of the 7 cognitive domains 
assessed by the MATRICS primary outcome measure for clinical trials of new medications to 
improve cognition in schizophrenia [29]. The scale is intended to incorporate information 
obtained from an informant who bases his/her responses on interaction with and knowledge of 
the patient. The SCoRS includes 20 items focusing on cognitive impairment and the degree to 
which it affects day-to-day functioning, as well as a global functioning scale; at follow-up visits 
there is also a global scale reflecting change from the beginning of the subject’s treatment rated 
by the administrator, the informant, and the subject.
9.1.10.7
CDSS
The CDSS was developed to assess symptoms of major depressive disorder in patients with 
schizophrenia, and specifically designed to assess comorbid depressive symptoms [36]. The 
CDSS consists of 9 items: depressed mood, hopelessness, self-deprecation, guilty ideas of 
reference, pathological guilt, depression worse in the morning, early wakening, suicide, and 
observed depression. The items on the CDSS are all typical depressive symptoms and do not 
appear to overlap with the negative symptoms of schizophrenia. The tool is administered via an 
interview with the subject.


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9.1.10.8
 
 
 
 
 
 
 
 
 
9.1.10.9
 
 
9.1.10.10
 
 
 
 
 
 
 
9.1.10.10.1
Optional Smartphone Passive Data Collection
Data will be collected with an application on a smartphone that will be periodically sent to a 
secure database. After completing informed consent, an application will be installed in a 
provided smartphone or the subject’s smartphone. The application will collect data from the 
smartphone from Day -14 through Day 84/early termination. These data will be collected during 
the typical use of the smartphone and do not require any additional action on the subject’s part. 
The subject can at any time choose to discontinue participating in the passive data collection 
assessments; in this case, the application will be deactivated or uninstalled. The data captured by 
the application will be transmitted over a secure channel to a secure data storage site. All data 
captured by the application will be encrypted and stored encrypted at rest. The data collected 


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from the smartphone will include the number and time of certain activities during phone use such 
as texts, emails, and phone calls (but not any content from these activities); keyboard input 
activities and gestures (without collecting the specific keyboard characters); location information 
(from the Global Positioning System [GPS]); and movement and orientation (position) of the 
smartphone. No absolute GPS data will be captured; GPS data will be measured relative to a 
random location, masking the user’s true location. These data will be used to develop a digital 
phenotype of subjects with schizophrenia and will be analyzed for any correlations with clinical 
endpoints. The data collection application does not collect information on who or what phone 
numbers are called, nor similar information from received calls. The data collection application 
does not capture the content of text messages that are sent or received. No personally identifiable 
information is captured, and all other data is encrypted on the smartphone before transmission to 
the secure database.
9.1.10.10.2
Optional Smartphone Visual/Audio/Electronic Clinical Assessments and Patient-
Reported Outcome Assessments
These assessments will combine active and passive data collection via the smartphone that is 
used for study drug compliance monitoring. Active data collection assessments will include 
(1) standard schizophrenia symptom assessments and self-report questionnaires administered at 
regular intervals during the study, and (2) presentation of images from a standard set developed 
to elicit moderate emotional responses of positive valence (eg, duckling) or negative valence 
(eg, trash) and asking the subject to describe the image in a few sentences. The subject’s facial 
expression, head posture, and properties of speech are analyzed after each image presentation. 
Passive data collection will be conducted during use of the device’s compliance monitoring 
function and will include (1) analyzing the subject’s facial expressions, head movements, and 
gestures, and (2) passive collection of smartphone use and movement/location data, as described 
above.
9.1.11
Additional Safety Assessments
9.1.11.1
Modified SAS
The SAS is a clinician-administered rating scale that has been widely used to assess 
antipsychotic-induced parkinsonism in clinical practice and research settings [42]. The present 
study uses a modified 10-item version of the SAS (for the screening and Day 1 assessment of 
eligibility) in which “Leg Pendulousness” and “Head Dropping” items included in the original 
version have been replaced with “Head Rotation” and “Akathisia,” which has been used 
frequently in schizophrenia clinical trials [43]. Each item is rated using a 5-point scale (0-4); the 
modified SAS scores can range from 0 to 40.
9.1.11.2
C-SSRS
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 
study of centrally-acting drugs [32]. The C-SSRS is composed of 3 questions addressing suicidal 


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behavior and 5 questions addressing suicidal ideation, with subquestions assessing the severity. 
The tool is administered via an interview with the subject.
Two versions of the C-SSRS will be used in this study: the Screening/Baseline C-SSRS Lifetime 
(assessing lifetime and the past year separately) and the Since-Last-Visit C-SSRS.
9.1.12
Order of Psychiatric/Neurological Rating Scales/Assessments
At screening, it is recommended to administer the BNSS first, followed by the C-SSRS. These 
assessments should precede all other psychiatric and neurological assessments at screening. After 
these assessments, the PANSS and then the MINI should be administered. At all other visits, the 
PANSS should take precedence over all other psychiatric assessments, and the BNSS should be 
administered after the PANSS. Thereafter, the order of assessments is not defined, except for the 
requirement that the CGI-SCH-I and CGI-SCH-S are completed after completion of all other 
psychiatric assessments (with an exception for the BACS, which does not contribute to the CGI 
assessments). Efforts should be made to perform the BACS cognition testing at approximately 
the same time of day throughout the study (postbaseline assessments must be administered 
±2 hours from the time of baseline assessment administration).
9.1.13
PK Measurements
9.1.13.1
PK Sample Collection
Serial blood samples (one 4 mL sample per scheduled time point) for measurement of TAK-831 
plasma concentrations will be collected into chilled Vacutainers containing the anticoagulant 
dipotassium ethylenediaminetetraacetic acid (K2EDTA), according to the Schedule of Study 
Procedures (Appendix A).
The actual date and time of each PK blood sample collection, time since last dose was 
administered, and time since last meal will be recorded on the source document and eCRF.
Instructions for sample collection, processing, and shipment are provided in the laboratory 
manual.
9.1.13.2
Bioanalytical Methods
Plasma concentrations of TAK-831 will be measured by a validated high-performance liquid 
chromatography (HPLC) with tandem mass spectrometry method.
9.1.13.3
Population PK
PK will be assessed via population PK analysis (see Section 13.1.4).
9.1.14


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9.1.14.1
 
 
 
 
 
 
 
 
 
 
 
9.1.14.2
 
9.1.14.3
 
9.1.15
 
 
 


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9.1.15.1
 
 
 
 
 
 
 
 
 
 
9.1.16
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single visit is approximately 39 mL (Visit 3), and the 
approximate total volume of blood for the study is 182 mL. Details of these procedures and 
required safety monitoring will be given in the laboratory manual.


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Table 9.a
Approximate Blood Volume
Sample
Volume
per
Sample
(mL)
Number of Samples Per Subject
Total
Volume
(mL)
Screening
(Days -28
to -15)
Placebo
Run-in
(Day -14)
Baseline
(Predose
Day 1)
Day 28
Day 42
Day 56
Day 70
Day 84/ET
Safety
Follow-up
(Days 94 to 98)
(Visit 1)
(Visit 2)
(Visit 3)
(Visit 6)
(Visit 7)
(Visit 8)
(Visit 9)
(Visit 10)
(Visit 11)
HBsAg, anti-HCV
4
1
4
Hb1Ac
2
1
2
Serum chemistry a
6
1
1
1
1
1
1 b
36
Hematology
2
1
1
1
1
1
1 c
12
Antipsychotic 
medications e
4
1
1
1
1
16
PK (TAK-831)
4
1
2
1
1
1
24
PD (D- and L-serine)
6
1
1
2
1
1
1
42
Total
182
Anti-HCV: antibody to hepatitis C virus; HBsAg: hepatitis B surface antigen; Hb1Ac: glycosylated hemoglobin; ET: early termination; PD: pharmacodynamics; 
: 
; PK: pharmacokinetics.
a Includes serum pregnancy test at the screening and safety follow-up visits and follicle-stimulating hormone (FSH) test at screening.
b Serum chemistry tests will be performed at this visit only if clinically significant test results were reported at Day 84/ET. However, a serum pregnancy test must be performed for 
women of childbearing potential at this visit (blood sample volume will be reduced to 2 mL if other serum chemistry tests are not required).
c Hematology will be performed at this visit only if clinically significant test results were reported at Day 84/ET.
e Levels may be retested at investigator’s request.


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The tests that will be performed for each clinical laboratory sample are listed in Table 9.b. 
Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hematocrit 
Hemoglobin 
RBC 
Mean cell volume 
Mean cell hemoglobin 
Mean cell hemoglobin concentration 
WBC with differential % and absolute
(neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Platelets 
Sodium 
Potassium
Bicarbonate
Chloride
Calcium
Magnesium
Phosphorus
Glucose 
Blood urea nitrogen 
Uric acid 
Total cholesterol
Triglycerides
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
Total protein 
Albumin 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
ALT 
AST 
GGT 
Creatine kinase 
Amylase 
Prolactin
Lactate dehydrogenase
Creatinine
Thyroid-stimulating hormone
Specific gravity
pH 
Glucose 
Protein 
Occult blood 
Microscopic battery (WBC, 
RBC, epithelial cells, casts) 
Other
Serum
Urine
HbA1c
HBsAg and anti-HCV
hCG (for pregnancy) a
FSH b
Antipsychotic medications c
Drug screen including: amphetamine, barbiturates, benzodiazepines, 
cocaine, marijuana, methadone, methamphetamine, MDMA, opiates 
(including oxycodone) and phencyclidine
hCG (for pregnancy) a
ALT: alanine aminotransferase; anti-HCV: antibody to hepatitis C virus; AST: aspartate aminotransferase; FSH: 
follicle-stimulating hormone; GGT: -glutamyl transferase; HbA1c: glycosylated hemoglobin; HBsAg: hepatitis B 
surface antigen; MDMA: 3,4-methylenedioxymethamphetamine; hCG: human chorionic gonadotropin; RBC: red 
blood cells; WBC: white blood cells.
a Women of childbearing potential only. Serum hCG test to be performed at the screening and safety follow-up 
visits, and urine hCG test to be performed at all other scheduled time points. The hCG test can be repeated at any 
time at the investigator’s discretion.
b Postmenopausal females only. 
c For all antipsychotics for which an assay is available at the central laboratory.


