Clinical trial NCT03359785
Conditions: Schizophrenia
Keywords: Drug therapy
Sponsor: Neurocrine Biosciences
Start date: 2018-01-10; Completion date: 2020-12-21
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine whether luvadaxistat is superior to placebo in improving cerebellar function as measured with the average percentage of conditioned responses during the eyeblink conditioning (EBC) test.

Detailed description:
The drug being tested in this study is called luvadaxistat. Luvadaxistat is being tested to treat people with schizophrenia.

Participants will be randomly assigned to one of the two treatment sequences which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Luvadaxistat 500 milligrams (mg) followed by matching placebo
* Matching placebo followed by luvadaxistat 50 mg

Participants will receive luvadaxistat 500 mg during the treatment period in which they are assigned to luvadaxistat. Following an interim analysis, there will be a study-wide decision about whether to treat the additional participants with luvadaxistat 500 mg during the active treatment period to or treat them with luvadaxistat 50 mg during this period. After the interim analysis, the participant and study doctor will not be aware of which luvadaxistat dose is being used.

Arms: arm 1: Participants first received luvadaxistat 500 mg orally once daily (QD) for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. arm 2: Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. arm 3: Participants first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received matching placebo orally QD for 8 days during treatment period 2. arm 4: Participants first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, participants then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2.
Interventions: intervention 1: Luvadaxistat intervention 2: Matching Placebo
Intervention descriptions: intervention 1: TAK-831 Tablets. intervention 2: Matching Placebo Tablets.

Protocol documents:
Prot_000.pdf: 
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate 
Pharmacodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Multiple Oral 
Doses of TAK-831 in Adult Subjects With Schizophrenia
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge MA 02139
USA
Study Number:
TAK-831-2001
Compound:
TAK-831
Date:
14 January 2020
Version/Amendment 
Number:
06
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
28 April 2017
Initial Protocol
Not applicable
Global
08 September 2017
Amendment 01
Nonsubstantial
Global
11 October 2017
Amendment 02
Substantial
Global
30 May 2018
Amendment 03
Substantial
Global
17 December 2018
Amendment 04
Substantial
Global
19 September 2019
Amendment 05
Substantial
Global
14 January 2020
Amendment 06
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 #: NCT03359785


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................12
2.1
Protocol Amendment No. 06 Summary of Changes .................................................13
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................14
4.0
INTRODUCTION.........................................................................................................16
4.1
Background .............................................................................................................16
4.2
Clinical Background ................................................................................................17
4.3
Rationale for the Proposed Study.............................................................................18
4.4
Benefit/Risk Profile .................................................................................................19
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................21
5.1
Trial Objectives .......................................................................................................21
5.1.1
Trial Primary Objective......................................................................................21
5.1.2
Trial Secondary Objectives ................................................................................21
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoints .............................................................................................22
5.2.2
Secondary Endpoints..........................................................................................22
5.2.4
Safety Endpoints................................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................24
6.2.1
Rationale of Study Design and Regimen ............................................................24
6.2.2
Rationale for Dose .............................................................................................25
6.2.3
Rationale for Endpoints......................................................................................25
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............29
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.4
Study Beginning and End/Completion .....................................................................30
6.4.1
Definition of Beginning of the Study..................................................................30
6.4.2
Definition of End of the Study ...........................................................................30
6.4.3
Definition of Study Completion .........................................................................30
6.4.4
Definition of Study Discontinuation...................................................................30
6.4.5
Criteria for Premature Termination or Suspension of the Study..........................30


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............32
7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................33
7.3
Excluded Medications, Supplements, Dietary Products............................................35
7.4
Diet, Fluid, Activity.................................................................................................37
7.4.1
Diet and Fluid ....................................................................................................37
7.4.2
Activity..............................................................................................................37
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................37
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................38
7.7
Subject Replacement................................................................................................38
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................39
8.1
Clinical Study Drug .................................................................................................39
8.1.1
Clinical Study Drug Labeling.............................................................................39
8.1.2
Clinical Study Drug Inventory and Storage ........................................................39
8.1.3
Clinical Study Drug Blinding.............................................................................39
8.1.4
Randomization Code Creation and Storage ........................................................39
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure...................................39
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................39
8.1.7
Ancillary Supplies..............................................................................................40
9.0
STUDY PROCEDURES...............................................................................................41
9.1
Administrative Procedures.......................................................................................41
9.1.1
Informed Consent Procedure..............................................................................41
9.1.2
Inclusion and Exclusion Criteria.........................................................................42
9.1.3
Medical History/Demographics..........................................................................42
9.1.4
Prior and Concomitant Medication Review ........................................................42
9.2
Clinical Procedures and Assessments.......................................................................42
9.2.1
Full Physical Examination..................................................................................42
9.2.2
Psychiatric Examination.....................................................................................42
9.2.3
Height and Weight .............................................................................................42
9.2.4
BMI ...................................................................................................................43
9.2.5
Vitals (Body Temperature, Heart Rate, Blood Pressure).....................................43
9.2.6
12-Lead ECG.....................................................................................................43
9.2.7
C-SSRS..............................................................................................................44
9.2.8
CDSS.................................................................................................................44
9.2.9
PANSS ..............................................................................................................44


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9.2.10 Study Drug Administration ................................................................................45
9.2.11 Cognitive Assessments.......................................................................................45
9.2.12 ERPs..................................................................................................................45
9.2.13 Delay EBC Test .................................................................................................45
9.2.14 AE Monitoring...................................................................................................46
9.2.15 Laboratory Procedures and Assessments ............................................................46
9.3
Biomarker, PK, PD, and 
, Samples....................................................................47
9.3.1
PK Measurements..............................................................................................48
9.3.2
Biomarker Measurements...................................................................................48
9.3.4
Confinement ......................................................................................................50
10.0
ADVERSE EVENTS ....................................................................................................51
10.1
Definitions and Elements of AEs .............................................................................51
10.1.1 SAEs..................................................................................................................53
10.1.2 Special Interest AEs...........................................................................................54
10.2
AE Procedures.........................................................................................................54
10.2.1 Assigning Severity/Intensity of AEs...................................................................54
10.2.2 Assigning Causality of AEs................................................................................55
10.2.3 Start Date...........................................................................................................55
10.2.4 End Date............................................................................................................55
10.2.5 Pattern of Adverse Event (Frequency)................................................................55
10.2.6 Action Concerning Study Drug ..........................................................................55
10.2.7 Outcome ............................................................................................................56
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and DILI............56
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....58
11.0
STATISTICAL METHODS..........................................................................................59
11.1
Statistical and Analytical Plans ................................................................................59
11.1.1 Analysis Sets......................................................................................................59
11.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................59
11.1.3 PK Analysis .......................................................................................................59
11.1.4 PD Analysis .......................................................................................................60
11.1.5 Safety Analysis ..................................................................................................61
11.2
Interim Analysis and Criteria for Early Termination ................................................62
11.3
Determination of Sample Size..................................................................................62
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................63


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12.1
Study-Site Monitoring Visits ...................................................................................63
12.2
Protocol Deviations..................................................................................................63
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................63
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................64
13.1
IRB and/or IEC Approval ........................................................................................64
13.2
Subject Information, Informed Consent, and Subject Authorization .........................65
13.3
Subject Confidentiality ............................................................................................66
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................66
13.4.1 Publication and Disclosure.................................................................................66
13.4.2 Clinical Study Registration.................................................................................67
13.4.3 Clinical Study Results Disclosure.......................................................................67
13.5
Insurance and Compensation for Injury....................................................................67
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................68
14.1
Administrative Information......................................................................................68
14.1.1 Study Contact Information .................................................................................68
14.1.2 INVESTIGATOR AGREEMENT......................................................................69
14.1.3 Study-Related Responsibilities...........................................................................69
14.1.4 List of Abbreviations .........................................................................................70
15.0
DATA HANDLING AND RECORDKEEPING............................................................72
15.1
CRFs (Electronic and Paper)....................................................................................72
15.2
Record Retention .....................................................................................................72
16.0
REFERENCES..............................................................................................................74
17.0
APPENDICES...............................................................................................................78
LIST OF IN-TEXT TABLES
Table 6.a
Part 1: Study Schedule .......................................................................................24
Table 7.a
Excluded Medications and Dietary Products ......................................................36
Table 9.a
Primary Specimen Collections ...........................................................................48
Table 10.a
Takeda Medically Significant AE List................................................................54