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The central laboratory will perform the hematology, serum chemistry, urinalysis, and other 
clinical laboratory tests. The results of laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results.
If subjects experience ALT or AST >3× ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. (Refer 
to Section 7.6 and Section 10.2.3 for the appropriate guidance on reporting abnormal LFTs.)
If ALT or AST remains elevated >3× ULN on these 2 consecutive occasions, the investigator 
must contact the sponsor or designee for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details, and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3). 
9.1.16.1
Antipsychotic Plasma Levels
Experience with therapeutic blood monitoring of antipsychotic medications in clinical settings 
has demonstrated that a single antipsychotic plasma assessment may not be reliably 
representative of adherence to antipsychotic medications, so repeat testing may be warranted to 
confirm an initial finding of a lower than adequate plasma level. 
Screening antipsychotic plasma levels that do not meet the criteria listed in the Antipsychotic 
Reference document should be repeated as soon as possible if, in the judgment of the 
investigator, the subject may actually be adherent to their medication regimen. Importantly, if the 
investigator’s initial assessment results in a determination that the subject is most likely not 
being adherent with their antipsychotic medication regimen, the plasma level should not be 
repeated and the subject should be a screen failure. 
If it is uncertain whether the subject is being adherent with treatment, it is recommended that 
antipsychotic plasma levels be urgently collected and sent to the central laboratory while the 
investigator collects additional information. If the investigator subsequently determines that the 
subject is not adherent to their medication regimen, the subject should be a screen failure. 
It is important to note that Visit 2 should not be conducted before receipt of the antipsychotic 
plasma level indicating an acceptable value (in addition to the sponsor or designee and 
centralized eligibility vendor approvals). The Antipsychotic Reference document should be 
consulted for additional guidance in the management and interpretation of antipsychotic plasma 
level assays.
9.1.17
Contraception and Pregnancy Avoidance Procedure
9.1.17.1
Male Subjects and Their Female Partners
Male subjects are not required to use barrier contraception in this study.


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9.1.17.2
Female Subjects and Their Male Partners 
From signing of informed consent, throughout the duration of the study, and for 35 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use an acceptable effective method of contraception (from the 
list below). In addition, they must be advised not to donate ova during this period.
9.1.17.3
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, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy 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, <45 years of age) 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 males should be at least 1 year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are as follows:

Nonhormonal Methods:
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
subject 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 prior to the first dose until 35 days 
after last dose.
–
Cervical cap (PLUS spermicidal cream or jelly) PLUS male condom.
–
Diaphragm (PLUS spermicide cream or jelly) PLUS male condom.

Hormonal Methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 


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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 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 shorter until she has 
been on contraceptive for 3 months. 

Progestogen-only hormonal contraception, where inhibition of ovulation is not the 
primary mode of action, PLUS condom with or without spermicide.

Oral. 

Injectable. 

Implantable.
2. Unacceptable methods of contraception are as follows:

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.
3. Subjects will be provided with information on acceptable effective methods of contraception 
as part of the subject informed consent process and will be asked to sign a consent form 
stating that they understand the requirements for avoidance of pregnancy and donation of ova 
during the course of the study.
4. During the course of the study, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential, and all female subjects will receive continued guidance 
with respect to the avoidance of pregnancy as part of the study procedures. Such guidance 
should include a reminder of the following:
a) Contraceptive requirements of the study. 
b) Assessment of subject compliance through questions such as the following:
i.
Have you used the contraception consistently and correctly since the last visit?
ii.
Have you forgotten to use contraception since the last visit?


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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?
5. 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). At the single-blind placebo run-in visit (Day -14) and the 
baseline/randomization visit (Day 1), a negative urine hCG pregnancy test must be 
established prior to the subject receiving any dose of study drug.
9.1.18
Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug (TAK-831 or placebo) should be immediately discontinued. 
If the pregnancy occurs during administration of active study drug, eg, after Visit 3 
(baseline/randomization visit) or within 95 days of the last dose of active study drug, the 
pregnancy should be reported immediately, using a pregnancy notification form, to the contact 
listed in Section 1.1.
Should the pregnancy occur during or after administration of blinded study 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 a female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the female 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 in subjects on active study drug 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.
9.1.19
ECG Procedure
A standard 12-lead ECG will be recorded. The following parameters will be recorded 
electronically by a central reader from the subject’s ECG trace: heart rate, RR interval, PR 
interval, QT interval, QRS interval and QTcF. The central reader will interpret the ECG using 1 
of the following categories: within normal limits or abnormal. If interpreted as abnormal, the 
investigator will assess the findings as either abnormal clinically significant, or abnormal not 
clinically significant. The interpretation of the ECG will be recorded in the source documents 
and in the eCRF. ECG traces recorded on thermal paper will be photocopied to avoid 
degradation of the trace over time. Requirements for the ECG equipment and procedure for 
collecting and transferring information to the central reader will be provided in the study 
reference manual.


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9.1.20
Documentation of Screen Failure
Investigators must account for all subjects who sign an informed consent. If the subject is found 
to be ineligible at the screening visit, the investigator should complete the eCRF. The IRT should 
be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Important protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason including unavoidable circumstances such as the COVID-19 
pandemic).
Subject ID numbers assigned to subjects who fail screening should not be reused.
9.1.21
Documentation of Randomization Failure
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the double-blind treatment period on Day 1. The IRT will be contacted for 
treatment assignment and this information should be captured on the appropriate eCRF. If the 
subject is found to be ineligible for randomization during the screening period, the investigator 
should record the primary reason for failure on the applicable eCRF and register the subject as a 
randomization failure in the IRT.
In addition, the primary reason for randomization failure will be recorded in the eCRF using the 
following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Did not meet study drug compliance criteria.

Important protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason including unavoidable circumstances such as the COVID-19 
pandemic).


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9.1.22
Rater Qualification and Certification Process
To ensure collection of quality data from scales administered by raters, raters assigned to this 
study will be required to fulfill qualification and/or training requirements. The process for 
qualifying and training raters will be described in manuals provided by rater training and 
assessment vendors. Furthermore, the study will include additional steps related to monitoring 
the quality of rater activity, which will be described in the manuals provided by these vendors.
All raters will be required to successfully fulfill the full scope of rater training requirements for 
any scale they will be administering prior to rating any subjects in this study. The sites will be 
responsible for ensuring that they have qualified raters who can conduct assessments in the study 
prior to enrollment of study subjects.
The training materials and requirements may be adjusted or modified as needed throughout the 
course of the study.
9.1.22.1
Rater Qualifications 
Each site will be required to identify and provide skilled raters who meet appropriate 
prespecified qualifications. Takeda and/or designee will make the final decision regarding 
whether the site-assigned raters are acceptable to participate in the study.
9.1.22.2
Submission of Experience Details
Raters will be required to complete and submit experience details and curriculum vitae (if 
applicable) to the rater vendor in a timely manner. Once the rater’s experience level is reviewed 
and deemed adequate, then study-assigned raters will be approved to participate in the rater 
certification process.
9.1.22.3
Rater Training and Qualification Program
Formal rater training and qualification will be conducted at the Investigator’s Meeting and via 
web portals. For those raters who need to be trained outside of the Investigator’s Meeting, the 
training will be conducted via web portals and/or on-site or remote training. Specific elements of 
the rater training and qualification program will be described further in the rater training and 
assessment vendor manuals.
Raters who receive an unacceptable rating will be required to complete additional training in 
conjunction with the Takeda-designated rater training vendor.
9.1.22.4
Site Changes to Rater Personnel During the Study
If a site rater changes during the course of the study, the newly appointed rater must be approved 
by Takeda for participation and must complete all training and certification requirements 
satisfactorily before the rater can begin participation on any study-related activities.
9.1.22.5
Rater Monitoring
This study will use electronic clinical outcome assessments (eCOAs) to capture questionnaire 
data. The data will be transmitted electronically to a centralized database at the eCOA vendor. 


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Data may be reviewed by site staff via secure access. eCOA data will be collected using a device 
provided by the eCOA vendor. The device is designed for entry of data in a way that is 
compliant with regulations for electronic records.
Appropriateness of the MINI, PANSS, and BNSS assessment administration and the scoring of 
responses will be monitored through video recordings (for exceptions, see Section 9.1.10) and 
electronic workbooks at predefined intervals (see Sections 9.1.10.1, 9.1.10.2, and 9.1.10.5) 
located in the ratings vendor manual.
Additional scale data will be monitored for consistency and quality control throughout the study. 
Further instructional activities or advisement will occur and may be requested for certain sites, if 
necessary.
BACS and SCoRS ratings may be reviewed by the vendor providing these assessments at a 
frequency determined by the sponsor. Copies of BACS and SCoRS source documents will be 
reviewed by the vendor’s data review specialists for errors in scoring and administration. Errors 
will be noted by reviewers, and feedback delivered to raters so that corrected scores can be 
entered into the study database.
9.2
Monitoring Subject Treatment Compliance
A digital compliance technology will be implemented in this study. Further details regarding this 
technology is provided in the study reference manual. Subjects also will be required to bring 
study drug packaging to each clinic visit, regardless of whether the study drug packaging is 
empty.
All subjects should be reinstructed about the dosing requirement during study contacts. The 
authorized study personnel conducting the re-education must document the process in the subject 
source records.
Noncompliance with study drug includes subjects who are <75% compliant between visits 
(including noncompliance as assessed via the digital compliance technology). If these criteria for 
noncompliance are met on more than 1 occasion during the study, the subject will be considered 
significantly out of compliance and the site investigator will need to discuss the subject’s 
continuation in the study with the sponsor (or designee). Based upon the assessment of the 
investigator and sponsor (or designee), an out-of-compliance subject may be withdrawn from the 
study. As an exception, subjects who are living in a residential setting that incorporates directly 
observed medication administration demonstrate ≥75% compliance (but not via the digital 
compliance technology) may be considered to be within these compliance requirements with 
study site documentation and approval of the sponsor or designee.
9.3
Schedule of Observations and Procedures
The Schedule of Study Procedures is provided in Appendix A. Assessments should be completed 
at the designated visit/time point(s).