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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................78
Appendix B
Elements of the Subject Informed Consent.........................................................80
Appendix C
Investigator Consent to Use of Personal Information..........................................83
Appendix D
Pregnancy and Contraception.............................................................................84
Appendix E
Detailed Description of Amendments to Text.....................................................88


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1.0
STUDY SUMMARY
Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge MA 02139
USA
Compound:
TAK-831
Study Number: 
TAK-831-2001
Phase: 2
Protocol Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate 
Pharmacodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adult 
Subjects With Schizophrenia
Study Design:
This study is a randomized, double-blind, placebo-controlled, 2-period crossover phase 2 study to evaluate the 
pharmacodynamic (PD) effects, safety, tolerability and pharmacokinetics (PK) of multiple daily oral doses of 
TAK-831 in adult patients with schizophrenia.
Effects of up to 2 dose levels of TAK-831 or placebo will be assessed. Each treatment will be administered daily for a 
period of 8 consecutive days, separated by a 14- to 21-day washout. The planned dose levels of TAK-831 to be 
evaluated will be 500 and 50 mg. 
The study will consist of 2 treatment periods, and visits to the clinic at the following times: (1) Screening Period (Days 
-30 to -3) covering full medical, neurological, and psychiatric examinations; (2) Treatment Visits and inpatient stays: 
On Day -2 of Periods 1 and 2, subjects will be admitted to the clinic for 2-night stays; on Day -2, subjects will undergo 
baseline clinical assessment procedures and cognitive battery assessment. On Day -1, subjects will receive the 
baseline EEG and EBC assessments. In Period 1, those who continue to meet all eligibility criteria will be randomized 
via an interactive response technology (IRT) system to 1 of 2 treatment sequences. On Day 1, subjects will undergo 
predose blood PK/PD samples, first dosing, and postdose blood draws, after which they will be discharged from the 
clinic to continue dosing at their residence. Subjects will receive double-blind treatment from Days 1 through 8 
(inclusive) with completion of efficacy and PK/PD-related assessments on Days 7 and 8 of each treatment period; and 
(3), a washout period between Treatment Periods 1 and 2 lasting between 14 to 21 days.
Subjects will be adults between ages 18 and 60, with a Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) diagnosis of schizophrenia who are receiving stable antipsychotic therapy (no increase or decrease 
>25% in dose in the preceding 2 months), and stable negative symptoms, as measured by the Positive and Negative 
Syndrome Scale (PANSS) during Screening and Baseline (no fluctuations in PANSS negative symptom factor score 
[NSFS] >25%). PANSS total score will not exceed 90 points and the NSFS will be at least 15. Subjects with 
extrapyramidal signs or depressive symptoms will be excluded.
Additional screening assessments include physical and neurological examinations, clinical laboratory and 
electrocardiogram (ECG) measures, a toxicological screen, Screening for suicidality and depression using the 
Columbia Suicide Severity Rating Scale (C-SSRS) and the Calgary Depression Scale Score (CDSS), respectively, 
assessment of extrapyramidal symptoms will be performed with the Simpson Angus Scale (SAS), and the presence of 
dyskinesias will be assessed with the Abnormal Involuntary Movement Scale (AIMS).
Clinical laboratory testing, PK and D- and L-serine sample collection will be performed as per the schedule of events. 
If caregiver accompaniment is required, an adult caregiver will be permitted to attend clinical assessment visits with 
the study participant. After completion of the initial treatment period, subjects will participate in a washout period 
lasting between 14 to 21 days. After the second treatment period, a final follow-up safety assessment visit will be 
conducted approximately 10 to 14 days after the last administration of study drug.
During the double-blind treatment periods, subjects will arrive at the clinic on Day 7 of each Treatment Period, as 
required (see schedule of events for details), to receive study drug and/or undergo specified study procedures. Study 
drug for Days 2 to 6 may be dispensed to the participant to take at their place of residence, or may be dispensed at the 
clinic through a qualified member of the research team. A process for ensuring adherence to study drug intake at the 


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subject’s place of residence, such as supervision by study staff, a caregiver or a mobile device application to remotely 
monitor study drug adherence will be implemented.
A previous version of this protocol was started at a different site and stopped after 1 subject completed all study 
procedures. The data from that subject, including safety endpoints, will be analyzed separately from those obtained in 
the subjects enrolled in this study.
Primary Objectives:

To determine whether TAK-831 is superior to placebo in improving cerebellar function as measured with the 
average % of conditioned responses during the eyeblink conditioning (EBC) test. 
Secondary Objectives:

To determine whether add-on TAK-831 compared to placebo improves sensory processing as measured by event 
related potentials (ERPs) mismatch negativity (MMN) and p300. 

To determine whether add-on TAK-831 compared to placebo improves the auditory steady-state response 
(ASSR) to 40 Hz stimulation.

To determine whether add-on TAK-831 compared to placebo improves the composite score of a neurocognitive 
test battery.

To assess the safety and tolerability of TAK-831. 

To assess the PK of TAK-831.

To assess the PD of TAK-831 by measurement of plasma D-serine and L-serine levels, as well as D-serine: total 
serine ratios.
Subject Population: Adults between ages 18 and 60, inclusive, with a DSM-5 diagnosis of schizophrenia who are 
receiving stable antipsychotic therapy.
Number of Subjects:
32
Number of Sites:
up to 2
Dose Levels:
TAK-831 500 mg and matching placebo once daily 
(QD) for 8 days
TAK-831 50 mg and matching placebo QD for 8 days
Route of Administration:
Oral
Duration of Treatment:
Eight days in each period.
Period of Evaluation:
Total approximately up to 81 days (Screening: 30 days, 
Treatment Period 1: 8 days, Washout 14 to 21 days, 
Treatment Period 2: 8 days, Follow-up: 10 to 14 days)
Main Criteria for Inclusion:
In order to be eligible for study participation, subjects must be: 

Provide written informed consent or from a legally acceptable representative. 

Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, 
medical history, physical examination, 12-lead ECG, and vital sign measurements performed at the Screening 
Visit and prior to administration of the initial dose of study drug/invasive procedure.

Between 18 and 60 years old, inclusive.

Body weight >45 kg; body mass index (BMI) between 18.5 to 40 kg/m2. 

With stable schizophrenia. 

Receiving stable antipsychotic medication at doses not to exceed risperidone 6 mg or its equivalent. 

Known to be stable with no clinically meaningful change in psychotropic medications for the preceding 2 months 


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prior to Baseline. 

Have a PANSS Negative Symptom Factor Score (NSFS) ≥15; stable screening and baseline PANSS NSFS scores 
(≤25% change).

Have a PANSS total score ≤90; stable screening and baseline PANSS total score (<20% change).

Willing and able to comply with all study procedures and restrictions.

A female participant is eligible to participate if she is of:
–
Nonchildbearing potential.
–
Childbearing potential and agrees to use 2 forms of contraception methods.
–
Women of childbearing potential must have a negative pregnancy test at Screening and at Baseline.

A male subject who is nonsterilized and sexually active with a female partner of childbearing potential must agree 
to use adequate contraception from signing of informed consent throughout the duration of the study and for 
95 days after last dose.

Able to swallow study drug in tablet form.

Should a subject require a caregiver to accompany him/her during the study, the caregiver should be available for 
the full duration of the study.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 

Ongoing disability, medical, neurological, or psychiatric history, cognitive impairment or conditions that, in the 
opinion of the investigator, are of a nature or severity that may interfere with study conduct or clinical 
assessments.

The subject has a recent (within the last 6 months) diagnosis of panic disorder, depressive episode, or other 
comorbid psychiatric conditions requiring clinical attention based on the DSM-5 and the general psychiatric 
evaluation. 

Substance abuse or dependence (with the exception of nicotine dependence) within the preceding 6 months based 
on the DSM-5 and the general psychiatric evaluation. 