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9.3.1
Poststudy Care
Study drug will not be available upon completion of the subject’s participation in the study. 
Since suitable subjects for this study will be symptomatically stable and on a stable antipsychotic 
treatment regimen, it is recognized that they will be under the care of the investigator or another 
treating physician before entry into the study and during study conduct. The subject should be 
returned to the care of a physician and standard therapies as required after study participation.
9.4
Biological Sample Retention and Destruction 
In this study, specimens for genome/gene analysis will be collected as described in 
Section 9.1.15. The genetic material will be preserved and retained at the long-term storage 
biorepository for up to but not longer than 15 years or as required by applicable law. The sponsor 
has put into place a system to protect the subjects’ personal information to ensure optimal 
confidentiality and defined standard processes for sample and data collection, storage, analysis, 
and destruction.
The sponsor and researchers working with the sponsor will have access to the samples collected 
and any test results. All samples collected during the study will be stored securely with limited 
access and the sponsor will require anyone who works with the samples to agree to hold the 
research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study 
but using a code that is different from the code attached to the health information and other 
clinical test results collected in the study. The sample and data are linked to personal health 
information with code numbers. This link means that the subject may be identified but only 
indirectly. The code numbers will be kept secure by or on behalf of the sponsor.
 
. Notify sponsor of consent 
withdrawal.
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1
PTEs
A 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 drug; it 
does not necessarily have to have a causal relationship with study participation. Placebo 
administered during the single-blind placebo run-in period is not considered study drug for this 
definition.


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10.1.2
AEs
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.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as 
a PTE/AE.
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 a PTE(s) or AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or 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 or ECG retest and/or continued monitoring of an abnormal value or finding 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 a PTE or AE.


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Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an 
AE (worsening or complication occurs after start of study drug). 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 concurrent medical condition (eg, asthma, epilepsy), 
any occurrence of an episode should only be captured as a PTE or AE if the condition 
becomes more frequent, serious, or severe in nature. Investigators should ensure that the AE 
term recorded captures the change in the condition from baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE or AE if occurring to 
a greater extent to that which would be expected. Investigators should ensure that the AE 
term recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after the first administration 
of study drug or any change in study drug, 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/serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be recorded as a PTE or AE. Complications resulting from 
any planned surgery should be reported as AEs.


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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF.
10.1.4
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).


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Table 10.a
Takeda Medically Significant AEs
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation / 
ventricular tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome
Confirmed or suspected transmission of infectious agent by a 
medicinal product
COVID-19-related disease
Neuroleptic malignant syndrome/malignant hyperthermia
COVID-19 pneumonia
Spontaneous abortion/stillbirth and fetal death
AE: adverse event; COVID-19: coronavirus disease 2019; SAE: serious adverse event.
Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
AEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
AEs of Special Interest
No AEs of special interest have been identified for TAK-831.
10.1.6
Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject. 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.


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10.1.7
Assigning Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications, 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.
10.1.8
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related.
10.1.9
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae, or the subject died.
10.1.11
Frequency 
Episodic AEs/PTEs (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous or once.
10.1.12
Action Concerning Study Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been 
taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE, eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped 
before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.


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10.1.13
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE/PTE.

Recovering/resolving – the intensity is lowered by 1 or more stages; the diagnosis or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or baseline; the subject died from a cause other than the 
particular AE/PTE 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 got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“not recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs/PTEs are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered double-blind study 
drug (Day 1; Visit 3) or until screen failure. For subjects who discontinue prior to double-blind 
study drug administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered double-
blind study drug (Day 1; Visit 3). Routine collection of AEs will continue until the Safety 
follow-up visit (between Days 94 and 98; Visit 11).
10.2.1.2
PTE and AE Reporting
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 a 
SAE 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, related or unrelated to the study procedure, need not be followed-up for the 
purposes of the protocol.


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All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs/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:
1. Event term.
2. Start and stop date and time.
3. Pattern of AE (Frequency).
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure.
7. Action concerning study drug (not completed for PTEs).
8. Outcome of event.
9. Seriousness.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:

A short description of the event and the reason why the event is categorized as serious.
-
Subject ID number.
-
Investigator’s name.
-
Name of the study drug(s).
-
Causality assessment.

SAEs should be reported via the SAE eCRF page in electronic data capture 
([EDC]/RAVE), which is the preferred method of reporting SAEs.

If access to EDC/RAVE is not feasible within 24 hours of receiving the event, the paper 
SAE forms should be submitted via fax (please see fax numbers below). 
–
In case of fax, site personnel need to confirm successful transmission of all pages and 
include an email address on the fax cover sheet so that an acknowledgment of receipt 
can be returned via email within 1 business day.

Email submission of SAE forms with a PDF attachment should only be used in the case 
where fax is not possible and EDC is not feasible within 24 hours of receiving the event. 


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–
In case of email, site personnel need to confirm successful transmission by awaiting 
an acknowledgment of the receipt via email within 1 business day. 

If SAEs are reported via fax or by email, EDC/RAVE must be updated as soon as 
possible with the appropriate information.

Fax Numbers: 
–
United States and Canada: +1-224 554-1052
–
Rest of World: +1-224 554-1052

Email Addresses:
–
United States and Canada: PVSafetyAmericas@tpna.com
–
Rest of World: eupv@tgrd.com.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
10.2.3
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 appropriate 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 10.2.2. The investigator must contact the sponsor or designee 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 must also be performed. In addition, an LFT 
Increases eCRF must be completed and transmitted with the Takeda SAE form (as per Section 
10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up entry in the EDC by completing a SAE eCRF per 
Section 10.2.2 immediately or within 24 hours of receipt. Follow up SAE forms (if EDC is 
unavailable) or other written documentation must be faxed immediately or 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.


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10.3.1
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, including the European 
Medicines Agency, 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 designee, SUSARs will be submitted to the 
regulatory authorities as expedited report within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
will also prepare an expedited report for other safety issues where these might materially alter 
the current benefit-risk assessment of a study drug/sponsor-supplied drug or that would be 
sufficient to consider changes in the study drug/sponsor-supplied drug administration or in the 
overall conduct of the trial. The study site also will forward a copy of all expedited reports to his 
or her IRB or IEC in accordance with local regulations.
11.0
STUDY-SPECIFIC COMMITTEES
11.1
Data Monitoring Committee 
This study does not include endpoints related to assessing mortality or major adverse health 
outcomes, and the study population is not at risk of serious safety events since subjects will be 
required to be symptomatically stable and maintained on their current standard of care treatments 
throughout the conduct of the study. In addition, as summarized in Section 4.1.3, TAK-831 has 
been well tolerated and safe across the full range of doses examined in clinical studies, and there 
have not been any safety findings that indicate the need for an independent Data Monitoring 
Committee (DMC).
However, in addition to the ongoing review of blinded safety data by the sponsor and designee 
during the conduct of this study, the sponsor will establish an internal DMC that is independent 
of the study and project teams to periodically review unblinded safety data during conduct of the 
study to complement the routine safety monitoring approach for drugs at this stage of 
development. If there is an interim analysis for futility, this committee will also be engaged to 
review the interim analysis results and make recommendations per the interim analysis plan. The 
functions and procedures of the committee will be outlined in a DMC Charter prior to the first 
DMC review meeting.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.


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The sponsor or designee will supply study sites with access to eCRFs. The sponsor or designee 
will make arrangements to train appropriate site staff in the use of the eCRF. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. Data are transcribed directly onto 
eCRFs. 
After completion of the data entry process, computer logic checks will be run to identify items, 
such as inconsistent dates, missing data, and questionable values. Queries may be issued by 
Takeda personnel (or designees) and will be answered by the site.
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must e-
sign 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 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 e-sign and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or designee. The sponsor or 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.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 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), 
copies of all paper CRFs and query responses/electronic copy of eCRFs, including the audit trail, 
and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities or from the sponsor or designees. Any source 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, International Council for 
Harmonisation (ICH) E6 (R2) Section 4.9.5 requires the investigator to retain essential 
documents specified in ICH E6 (R2) (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 (R2) Section 4.9.5 states that the study records 


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should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
An SAP will be prepared and finalized prior to unblinding of treatment assignments to the study 
team. This document will provide further details regarding the definition of analysis variables 
and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of treatment assignments to the 
study team. This review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods.
13.1.1
Analysis Sets
The Full Analysis Set (FAS) will include all subjects who were randomized and received at least 
1 dose of the study drug during the double-blind treatment period. In FAS summaries, subjects 
will be analyzed by the treatment to which they were randomized.
The Safety Analysis Set will include all randomized subjects who received at least 1 dose of 
double-blind study drug. In safety summaries, subjects will be analyzed according to the 
treatment they received.
The PK Analysis Set will include all randomized subjects who received at least 1 dose of double-
blind study drug and who have any available TAK-831 plasma concentration data.
The PD Analysis Set will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 postdose PD (plasma D-serine and L-serine) measurement.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics including age, gender, race, BMI, and medical 
history will be listed and summarized by treatment group and overall based on the FAS.
Baseline values for efficacy assessments will also be summarized by treatment group and overall 
based on the FAS.
13.1.3
Efficacy Analysis
13.1.3.1
Analysis of Primary Efficacy Endpoint 
The primary endpoint will be analyzed by comparing TAK-831 and placebo over all assessed 
time points using estimates from a mixed model for repeated measures (MMRM) with baseline 
value as a covariate; pooled site, visit, treatment, and categorical age (randomization factor) as 