Positive drug screen for disallowed substances at Screening or Baseline.

Evidence of extrapyramidal adverse events as measured by a SAS score >6 at Screening or Baseline.

Evidence of depression as measured by a CDSS score >11 at Screening. Subjects with a CDSS score of 9 to 11 
must be discussed with the sponsor and will also be excluded if the item scores are determined to reflect the 
presence of depression rather than schizophrenia negative symptoms.

Evidence of suicidality as measured by a C-SSRS score >3 at Screening or Baseline.

Hearing deficits preventing participation in event related potential testing.

History of brain trauma associated with loss of consciousness for >15 minutes. 

Female subjects who are lactating or pregnant (positive pre-randomization serum pregnancy test) or plan to 
become pregnant during the study.

Received treatment with other experimental therapies within the preceding 30 days or <5 half-lives prior to the 
first dose.

Unwilling or unable to comply with the requirements of the protocol Subject has a known hypersensitivity to any 
component of the formulation of TAK-831

Subjects known to be positive for hepatitis B surface antigen (HBsAg)-positive, or known or suspected active 
hepatitis C infection. 

Use of disallowed concomitant medications.


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Main Criteria for Evaluation and Analyses:
All analyses are for comparison between TAK-831 and placebo.
The primary endpoints of the study are:

Average percentage of conditioned responses during the EBC test at Day 8. 
The secondary endpoints will be assessed through evaluation of the following parameters: 

MMN amplitude at Fz (midline frontal electrode, EEG) at Day 8. 

P300 amplitude at Pz (midline parietal electrode, EEG) at Day 8. 

ASSR at Cz (midline central electrode, EEG) at Day 8. 

BACS Cognitive battery composite score at Day 7. 

Plasma D-serine and L-serine levels, and D-serine:total serine ratio.

TAK-831 plasma concentrations. 
Statistical Considerations:
The 2-period crossover design for this study will allow for each subject to provide data on each of the 2 active doses as 
well as placebo. The crossover analysis of this design will take into account the within-subject correlation. While some 
subjects may drop from the study before completing all periods, all available data will be used for analyses.
The expected effect size, defined as the ratio between the mean difference between treatment and placebo divided by 
the standard deviation of this difference, is 0.6 for the primary endpoint. This effect size is a conservative estimate 
based on data from a previous report, which showed an effect size of 0.74 on the EBC test at 24 hours after initiation of 
treatment with secretin. 
A frequentist analysis will be done for the full data set, using simulations to adjust for effect of the interim analysis on 
the type 1 error. The results of the primary endpoint will be considered statistically significant at either of the 2 doses 
(as applicable) if the one-sided p <0.05, without adjustment for multiplicity (ie, the type 1 error rate will be separately 
controlled for each dose).
In addition, the primary endpoint will be analyzed using a Bayesian normal linear model with treatment sequence, 
period, and treatment as fixed effects and subject within sequence as a repeated factor. The dependent variable is the 
change in response from the period baseline assessment to the final treatment day for each period. The response data 
will be logit transformed before the change is calculated. The Bayesian model will be used to estimate the posterior 
distribution of the treatment effect from each dose (as applicable).
Interim Analysis:
A small group from the sponsor will remain unblinded to treatment assignment during the study for the purpose of 
conducting interim analyses of PD effects. In order to minimize any potential unblinding of investigators, these staff 
will not interact with the investigators or their staff.
A planned unblinded interim analysis of the primary endpoint will be conducted when approximately 14 patients have 
completed the evaluation for the primary endpoint. The site will be allowed to continue enrollment to the high/placebo 
comparison, with the goal that approximately 16 patients will be randomized by the time the interim analysis is 
complete. (The additional approximately 2 subjects will be included in the final analysis but not the interim.) The 
purpose of the interim PD analysis will be to determine whether to continue enrolling subjects to the 
high-dose/placebo comparison, switch enrollment to the low-dose/placebo comparison, or discontinue enrollment. 
The decision rule will be specified in an interim analysis plan before the data are unblinded for the interim analysis. In 
addition, a decision to switch to the low dose may be made based on safety or tolerability of the high dose.


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Sample Size Justification:
Up to 32 subjects will be enrolled into this 2-period crossover study. Initially 16 subjects will be randomized to one of 
the 2 sequences comparing the high dose to placebo: high-placebo or placebo-high. Based on the results of an interim 
analysis, an additional 16 subjects may be randomized to one of the 2 sequences comparing the low dose to placebo: 
low-placebo or placebo-low. This design and choice of sample sizes has been selected to be sensitive to a plausible and 
biologically meaningful range of effect sizes.


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2.0
STUDY SCHEMATIC
(a) Assessments on Days 7 and 8 may be performed 1 day before or after, (ie, Day 6 or 8 for Day 7 and Day 7 or 9 for 
Day 8).
Period 1
Final 
Assessments 
(Days 7 and 8) 
(a)
8 days
TAK-831
or placebo
Washout
14 to 21 days 
8 days
Period 1
Predose 
Assessments 
(Days -2, -1 
and 1)
Safety 
Follow-up
Screening
Period 2
Final 
Assessments 
(Days 7 and 8) 
(a)
Period 2
Predose 
Assessments 
(Days -2, -1 
and 1)
Up to 30 
days
10 to 14 days 
TAK-831
or placebo


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2.1
Protocol Amendment No. 06 Summary of Changes 
Rationale for Amendment No. 06
This document describes the changes in reference to the protocol incorporating Amendment 
No. 06. 
The primary reason for this amendment is to modify inclusion criterion 3 to revise the maximum
subject age from 50 to 60 years of age, to allow for increasing patient recruitment.
For specific description of text changes and where the changes are located, see Appendix E. 
Changes in Amendment No. 06
1. Updated entry criteria.


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3.0
SCHEDULE OF STUDY PROCEDURES 
Screening
Periods 1 and 2 (a)
Safety 
Follow-Up (b)
Early 
Termina-
tion Visit
Pretreat-
ment Day
Treatment Day (c)
Study Day
Days 
-30 to -3
-2
-1 
1
2
3
4
5
6
7
8
Post-
Treatment 2 
Day 20±2
Administrative Procedures
Confinement
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria (d)
X
X
X
X
Demographics/ medical 
history 
X
Medication history
X
Concurrent medical 
conditions
X
Clinical Procedures/Assessments
Full physical 
examination
X
X
X
X
Psychiatric examination
X
Height
X
Weight, and BMI
X
Vital signs (oral [floor of 
the mouth]/ tympanic 
temperature) (e)
X
X
X
X
X
X
X
X
Concomitant 
medications (e)
X
X
X
X
X
X
X
X
ECG
X
X
X
X
C-SSRS 
X
X
X
X
X
CDSS
X
SAS
X
AIMS
X
PANSS
X
X
X
EBC test (f)
X
X (f)
ERPs (f, g)
X
X (f)
Resting state EEG (f)
X 
X (f)
BACS cognitive battery 
(f)
X
X (f)
Dispense study 
medication (h)
X
Study drug dosing (c) (h)
X
X
X
X
X
X
X
X
AE assessment (e)
X
X
X
X
X
X
X
X
Laboratory Procedures
Clinical laboratory tests 
(hematology, serum 
chemistry, urinalysis) (i)
X
X
X
X
Hepatitis panel (HBsAg 
and Anti-HCV) 
X
FSH
X
Pregnancy test (hCG) (i) 
(j)
X
X
X
X
X
Drug screen (i)
X
X
X
X