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fixed factors; and treatment-by-visit and baseline-by-visit interactions. Based on a Missing at 
Random Assumption, this analysis will be performed using observed case data only. The effect 
at each time point for each treatment is allowed to vary freely and an unstructured covariance 
matrix is assumed. If the model does not converge, other covariance structures (unstructured, 
compound symmetry, 2-Toeplitz, etc) will be considered.
Additional analyses to address sensitivity to missing data will be specified in the SAP.
Multiplicity will be controlled across dose-arms by first testing the 125 mg QD and 500 mg QD 
dose-arms in parallel using Holm’s method to control the overall type I error rate at the 0.10 
level (one-sided), then testing the 50 mg QD dose-arm at the 0.10 level if at least 1 of other doses 
is found to be statistically superior to placebo.
In order to provide additional insight about dose-response, the primary endpoint may be analyzed 
using a Multiple Comparison Procedure-Modeling (MCP-Mod) approach. Additional details of 
the MCP-Mod analysis will be specified in the SAP.
Before unblinding the data, the team will assess the degree of impact from COVID-19 on 
PANSS NSFS data completeness or collection modality. If the impact is deemed minimal, which 
is defined as less than 5% of the enrolled subjects having remote or missing final assessments 
due to COVID-19, then the original analysis plan will be followed. If there is more than a 
minimal impact, then a more thorough blinded review will be performed. After the blinded 
assessment, if substantial changes to the statistical analyses are needed to address the impact, the 
SAP will be amended before study unblinding. Minor changes may be documented in the clinical 
study report.
13.1.3.2
Analysis of Other Efficacy Endpoints 
Other change from baseline endpoints will be analyzed in the same manner as the primary 
endpoint, but without control for multiple doses. 
The change from baseline on the CGI-SCH-S at Day 84, and the CGI-SCH-I score at Day 84 will 
be analyzed using a Cochran-Mantel-Haenszel test. This analysis will be stratified by age and 
performed using observed cases only.
For BNSS, BACS, CGI-SCH-I, CGI-SCH-S, SCoRS, PANSS total score and additional 
subscales and factors, the degree of impact from COVID-19 on completeness or collection 
modality will be assessed before unblinding the data. If the impact on an endpoint is deemed 
minimal, which is defined as less than 5% of the enrolled subjects having remote or missing final 
assessments due to COVID-19, then the original analysis plan will be followed. If there is more 
than a minimal impact, then a more thorough blinded review will be performed. After the 
blinded assessment, if substantial changes to the statistical analyses are needed to address the 
impact, the SAP will be amended before study unblinding. Minor changes may be documented in 
the clinical study report.


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13.1.4
PK Analysis
PK samples will be collected for the purpose of assessing exposure and compliance with study 
drug treatment. Plasma concentrations of TAK-831 will be presented in the data listings.
Plasma concentrations of TAK-831 will be listed for each subject and summarized by each time 
point for each TAK-831 treatment group. Of note, the sparse PK sampling approach in this study 
will not support generation of typical PK parameters.
Individual concentration-time data will be pooled to describe the population PK of TAK-831. As 
data permit, a nonlinear mixed effects modeling approach (NONMEM software) will be used to 
assess TAK-831 exposure. PK information generated in this study will be further utilized in 
subsequent population PK-PD analyses. The relationships between TAK-831 plasma 
concentrations and drug response (D- or L-serine plasma levels and/or selected measures of 
efficacy) will be explored. As appropriate, historical data may be used in this analysis to increase 
the robustness of the model and precision of estimated parameters. Details of the modeling 
approach will be provided in a separate analysis plan, and the results of these analyses will be 
reported separately.
13.1.5
PD Analysis 
For each regimen, the concentrations of D-serine, L-serine, and the ratio of D-serine to total serine 
with change and percent change from baseline will be summarized at each time point using 
descriptive statistics. In addition, mixed effects regression models will be fitted to the change 
from baseline in these concentrations. Pairwise comparisons between the test regimens 
(TAK-831 doses and placebo) will be made and the CIs for the difference in the LS means will 
be constructed for selected time points. Additional details and further analyses will be specified 
in the SAP (also see Section 13.1.4).
 
 
13.1.6
 
 
 
 
13.1.7
Safety Analysis
13.1.7.1
AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA. 
TEAEs with onset occurring within 30 days (onset date – last date of dose +1≤30) after study 


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drug administration will be included in the summary tables. TEAEs will be summarized by SOC 
and PT. The following summary tables will be generated: summary of TEAEs and drug-related 
TEAEs, relationship of TEAEs to study drug (related vs not related), severity of TEAEs, and 
related TEAEs. Data listings will be provided for all AEs, including TEAEs, TEAEs leading to 
study drug discontinuation, and SAEs.
13.1.7.2
Clinical Laboratory Evaluation
Individual results of clinical 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.
13.1.7.3
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.
13.1.7.4
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.
13.1.7.5
C-SSRS
C-SSRS will be summarized at all time points for each treatment group using descriptive 
statistics.
13.2
Interim Analysis and Criteria for Early Termination
An interim analysis for futility may be performed during the study, allowing for early study 
termination if the probability of success on the primary endpoint fails to meet a pre-specified 
criterion. The specifics of this analysis will be included in an interim analysis plan that will be 
finalized before interim unblinding. 
13.3
Determination of Sample Size
Assuming that the effect size is at least 0.4 for the 125 mg QD and 500 mg QD doses and that at 
least 85% of the 234 subjects complete the Day 84 assessment, the study has at least 82% power 
for at least 1 dose to be statistically-significant at the 0.10 level with correction for multiple 
doses.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
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 the study site guarantee access to source documents by the sponsor or 
designee and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and 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.
14.2
Data Monitoring
A data monitoring plan will be developed to assess the cognition and functionality data in an 
ongoing manner over the course of the study to ensure validity and integrity of key study 
endpoint data.
14.3
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, such as the COVID-19 pandemic, 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.
The site should document all protocol deviations in the subject’s source documents. In the event 
of an important protocol deviation, the site should notify the sponsor or designee (and IRB or 
IEC, as required). Important 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. Important protocol deviations will be reviewed at regular intervals by the sponsor 
and designee.
14.4
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 study drug is stored and prepared, and any other facility used during the study. In addition, 
there is the possibility that this study may be inspected by regulatory agencies, including those of 
foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 


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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 and study sites guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1.
15.0
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 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 B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities.
15.1
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 due to 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. 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 or designee will ship 
drug/notify site once the sponsor or designee has confirmed the adequacy of site regulatory 
documentation.
Study 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 designee.


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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
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 prior to 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 prior to 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 
prior to 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 


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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.
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.
 
Investigator 
will notify sponsor of consent withdrawal.
15.3
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 trial database or documentation via a subject ID 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 ID 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, 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 15.2).
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).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
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 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.


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The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the study site agreement. In the event of any discrepancy 
between the protocol and the study site agreement, the study site agreement will prevail. 
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association. 
15.4.2
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. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws, and/or regulations.
15.5
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 
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 designee.


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16.0
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Appendix A
Schedule of Study Procedures
Study Day
Screening
Placebo
Run-in
12-Week Double-Blind Treatment Period
Safety
Follow-
up
Days -42
to -15 a
Day -14
Day 
1 b
Day 
7 q
Day 
14 q
Day 
28 q
Day 
42 q
Day 
56 q
Day 
70 q
Day 
84/
ET 
b, c
Days 94-
98
(10-14 
days
after last 
dose)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Visit Window (Days) d
+7 e
±2
±2
±1
±2
±2
±2
±2
±5
±2
Informed consent 
X
Clinical Trial Subject 
Database consent
X
Informant informed consent f
X
X
MINI
X
Centralized subject eligibility 
assessment
X
X
Inclusion/exclusion criteria
X
X
X
Demographics, medical 
history, substance use
X
Medication history 
X
Concurrent medical conditions 
X
Physical examination
X
X
Vital signs g
X
X
X
X
X
X
X
X
X
X
X
Height, BMI, weight h
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory tests i
X
X
X
X
X
HBsAg, anti-HCV
X
FSH
X
HbA1c
X
Pregnancy test (hCG) j
X
X
X
X
X
X
X
Urine drug screen k
X
X
X
X
X
X
12-lead ECG
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
CDSS
X
Modified SAS
X
PANSS
X
X
X
X
X
X
BNSS
X
X
X
X
X
X
CGI-SCH-I
X
X
X
CGI-SCH-S
X
X
X
X
X
X
BACS l
X
X
X
X


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Study Day
Screening
Placebo
Run-in
12-Week Double-Blind Treatment Period
Safety
Follow-
up
Days -42
to -15 a
Day -14
Day 
1 b
Day 
7 q
Day 
14 q
Day 
28 q
Day 
42 q
Day 
56 q
Day 
70 q
Day 
84/
ET 
b, c
Days 94-
98
(10-14 
days
after last 
dose)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Visit Window (Days) d
+7 e
±2
±2
±1
±2
±2
±2
±2
±5
±2
SCoRS
X
X
Plasma sample for TAK-831 
PK n
X
X
X
X
X
Plasma sample for PD (D- and 
L-serine) n
X
X
X
X
X
X
Plasma sample for 
antipsychotic medications
X
X
X
X
PTE/AE assessment
X
X
X
X
X
X
X
X
X
X
X
Call IRT for subject 
ID/medication ID
X
X
X
X
X
X
X
X
X
Digital compliance technology 
training
X
Randomization
X
Dispense study drug p
X
X
X
X
X
X
X
X
Study drug 
return/accountability/complian
ce
X
X
X
X
X
X
X
X
In-clinic study drug dosing
X
X
X
AE: adverse event; anti-HCV: antibody to hepatitis C virus; BACS: Brief Assessment of Cognition in 
Schizophrenia; BMI: body mass index; BNSS: Brief Negative Symptom Scale; CDSS: Calgary Depression Scale 
Score; CGI-SCH-I: Clinical Global Impression-Schizophrenia-Improvement; CGI-SCH-S: Clinical Global 
Impression-Schizophrenia-Severity; COVID-19: coronavirus disease 2019; C-SSRS: Columbia-Suicide Severity 
Rating Scale; ECG: electrocardiogram; eCRF: electronic case report form; 
; ET: early termination; FSH: follicle-stimulating hormone; HbA1c: glycosylated hemoglobin; HBsAg: 
hepatitis B surface antigen; hCG: human chorionic gonadotropin; ID: identification; IRT: interactive response 
technology; MINI: Mini International Neuropsychiatric Interview; 
; PANSS: 
Positive and Negative Syndrome Scale; PD: pharmacodynamic(s); 
; PK: 
pharmacokinetic(s); PTE: pretreatment event: QD: once daily; SAS: Simpson Angus S0ocale; SCoRS: 
Schizophrenia Cognition Rating Scale.
a Medical Evaluation Form must be reviewed by the sponsor or designee, and a third-party independent expert 
clinician review of selected assessments included in the study Entry Criteria must be completed, prior to subject 
entry into the placebo run-in period.