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Screening
Periods 1 and 2 (a)
Safety 
Follow-Up (b)
Early 
Termina-
tion Visit
Pretreat-
ment Day
Treatment Day (c)
Study Day
Days 
-30 to -3
-2
-1 
1
2
3
4
5
6
7
8
Post-
Treatment 2 
Day 20±2
PK Evaluations
PK blood collection (m)
X
X
X
X
PD/Biomarker Evaluations
Blood collection (D- and 
L-serine) (n)
X
X
X
X
AE=adverse event, BMI-body mass index, ERP=event-related field, FSH=follicle-stimulating hormone, HBcAg=hepatitis B core 
antigen, hCG=human chorionic gonadotropin, HCV=hepatitis C virus, PANSS=Positive and Negative Syndrome Scale.
(a) A washout interval of 14 to 21 days will separate the last dose of study drug in Period 1 and the first dose in Period 2.
(b) A follow-up safety visit will be conducted 10 to 14 Days post-treatment Period 2.
(c) Assessments on Days 7 and 8 may be performed 1 day before or after (ie, Day 6 or 8 for Day 7 and Day 7 or 9 for Day 8). If the 
Day 8 assessments are conducted on Day 9, study drug dosing duration will be extended for 1 additional day as well.
(d) Inclusion/exclusion criteria will be assessed only in Period 1.
(e) Vital signs, concomitant medications and AE assessment on Days 2 to 6 to be performed only on subjects who attend the clinic 
site for any reason. Vital signs will be conducted for safety only and will not be entered into the database for these visits. 
(f) Day 8 EBC, ERP, and EEG assessments are to be performed at approximately (± 1 hour) the same time as on Day -1, and the 
Day 7 BACS cognitive battery assessments are to be performed at approximately (± 1 hour) the same time of day as on Day -2.
(g) Procedures to be conducted only in subjects who receive at least 1 dose of study medication and are assessed within 36 hours of 
the last dose.
(h) Study drug intake on Days 2 to 6 may be supervised by a caregiver or family member, conducted at the investigator site or
supervised by a qualified designee. 
(i) These tests can be repeated at any time at investigator discretion.
(j) Serum Beta hCG at Screening and at the Final Visit, at other visits urine Beta hCG determination on women of childbearing
potential only. 
 
 
(m) Blood samples (approximately 4 mL) will be collected from each subject for the determination of plasma concentrations of 
TAK-831 at the following time points: Day 1 (predose and at 0.25 to 2 hours and 3 to 6 hours postdose), Day 7 (predose and at 0.25 
to 2 hours and 3 to 6 hours postdose), and Day 8 (predose). One additional blood sample will be collected for subjects at the Early 
Termination Visit, if applicable. The sampling schedule may change based on emerging data but will not exceed the number of 
planned samples.
(n) Blood sample (6 mL) will be collected for analysis of plasma concentrations of D- and L-serine immediately following PK 
blood collections on Day 1 (predose and 3 to 6 hours postdose), Day 7 (predose and 3 to 6 hours postdose), and Day 8 (predose). 
Time of sample collection, time since last dose administered and time of last meal should be recorded for each sample collection. 
Samples may be analyzed for other amino acids, but total blood volume collected will not change.


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4.0
INTRODUCTION
4.1
Background
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and 
behaves. The onset of the disease is usually in late adolescence or early adulthood, it 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) [1-3]. Symptoms of schizophrenia can be 
subdivided into 3 broad classes: positive, negative, and cognitive symptoms [4]. Positive 
symptoms include hallucinations, delusions, and disordered thought and speech, and can be 
summarized as psychosis. Negative symptoms include reduced emotion, reduced ability to 
experience pleasure (anhedonia), lack of motivation and reduced social interaction. Finally, 
cognitive symptoms include poor information processing, impaired ability to focus on objectives, 
and abnormalities of working memory and learning [4]. 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, negative symptoms, and anhedonia [5]. 
While currently available antipsychotics are broadly effective for the treatment of positive 
symptoms, the treatment of negative symptoms and cognitive deficits of schizophrenia remains a 
major unmet medical need. These are the most disabling aspects of schizophrenia, for which there 
are no approved therapies.
Inhibition of D-amino acid oxidase (DAO) is a promising target for the treatment of schizophrenia. 
Hypofunction of N-methyl-D-aspartate (NMDA) receptors is considered a potential mechanism in 
the pathophysiology of schizophrenia, which could be mitigated with increased D-serine levels in 
the brain [6]. Changes in the D-serine levels or D-serine to total serine ratios have been reported in 
the plasma of patients with schizophrenia both naive and under drug treatment [7-10]. 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 sits 
[11].
DAO is involved in D-serine metabolism in the brain and has been associated with the regulation 
of glutamatergic neurotransmission [12]. Inhibition of DAO elevates endogenous D-serine in the 
cerebellum, increasing Purkinje cell long term depression via activation of glutamate receptor
(GluR)2 and/or NMDA receptors with subsequent α-amino-3-hydroxy-5-methyl-4-isoxazole 
propionic acid (AMPA) receptor internalization [13].
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 [14].
While current medications mitigate positive symptoms of schizophrenia, persistent negative 
symptoms and cognitive impairment represent areas of unmet medical need. Moreover, cognitive 
impairment and negative symptoms are associated with functional outcomes to a greater degree 
than positive symptoms and remain an area of focus for the development of novel therapeutics.