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b Randomization is performed at Day 1 (Visit 3). If courier-related delays of laboratory test results occur (eg, due to 
COVID-19 related factors), Visit 3 may be delayed up to a maximum of 7 days after discussion with and approval 
from the sponsor or designee. For the screening and Day 1 visits, the study assessments may be conducted over 2 
days that must be completed within a 5-day period or less. All Day 1 procedures must be completed and compared 
with the relevant study entry criteria prior to randomization. The first dose of study drug will be administered in the 
clinic at the end of the Day 1 visit (or as the last procedure if the Day 1 visit is split over 2 days). Subjects will then 
take study drug QD in the morning from Day 2 onward during the double-blind treatment period. 
Study procedures for the Day 84/ET (Visit 10) may be conducted over 2 consecutive days for subject’s comfort and 
assessment feasibility. The final visit (Day 84/ET) should be performed in person. Alternative methods for 
administering study assessments may be considered when it is not possible for the subject to come to the study site 
or for the site staff or designated clinical personnel to go to the subject’s residence for the final visit (Day 84/ET) in 
cases where unavoidable circumstance such as the COVID-19 pandemic are prohibitive. Investigators should 
contact the sponsor or designee to discuss individual subject circumstances (Section 9.1.1).
c For subjects who prematurely discontinue the study, the PANSS, BNSS, BACS, SCoRS, CGI-SCH-I, CGI-SCH-S, 
and 
assessments should be performed only in subjects who received at least 1 dose of study drug and are 
assessed within 1 week of the last dose of study drug; all other ET procedures should be performed for subjects who 
are assessed >1 week after the last dose of study drug.
d If the date of a subject visit does not conform to the study plan, the timing of the subsequent visits should be 
planned to maintain the visit schedule relative to randomization.
e In cases where antipsychotic serum levels are not available within the expected 7 days window, additional 
screening window may be granted in these cases with sponsor or designee approval.
f May be obtained at screening (Visit 1) or placebo run-in (Visit 2) or at the informant’s location. The initial 
discussion with the informant may include an oral informed consent.
g Supine blood pressure and pulse will be measured at screening (Visit 1), Day 1 (Visit 3), Day 42 (Visit 7), and Day 
84/ET (Visit 10); sitting blood pressure and pulse will be measured at all other scheduled time points.
h Height and BMI will be collected at screening (Visit 1) only.
i Hematology, serum chemistry, and urinalysis. Clinical laboratory blood samples will be collected after a 6-hour 
fast, with the exception of screening (Visit 1) when fasting is not required. Antipsychotic serum blood levels may be 
retested at investigator’s request.
j Women of childbearing potential only. Serum hCG test will be performed at screening (Visit 1) and safety follow-
up (Visit 11). Urine hCG tests will be performed at all other scheduled time points. The hCG test can be repeated at 
any time at the investigator’s discretion.
k May be repeated at any time at the investigator’s discretion.
l Efforts should be made to perform the BACS assessment at approximately the same time of day throughout the 
study (postbaseline assessments must be administered ±2 hours from the time of baseline assessment 
administration).
 
n On Day -14 (Visit 2), 1 PD sample will be collected. On Day 1 (Visit 3), 1 PK blood sample and 1 PD blood 
sample will be collected predose. On Day 28 (Visit 6), subjects will take study drug at the site after predose PK and 
PD blood samples have been collected, and repeat PK and PD blood samples will be collected at the end of the visit. 
On Day 42 (Visit 7), Day 56 (Visit 8), and Day 84/ET (Visit 10), 1 PK blood sample and 1 PD blood sample will be 
collected at each visit; the subject will take study drug at the usual time in the morning before each of these 3 visits. 
For Days 42 and 56, it is recommended that sites schedule the clinic visit at different times of the day: 1 visit in the 
morning and 1 visit in the afternoon. It is recommended that the Day 42 Visit be scheduled in the afternoon because 
the subject does not have to fast for safety laboratory assessments. The actual date and time of each PK blood 
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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p Study subjects will be instructed to take their study drug QD in the morning with water or milk; subjects should 
avoid drinking juices 1 hour before and 1 hour after taking study drug.
q All attempts should be made to perform the assessments with the subject present at the site. However, in certain 
unavoidable circumstances (such as the COVID-19 pandemic), alternative methods for conducting subject visits (eg, 
video conferencing, telephone visits, or in-home study visits conducted by site personnel contingent upon local 
regulations) may be used per approval by the sponsor or designee. It may be necessary to perform some of the visit 
procedures remotely or at subjects’ residence contingent upon local regulations. Sites should contact the sponsor or 
designee (eg, contract research organization contact) to discuss individual subject and site circumstances. Approval 
may be granted for remote assessments, alternative methods to delivering investigational medicinal product or for 
study site personnel or designated clinical personnel to visit the subject at their residence. Additionally, approval 
may be granted to omit collection of certain study assessments and visit windows may be extended. There will be no 
interval longer than 8 weeks between visits at which clinical laboratory tests are performed and vital signs are 
measured. Should this 8 week interval be reached for a particular subject, the site should reach out to the sponsor or 
designee to discuss withdrawal of the subject (Section 9.1.1). 


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Appendix B
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 who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
5. 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.
6. 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.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. 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.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
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.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
13. 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.


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Appendix C
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 


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subject’s 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.
 
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 drug(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 acceptable effective contraception (as defined in the 
informed consent) from screening throughout the duration of the study, and for 35 days after 
last dose. 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 the study, study 
drug will be discontinued and the investigator will offer the subject the choice to receive 
unblinded treatment information. Male subjects are not required to use barrier contraception 
in this study.
26. 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 D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the 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 drug.

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 E
History of Protocol Amendments 01 through 03
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
30 October 2017
Initial Protocol
Not applicable
Global
26 June 2018
Amendment 01
Substantial
Global
19 July 2018
Amendment 02
Substantial
Local (Czech Republic)
13 March 2019
Amendment 03
Substantial
Global
Protocol Amendment No. 01 Summary of Changes and Rationale
This section describes the changes in reference to the protocol incorporating Amendment No. 01. 
The primary reason for this amendment was to revise elements of the study design.
In addition, inclusion/exclusion criteria, randomization criteria, excluded medications, criteria 
for discontinuation or withdrawal of a subject to include deterioration of the underlying illness, 
companion medications, monitoring of plasma levels of antipsychotic medication, contraception 
procedures, poststudy care, clarification of study procedures, and updating acceptable 
contraception options were revised for clarification or optimization of the prior protocol content. 
The number of subjects and statistical methods were revised for optimizing the study efficacy 
analysis based on re-evaluation of the relevant scientific contingencies.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study were included for clarification and administrative purposes only.
Changes in Amendment No. 01
1. Revision of elements of study design.
2. Revision of exploratory objectives, safety endpoints, and exploratory endpoints.
3. Revision of inclusion/exclusion criteria.
4. Clarification on randomization criteria.
5. Revision of excluded medication and dietary products.
6. Revision of criteria for discontinuation or withdrawal of a subject.
7. Revision of storage conditions for drug supplies.
8. Monitoring of antipsychotic plasma levels.
9. Clarification on contraception and pregnancy avoidance procedure.
10. Clarification on poststudy care.
11. Revision of statistical methods.
12. Revision of benefit risk profile.


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13. Updating treatment compliance.
Protocol Amendment No. 02 (Local Czech Republic)
The Czech Republic country-specific amendment was based on feedback from the Czech 
Republic regulatory authority in their review of the original protocol.
Protocol Amendment No. 03 Summary of Changes and Rationale
This section describes the changes in reference to the protocol incorporating Amendment No. 03. 
The primary reason for this amendment was to revise the assessments to reduce subject and site 
burden, revise inclusion/exclusion criteria to provide appropriate flexibility to the subject and 
site, revise concomitant medication requirements, and to update recommendations for the 
management of pregnancy and lactation based on the relevant TAK-831 nonclinical studies. In 
addition, additional clarifications were provided in study design, inclusion/exclusion criteria, 
randomization criteria, excluded medications, criteria for discontinuation or withdrawal of a 
subject, video monitoring for assessments, monitoring of plasma levels of antipsychotic 
medication, and rater monitoring. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Changes in Amendment No. 03
1. Updated medical monitor contact information.
2. Removed Q-LES-Q 18 assessment from the study.
3. Revised study design to increase the number of clinical sites, clarify management of run-in 
medication, clarify informed consent procedures for informants, and allow for flexibility in 
scheduling the Day 2 visit.
4. Revised inclusion and exclusion criteria based on updates made to excluded medications and 
new recommendations for the management of pregnancy and lactation; provided additional 
clarification of exclusionary characteristics for subjects with diabetes; added an exception for 
inclusion of subjects with Gilbert syndrome; and added criteria to exclude subjects who may 
be less likely to respond to treatment; additional changes were made for clarity and 
consistency.
5. Updated study drug compliance criteria and instructions for subject randomization approval. 
6. Removed anticonvulsants and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzyme 
inhibitors from excluded medications list and provided additional clarification on commonly 
prescribed concomitant medications permitted during the conduct of the study.
7. Revised study drug compliance threshold in criteria for discontinuation and added text for 
consistency with revisions to randomization criteria.
8. Clarified use of nonbenzodiazepine hypnotics.


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9. Modified rescue medications to include benzodiazepine hypnotics when used within their 
recommended dose ranges.
10. Added text to allow for flexibility with morning dosing.
11. Corrected instructions for the destruction of sponsor-supplied drugs.
12. Added text to allow for infra-axillary temperature measurement.
13. Added text to allow for individual exceptions for video recording of clinical interviews.
14. Revised order of psychiatric/neurological scales/assessments.
16. Added text to clarify the management and interpretation of antipsychotic plasma level assays.
17. Updated contraceptive and pregnancy avoidance procedures.
18. Updated pregnancy procedures.
19. Revised SAE collection procedures to include instructions for electronic data capture.
20. Revised CDSS and modified SAS assessments in Schedule of Study Procedures.
21. Revised Schedule of Study Procedures footnotes for consistency and clarification.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680db5728
Amendment 04 to A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to
Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose Levels of TAK-831 in Adjunctive
Treatment of Adult Subjects With Negative Symptoms of Schizophrenia
08-Jun-2020 12:54 UTC
08-Jun-2020 14:14 UTC
08-Jun-2020 16:23 UTC
08-Jun-2020 16:54 UTC

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-831-2002
A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate 
Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose levels of TAK-831 in Adjunctive 
Treatment of Adult Subjects With Negative Symptoms of Schizophrenia
PHASE 2
Version: Amendment 1
Date: 01 February 2021
Prepared by:
Based on:
Protocol Version: Amend 04
Protocol Date: 08 June 2020
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.
NCT #: NCT03382639


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


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
..............................................................................................6
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1.1
Primary Endpoint...............................................................................................11
5.1.2
Secondary Endpoints..........................................................................................11
5.1.3
Safety Endpoints................................................................................................11
5.1.4
.......................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.2
Study Definitions.....................................................................................................14
7.2.1
Definition of Study Days....................................................................................14
7.2.2
Definition of Study Visit Windows ....................................................................14
7.2.3
Conventions for Missing Adverse Event Dates...................................................14
7.2.4
Conventions for Missing Concomitant Medication Dates...................................15
7.2.5
Pooling of Sites..................................................................................................15
7.2.6
Protocol Deviations............................................................................................15
7.3
Analysis Sets ...........................................................................................................15
7.4
Disposition of Subjects ............................................................................................16
7.5
Demographic and Other Baseline Characteristics.....................................................16
7.6
Medical History and Concurrent Medical Conditions...............................................17
7.7
Medication History and Concomitant Medications...................................................17
7.8
Study Drug Exposure and Compliance.....................................................................17
7.9
Efficacy Analysis.....................................................................................................18
7.9.1
Primary Efficacy Endpoint(s).............................................................................18
7.9.2
Secondary Efficacy Endpoint(s).........................................................................19
7.9.3
.......................................................................19


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7.9.4
Analysis of PANSS Subscales and factors using the Marder Five-factor Model..19
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................20
7.10.1 Pharmacokinetic Analysis ..................................................................................20
7.10.2 Pharmacodynamic Analysis ...............................................................................20
7.11
Other Outcomes.......................................................................................................20
7.12
Safety Analysis........................................................................................................20
7.12.1 Adverse Events ..................................................................................................20
7.12.2 Clinical Laboratory Evaluations .........................................................................22
7.12.3 Vital Signs .........................................................................................................23
7.12.4 12-Lead ECGs ...................................................................................................23
7.12.5 Other Observations Related to Safety.................................................................24
7.13
Interim Analysis ......................................................................................................24
7.14
Changes in the Statistical Analysis Plan...................................................................24
8.0
REFERENCES..............................................................................................................30
LIST OF FIGURES
Figure 4.a
Schematic of Study Design ................................................................................10


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
BACS
Brief Assessment of Cognition in Schizophrenia
BNSS
Brief Negative Symptom Scale
CGI-SCH-I
Clinical Global Impression-Schizophrenia-Improvement
CGI-SCH-S
Clinical Global Impression-Schizophrenia-Severity
C-SSRS
Columbia-Suicide Severity Rating Scale 
DNA
deoxyribonucleic acid
DPAS
Defeatist Performance Attitude Scale
ECG
electrocardiogram
eCRF
electronic case report form
Emax
maximum drug-induced effect
FAS
Full Analysis Set
FWER
family-wise error rate
GGT
-glutamyl transferase
IPD
important protocol deviation
IRT
interactive response technology
MCP-Mod
Multiple Comparison Procedure-Modeling
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
mixed model for repeated measures
PANSS
Positive and Negative Syndrome Scale
PANSS NSFS
Positive and Negative Syndrome Scale Negative Symptom Factor Score
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PPS
Per Protocol Set
PT
preferred term
PTE
pretreatment event
QD
once daily
QTcF
QT interval with Fridericia correction method
RNA
ribonucleic acid
SAE
serious adverse event
SAS
Simpson Angus Scale
SCoRS
Schizophrenia Cognition Rating Scale
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of this study is to determine whether add-on TAK-831 is superior to 
placebo on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS 
NSFS).
4.2
Secondary Objectives

To determine whether add-on TAK-831 is superior to placebo on the Brief Negative 
Symptom Scale (BNSS) total score.

To determine whether add-on TAK-831 is superior to placebo on the Brief Assessment of 
Cognition in Schizophrenia (BACS) composite cognition score.

To determine whether add-on TAK-831 is superior to placebo on global severity as measured 
by the Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) score.

To determine whether add-on TAK-831 is superior to placebo on global improvement as 
measured by the Clinical Global Impression-Schizophrenia-Improvement (CGI-SCH-I) 
score.

To determine whether add-on TAK-831 is superior to placebo on the Schizophrenia 
Cognition Rating Scale (SCoRS) assessment of cognitive functional outcome.

To determine whether add-on TAK-831 is superior to placebo on the Positive and Negative 
Syndrome Scale (PANSS) total score and additional subscales and factors.

To assess the safety and tolerability of TAK-831.

To assess the pharmacokinetics (PK) of TAK-831.
4.3
 
 
 
 


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4.4
Study Design
This is a randomized, double-blind, parallel, placebo-controlled, phase 2 study to evaluate the 
efficacy, safety, tolerability, and PK of adjunctive treatment with TAK-831 when administered 
orally once daily (QD) in adult subjects with negative symptoms of schizophrenia. The study 
will consist of a Screening Period of up to 28 days, a 14-day Single-Blind Placebo Run-in 
Period, a 12-week Double-Blind Treatment Period, and a Safety Follow-up Visit.
Approximately 234 subjects will be enrolled at approximately 48 sites in North America and 
Europe.
At the Screening Visit (Visit 1), subjects who provide informed consent will proceed with 
screening procedures. Subjects who meet a current diagnosis of schizophrenia, as defined by the 
Mini International Neuropsychiatric Interview (MINI), will then be administered additional 
psychiatric and neurological rating scale assessments as specified in Protocol Section 9.1.11, and 
undergo other screening assessments. Subjects must be currently receiving stable treatment on 1 
antipsychotic medication at a total daily dose between 2 mg and 6 mg of risperidone equivalents 
(as outlined in an Antipsychotic Dose Equivalency reference supplied to the sites), with no 
clinically meaningful change in psychotropic medications (no increase, ≤25% decrease in dose) 
for the preceding 2 months before the Screening Visit and no dose adjustment is anticipated 
throughout study participation up to the Day 84/Early Termination Visit. Concomitant treatment 


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with a subtherapeutic dose of a second antipsychotic may be permitted with sponsor or designee 
approval if used as a hypnotic, but not if used for refractory positive psychosis symptoms. 
Subjects must have a BNSS total score (12-item, excluding item number 4) ≥28 and limited 
PANSS symptoms as outlined in the study inclusion criteria, and must demonstrate stable BNSS 
total scores (≤20% change from the Screening score) at the Single-Blind Placebo Run-in Visit 
(Day -14; Visit 2) and Baseline Visit (Day 1; Visit 3). Subjects with extrapyramidal 
signs/symptoms or depressive symptoms based on study assessments, as outlined in the study 
entry criteria, will be excluded.
During the Screening Period (Days -42 to -15), subjects will visit the clinic and receive full 
medical, neurological, and psychiatric examinations as well as be familiarized with study 
procedures. Additional screening procedures include diagnostic assessments, safety assessments, 
and other clinical assessments. An adult informant capable of providing information about the 
subject’s symptoms and function for the PANSS and SCoRS must attend the Screening or 
Placebo Run-in Visit for evaluation by site staff and to provide written informed consent for 
informant study participation. Alternatively, a site staff member may also go to the informant’s 
location to obtain informed consent and, if a qualified rater, obtain the informant interview; or 
the informant interview may be conducted by phone if the site staff is not a rater. If the informant 
is unavailable for an in-person interview at the screening visit, the initial informed consent may 
be obtained in a telephone discussion (as permitted by local ethics and regulatory policy) so that 
the informant information may be included in the screening assessments requiring informant 
input.
Subject eligibility for the study will be confirmed by a centralized vendor that will also provide 
rater qualification, training, and ongoing rater quality monitoring throughout the conduct of the 
study. For the Screening Visit, the centralized vendor will review documentation and recordings 
of the diagnostic and selected symptom assessment interviews as well as collected information 
addressing key study entry criteria. The study site must receive documentation of approval of 
subject eligibility before the subject can be enrolled into the Single-Blind Run-in Period.
The 2-week Single-Blind Placebo Run-in Period (Days -14 to -1) will be used to evaluate 
compliance with study drug intake and stability of BNSS and PANSS scores. During this period, 
all subjects will receive placebo tablets that appear identical to the study drug to be used during 
the randomized Double-Blind Treatment Period. Note: If the scheduling of the Day 1 visit is 
delayed for any reason, the subject should be instructed to continue treatment with run-in 
medication until the Day 1 visit is reschedule. 
At Baseline (predose Day 1; Visit 3), subjects who continue to meet all eligibility criteria, 
including placebo run-in drug compliance requirements, will be randomized via an interactive 
response technology (IRT) system to 1 of the following treatments: TAK-831 50 mg QD, 
TAK-831 125 mg QD, TAK-831 500 mg QD, and placebo QD. Randomization will be followed 
by a 12-week Double-Blind Treatment Period (Days 1 to 84), during which subjects will undergo 
assessments as outlined in Protocol Appendix A. Efforts will be made to perform cognition 
testing at approximately the same time of day throughout the Double-Blind Treatment Period 
(postbaseline assessments must be administered ±2 hours from the time of Baseline assessment 


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administration). A Safety Follow-up Visit (between Days 94 and 98; Visit 11) will be scheduled 
for all subjects 10 to 14 days after the last dose of study drug.
 
 
 
Subjects will be instructed to take 5 tablets QD during the Single-Blind Placebo Run-in and 
Double-Blind Treatment Periods, during which time study drug compliance will be monitored 
with a mobile technology system. Subjects will be instructed to take their study drug with water 
or milk and to avoid drinking juices 1 hour before and 1 hour after taking study drug.
Subjects who have been screened but have exceeded the 28-day screening period may proceed to 
the placebo run-in visit after a discussion with the sponsor/designee to obtain approval and to 
determine whether any screening procedures should be repeated before that study visit.
Subjects who do not meet symptom or medication stability criteria (or other entry criteria that 
may be met by the subject at a future time) may be considered for rescreening with the approval 
of the sponsor or designee.
In the event that a subject prematurely discontinues the study, an Early Termination Visit must 
be conducted, at which time all the assessments scheduled for the Final Visit will be performed.
An interim analysis for futility may be performed during the study, allowing for early study 
termination if the probability of success on the primary endpoint fails to meet a prespecified 
criterion. The specifics of this analysis will be included in an interim analysis plan that will be 
finalized before interim unblinding. 
The end of the study is defined as the date the last subject completes the Safety Follow-up Visit 
(Visit 11).
Permuted block randomization will be used. The randomization will be stratified by age at 
Screening (<35 and ≥35 years of age). The allocation ratio will be 2:2:2:3 to the 3 TAK-831 
arms and placebo arm respectively. 
A schematic of the study design is included as Figure 4.a.


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Figure 4.a
Schematic of Study Design


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5.0
ANALYSIS ENDPOINTS
Baseline is defined as the assessment prior to dosing on Day 1 for all assessments other than the 
 where Baseline is defined as the Day -14 assessment.
5.1.1
Primary Endpoint 

Change from Baseline on the PANSS NSFS at Day 84.
5.1.2
Secondary Endpoints

Change from Baseline on the PANSS NSFS at Days 28 and 56.

Change from Baseline on the BNSS at Day 84.

Change from Baseline on the BACS composite score at Day 84.

Change from Baseline on the CGI-SCH-S score at Day 84.

CGI-SCH-I score at Day 84.

Change from Baseline on the SCoRS at Day 84.

Change from Baseline on the PANSS total score and additional subscales and factors at 
Day 84.

TAK-831 plasma concentrations.
5.1.3
Safety Endpoints

Percentage of subjects who experience at least 1 TEAE.

Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once postdose.

Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements 
at least once postdose.

Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram 
(ECG) parameters at least once postdose.

Percentage of subjects with treatment-emergent suicidal ideation or suicidal behavior as 
measured using the C-SSRS.
5.1.4
 
 


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6.0
DETERMINATION OF SAMPLE SIZE
Assuming that the effect size is at least 0.4 for the as 125 mg QD and 500 mg QD doses and that 
at least 85% of the 234 subjects complete the Day 84 assessment, the study has at least 82% 
power for at least 1 dose to be statistically significant at the 0.10 level with correction for 
multiple doses.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Baseline values are defined as the last observed value before the first dose of study medication.
All statistical analyses will be conducted using SAS® Version 9.4, or higher, unless otherwise 
noted. 
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. P-values will be rounded to 
3 decimal places prior to assessment of statistical significance.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated. 
Screen failure subjects will be grouped and listed at the end.
7.2
Study Definitions
7.2.1
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of double-
blind medication. Other study days are defined relative to the Study Day 1 with Day 1 being 
Study Day 1 and Day -1 being the day prior to Study Day 1.
7.2.2
Definition of Study Visit Windows
A windowing convention will be used to determine the analysis value for a given study visit that 
applies to observed data. For each visit, a window will be defined such that the lower and upper 
bounds of each window is generally the midpoint between 2 consecutive study visits. 
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used.
7.2.3
Conventions for Missing Adverse Event Dates
Incomplete adverse event (AE) start dates will be imputed to determine the relationship between 
the start date and the informed consent date, as well as the start date and the first dose date of the 
double-blind study medication. Incomplete AE dates will be presented as they are in the listings.


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The following methods will be used to impute incomplete start dates of AEs:

If only the month and year of the start date are available and the month and year are different
than the month and year of the first dose of double-blind study medication or the stop date is 
prior to the first dose of study medication, then the first day of the month will be used for the 
start date. If only the month and year of the start date are available and the month and year 
are the same as the month and year of the first dose of double-blind study medication and the 
stop date is not prior to the date of first dose, then the date of first dose will be used for the 
start date.

If only the year of the start date is available and the year is different than the year of the first 
dose of double-blind study medication or the stop date is prior to the first dose of study 
medication, then January 1st will be used for start date. If only the year of the start date is 
available and the year is the same as the year of the first dose of double-blind study 
medication and the stop date is not prior to the date of first dose, then the date of first dose 
will be used for start date.
7.2.4
Conventions for Missing Concomitant Medication Dates
Missing concomitant medication dates will not be imputed. Also see Section 7.7.
7.2.5
Pooling of Sites
The study team has reviewed the data in blinded fashion and decided to group sites into the 
following two groups: European sites and Non-European sites.
7.2.6
Protocol Deviations
Significant protocol deviations will be summarized, and all protocol deviations will be listed. A 
sperate listing will be created for protocol deviations due to COVID-19.
Important Protocol Deviations (IPD) are those, which have the potential to influence the outcome 
of the primary analysis and therefore, will be used to define the Per Protocol Set. Along with 
other protocol deviations, the IPD will include subjects that had < 75% compliance between 
visits for more than one occasion during the study, as assessed via the digital compliance 
technology. Those noncompliant subjects will be listed.
Additional important protocol deviations may also be identified prior to unblinding. If so, the 
additional important protocol deviations will be finalized and documented prior to database lock 
and used for deleting subjects from FAS set to define the Per Protocol Set. Important protocol 
deviations will also be summarized in a table by treatment groups and overall, and presented in 
the CSR. Also, important protocol deviations will be marked in the protocol deviation listing.
7.3
Analysis Sets
The Full Analysis Set (FAS) will include all subjects who were randomized and received at least 
1 dose of the study drug during the Double-Blind Treatment Period. In FAS summaries, subjects 
will be analyzed by the treatment to which they were randomized.


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The Per Protocol Set (PPS) will include all subjects in the FAS excluding those who had 
important protocol deviations.
The Safety Analysis Set will include all randomized subjects who received at least 1 dose of 
double-blind study drug. In safety summaries, subjects will be analyzed according to the 
treatment they received.
The PK Analysis Set will include all randomized subjects who received at least 1 dose of double-
blind study drug and who have any available TAK-831 plasma concentration data.
The PD Analysis Set will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 postdose PD (plasma D-serine and L-serine) measurement.
7.4
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 treatment arm, TAK-831 overall and overall. 
Disposition of all randomized subjects will be tabulated: 

All subjects received at least one dose of study drug (denominator).

Subjects who completed the study.

Subjects who prematurely discontinued study treatment.

Subjects who prematurely discontinued study.
Primary reasons for discontinuation of study treatment or study will be entered on the electronic 
case report form (eCRF), will be tabulated. Reasons for premature discontinuation of study an 
and/or study treatment include death, adverse event, protocol deviation, lost to follow-up, 
withdrawal by subject, study termination by sponsor, pregnancy, lack of efficacy, noncompliance 
with study drug during the double-blind period, significant risk of suicide, 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. Subjects who enter the Single-
Blind Run-in Period but are not randomized, e.g., due to noncompliance with single-blind 
treatment, will be included as screen failures.
7.5
Demographic and Other Baseline Characteristics
Demographics and other Baseline characteristics including age, gender, race, body mass index, 
and medical history will be listed and summarized by treatment group and overall based on the 
FAS. Number of subjects by country and age category will be summarized.
Baseline values for efficacy assessments will also be summarized by treatment group and overall 
based on the FAS.


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7.6
Medical History and Concurrent Medical Conditions
Medical and psychiatric history to be obtained will include determining whether the subject has 
any significant conditions or diseases relevant to the condition/disease under study that stopped 
at or prior to informed consent, specifically psychiatric history, including number of previous 
hospitalizations (lifetime and in past year), duration of each hospitalization (in the past year), and 
age of initial diagnosis of schizophrenia. Ongoing medical or psychiatric conditions are 
considered concurrent medical conditions.
Medical history and concurrent medical conditions will be coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA, version 19.0) and will be summarized 
by treatment group and overall using System Organ Class (SOC) and MedDRA preferred term. 
The table will include number and percentages of subjects and will be sorted in alphabetical 
order by system organ class and preferred term. A subject will only be counted once within a 
particular class even if he/she has multiple conditions/symptoms. Summaries will be based on 
the safety analysis set.
All medical history and concurrent medical condition data will be presented in listings.
7.7
Medication History and Concomitant Medications
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent.
Concomitant medication is any drug given in addition to the study drug. If it is not possible to 
determine algorithmically from the reported data whether a medication was concomitant, it will 
be assumed to be concomitant.
Medication history and concomitant medications will be coded using the latest version of the 
World Health Organization (WHO, Version 01March2015) Drug Dictionary and summarized by 
giving the number and percentage of subjects by preferred term within each therapeutic class, 
with therapeutic class and medications in each class sorted in alphabetical order. The total 
number of subjects with medications in each selected therapeutic class will also be presented. If a 
subject reports taking 2 drugs belonging to the same class, he/she will only be counted once 
within that class. Summaries of medication history and concomitant medication will be based on 
the safety analysis set. 
All prior and concomitant medications data will be presented in listings.
7.8
Study Drug Exposure and Compliance
Duration of exposure to double-blind study medication is defined as (date of last dose – date of 
first dose +1). It will be summarized as a continuous variable. 
Study medication data will be collected by the study digital compliance technology and also by 
the number of tablets returned. The primary method of assessing compliance will be the digital 
technology.
The percentage of study drug compliance will be defined in two ways:


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1) Using the digital compliance technology, as {(number of tablets recorded as taken) / 
[5*(date of last dose – date of first dose +1)]}x 100%,
2) Using number of returned tablets, {(number of tablets dispensed – number of tablets 
returned) / [5*(date of last dose – date of first dose +1)]} x 100%.
For each treatment group, study medication compliance will be summarized by compliance 
category (<75%, 75 to 125%, and >125%) and the number of subjects in each compliance 
category. Study medication compliance will also be summarized as a continuous variable using 
descriptive statistics (n, mean, SD, median, minimum, and maximum) for each treatment group. 
All study drug administration and compliance data will also be summarized in a listing(s).
7.9
Efficacy Analysis
The analyses and summaries for efficacy will be based on the FAS, unless otherwise noted. 
7.9.1
Primary Efficacy Endpoint(s)
The primary endpoint is the change from Baseline on the PANSS NSFS at Day 84. The details of 
PANSS NSFS calculation can be found in Section 7.9.4. 
The primary endpoint will be analyzed by comparing TAK-831 and placebo over all assessed 
time points using estimates from a mixed model for repeated measures (MMRM) with Baseline 
value as a covariate; pooled site, visit, treatment, and categorical age (randomization factor) as 
fixed factors; and treatment-by-visit and Baseline-by-visit interactions. Based on a Missing at 
Random Assumption, this analysis will be performed using observed case data only. The effect 
at each time point for each treatment is allowed to vary freely and an unstructured covariance 
matrix is assumed. If the model does not converge, other covariance structures (unstructured, 
compound symmetry, 2-Toeplitz, etc) will be considered.
Multiplicity will be controlled across dose-arms by first testing the 125 mg QD and 500 mg QD 
dose-arms in parallel using Holm's method to control the overall type I error rate at the 0.10 level 
(one-sided), then testing the 50 mg QD dose-arm at the 0.10 level if at least 1 of other doses is 
found to be statistically superior to placebo.
In order to provide additional insight about dose-response, the primary endpoint may be analyzed 
using a Multiple Comparison Procedure-Modeling (MCP-Mod) approach (Pinheiro et al, 2014). 
For MCP-Mod approach, DoseFinding package in R statistical analysis software will be used. R 
has been validated by the contract research organization for this study. The following set of 
models will be fit to detect a dose response: linear, Emax, quadratic, and exponential. The 
stratification factor of age (<35 and ≥35 years) will be included in the models. Each of the dose-
response shapes in these models will be evaluated using optimal contrasts and applying MCP-
Mod techniques to preserve the family-wise error rate (FWER) with the overall 1-sided 
significance level of 0.10. The effective dose(s) will be determined within this framework. The 
stratification factor of age may be omitted if the dose response for the stratified models cannot be 
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The following supplementary analyses will also be conducted for the primary endpoint:
1) A method for missing value imputation based on pattern mixture models (PMM) using 
standard SAS STAT procedures. It is assumed that after discontinuation from the study, 
subjects receiving a TAK-831 dose will exhibit the same future evolution of the disease 
as subjects on the placebo treatment. The missing PANSS NSFS scores in the TAK-831 
dose arm will be imputed using placebo-based pattern mixture models. This method uses 
sequential regression and multiple imputation methodology to impute missing values for 
visits after a subject’s discontinuation from the study in the placebo arm. Then based on 
the available data from placebo subjects, the missing values from active treatment arm 
will be imputed using pattern mixture models until missing values at all visits are 
imputed.
2) The primary endpoint also be analyzed using analysis of covariance (ANCOVA), with 
pooled center, stratification factor, and treatment as fixed factors, and PANSS NSFS
Baseline score as a covariate. ANCOVA based on the multiply-imputed data will be 
performed. 
As a supportive analysis, the primary endpoint will be analyzed using MMRM in the same 
manner as described in section 7.9.1, but based on the PPS. 
7.9.2
Secondary Efficacy Endpoint(s)
Other continuous change from Baseline endpoints will be analyzed using MMRM in the same 
manner as the primary endpoint (as described in section 7.9.1), but without control for multiple 
doses. 
The change from Baseline on the BNSS total (12-item, excluding item 4) will be analyzed using 
MMRM in the same manner as the primary endpoint, but without control of multiple doses. The 
same analysis will be repeated on the change of Baseline on the BNSS total (13-item).
The change from Baseline on the CGI-SCH-S at Day 84, and the CGI-SCH-I score at Day 84 
will be analyzed using a Cochran-Mantel-Haenszel test. This analysis will be stratified by age 
and performed using observed cases only.
7.9.3
 
 
7.9.4
Analysis of PANSS Subscales and factors using the Marder Five-factor Model
The PANSS consists of 30 items across 3 subscales: positive symptoms (items P1-P7), negative 
symptoms (items N1-N7), and general psychopathology (items G1-G16). In addition, 5 factors 
are calculated by the Marder five-factor model [2]. The five factors are: (1) negative symptoms, 


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(2) positive symptoms, (3) disorganized thought, (4) uncontrolled hostility/excitement and (5) 
anxiety/depression. The items included in each factor are listed in Appendix E. 
PANSS subscales/ factors will be calculated by summing the individual items within each 
subscale/factor. For example, PANSS NSFS will be calculated by summing the individual items 
within the negative symptoms factor.
The PANSS total score will be calculating by summing the 30 individual items. If individual 
items are missing, the following rule will be used: PANSS total = sum of (non-missing items) ×
30] / (# non-missing items)], rounded to the nearest integer. If more than 5 of the items are 
missing, the PANSS total will be set to missing. 
7.10
Pharmacokinetic/Pharmacodynamic Analysis
7.10.1 Pharmacokinetic Analysis
Plasma concentrations of TAK-831 will be listed for each subject and summarized by each time 
point for each dose of the study.
Individual concentration-time data will be pooled to describe the population PK of TAK-831. As 
data permit, a nonlinear mixed effects modeling approach (NONMEM software) will be used to 
assess TAK-831 exposure. PK information generated in this study will be further utilized in 
subsequent population PK-PD analyses. The relationships between TAK-831 plasma 
concentrations and drug response (D- or L-serine plasma levels and/or selected measures of 
efficacy) will be explored. As appropriate, historical data may be used in this analysis to increase 
the robustness of the model and precision of estimated parameters. Additional details will be 
specified in a separate analysis plan.
7.10.2 Pharmacodynamic Analysis
For each regimen, the concentrations of D-serine, L-serine, and the ratio of D-serine to total 
serine with change and percent change from Baseline will be summarized at each time point 
using descriptive statistics. In addition, mixed effects regression models will be fitted to the 
change from Baseline in these concentrations. Pairwise comparisons between the test regimens 
(TAK-831 doses and placebo) will be made and the CIs for the difference in the LS means will 
be constructed for selected time points.
7.11
Other Outcomes
The analysis of the 
 will be described in a separate analysis plan.
7.12
Safety Analysis
7.12.1 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 drug; it does not necessarily have to have a causal relationship with 


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study participation. Placebo administered during the Single-Blind Placebo Run-in Period is not 
considered study drug for the purpose of this definition or for defining an AE.
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. In the protocol, this is also referred to as a treatment-emergent adverse event.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. To be included in summary tables, they must 
occur with 30 days (onset date – last date of dose + 1 ≤30) after the last dose of study drug or 
early termination.
AEs are recorded in the eCRF as being related or not related to study drug and/or study 
procedure. AEs that are recorded as related to study drug and/or study procedure will be 
summarized separately. AEs will also be presented by intensity/severity (mild, moderate, and 
severe). Serious AEs, AEs leading to study drug discontinuation, and AEs leading to death will 
also be summarized using SOC and PT. 
When calculating the frequency and percentage of subjects who reported AEs, a subject will be 
counted only once for each SOC or PT when multiple AEs are coded to the same SOC or PT. For 
the intensity or relatedness summaries, if a subject reports multiple AEs coded to the same SOC 
or PT, the AE 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. Summary tables that will be generated will 
include, but may not be limited to: 

Overview of Treatment-Emergent Adverse Events 

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Treatment-Emergent Adverse Events by Preferred Term

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 

Serious Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term


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
Drug-Related Treatment-Emergent Adverse Events by Preferred Term

Most Frequent (> 5% in Any Treatment Arm) Non-Serious 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 AEs by SOC and PT will be generated. For this study, 
Treatment-Emergent Adverse Event (TEAE) is synonymous with AE.
Data listings will be provided for PTEs, AEs, AEs leading to study drug discontinuation, liver 
function abnormalities, SAEs, and AEs that resulted in death. AEs happened after 3 days post the 
last dose of the study drug will be listed as well.
7.12.2 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 
9.1.10 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 Study Data Tabulation Model (SDTM) and Analysis Data Model (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 3 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 markedly abnormal values (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 
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.


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7.12.3 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 3 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.
7.12.4 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 3 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-
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.


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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.
7.12.5 Other Observations Related to Safety
The modified Simpson Angus Scale and C-SSRS will be summarized at all time points for each 
treatment group and TAK-831 total and overall total using descriptive statistics.
7.13
Interim Analysis
An interim analysis for futility may be performed during the study, allowing for early study 
termination if the probability of success on the primary endpoint fails to meet a pre-specified 
criterion. The specifics of this analysis will be included in an interim analysis plan that will be 
finalized before interim unblinding. 
7.14
Changes in the Statistical Analysis Plan 
Considering the potential impact of noncompliant subjects, a supportive analysis on the primary 
endpoint based on PPS described in section 7.9.1 is added.
Section 7.2.5 is updated to provide details on site pooling method.
A separate listing for protocol deviations due to COVID-19 is added.
In section 7.9.2, clarification is added to describe the analyses on BNSS total (12-item, excluding 
item 4) and BNSS total (13-item).
Typographical errors are corrected.


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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 PANSS Items Included in Each Factor using the Marder Five-Factor Model
Factor
Item (Item Number)
1.
Negative symptoms 
Blunted affect (N1)
Emotional withdrawal (N2)
Poor rapport (N3)
Passive/apathetic social withdrawal (N4)
Lack of spontaneity and flow of conversation (N6)
Motor retardation (G7)
Active social avoidance (G16)
2.
Positive symptoms
Delusions (P1)
Hallucinatory behavior (P3)
Grandiosity (P5)
Suspiciousness/persecution (P6)
Stereotyped thinking (N7)
Somatic concern (G1)
Unusual thought content (G9)
Lack of judgement and insight (G12)
3.
Disorganized thought
Conceptual disorganization (P2)
Difficulty in abstract thinking (N5)
Mannerisms and posturing (G5)
Disorientation (G10)
Poor attention (G11)
Disturbance of volition (G13)
Preoccupation (G15)
4.
Uncontrolled hostility/ excitement
Excitement (P4)
Hostility (P7)
Uncooperativeness (G8)
Poor impulse control (G14)
5.
Anxiety/depression
Anxiety (G2)
Guiltfeelings (G3)
Tension (G4)
Depression (G6)


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8.0
REFERENCES
1. Pinheiro, J., Bornkamp, B., Glimm, E. and Bretz, F. (2014), Model‐based dose finding 
under model uncertainty using general parametric models. Statist. Med., 33: 1646-1661. 
doi:10.1002/sim.6052
2. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of 
schizophrenia derived by factor analysis: combined results of the North American trials. J 
Clin Psychiatry 1997;58(12):538-46.


 
  
 
 
 
 
 
 
 
 
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