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4.2
Clinical Background
Two phase 1 clinical studies have been conducted in healthy subjects: a first-in-human study to 
determine the pharmacokinetic (PK) profiles of TAK-831 oral suspension after single-rising dose 
(SRD) and multiple-rising dose (MRD) administration, as well as the relative bioavailability and 
effect of food on the PK of the T1 tablet formulation of TAK-831 (TAK-831-1001); and a study to 
demonstrate DAO target engagement in the brain as measured by positron emission tomography 
(PET) (TAK-831-1003). Plasma D-serine levels, TAK-831 plasma concentrations and safety were 
also evaluated. Since these studies were conducted, a single dose PK and food-effect 
bioavailability study with the T2 tablet formulation (TAK-831-1004) has completed active dosing, 
and a study examining additional escalating multiple doses of TAK-831 higher than those 
achieved in the TAK-831-1001 study was initiated and is ongoing (TAK-831-1005).
TAK-831 was safe and well tolerated in 103 healthy subjects in doses administered in studies 
TAK-831-1001 and TAK-831-1003. Headache was the most common treatment-emergent adverse 
event. 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 the rate observed in 
placebo-treated subjects. There were no concerning trends in laboratory, ECG, or vital sign data. 
After both single and multiple dosing with TAK-831 (Study TAK-831-1001), increases in the area 
under the effect curve from time 0 to 24 hours of D-serine were dose-dependent; changes in 
D-serine were noticeably higher after multiple daily doses of TAK-831 400 mg than after multiple 
daily doses of TAK-831 30, 100, and 200 mg. Single oral doses of TAK-831 temporally increased 
plasma concentrations of D-serine in the PET study (TAK-831-1003); the results are similar to 
those obtained from Study TAK-831-1001. 
TAK-831-1004 was a phase 1, randomized, open-label, single-dose, 2-period crossover study 
designed to characterize the PK of a single dose of 400 mg of TAK-831 and assess the effect of 
food on the bioavailability of TAK-831 400 mg when administered as four 100 mg oral tablets of 
the T2 formulation in 15 healthy adult subjects. In the TAK-831-1004 study, there was only a 
single AE of mild upper respiratory tract infection, judged to be unrelated to study treatment. One 
subject met criteria for orthostatic hypotension at a single time point without an accompanying 
report of a dizziness AE. There were no concerning trends in laboratory, ECG, or vital sign data. 
Treatment with a single oral dose of 400 mg of TAK-831 T2 formulation temporally increased 
plasma concentration of D-serine, similar to the results obtained in the Study TAK-831-1001. The 
magnitude and kinetics of the change in plasma D-serine were similar when the drug was 
administered in either water or nutritional drink. TAK-831 given as a T2 tablet coadministered 
with the nutritional drink increased mean Cmax and AUC∞values by 35% and 21%, respectively. 
TAK-831-1005 is an ongoing investigator and subject blinded, sponsor unblinded, 
placebo-controlled clinical study progressively assessing independent cohorts of healthy subjects 
to continue evaluation of the safety, tolerability, PK, and pharmacodynamics (PD) of escalating 
multiple doses of TAK-831 at doses higher than those achieved in the TAK-831-1001 study. The 
following study information is preliminary and is based on blinded adverse event data reported by 
the investigator and blinded safety endpoint data in study TAK-831-1005. Although not expected, 
these data are subject to change upon finalization following study monitoring, source data 


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verification, and discrepancy query management prior to database lock. At this time, four cohorts 
with 8 subjects each (6 TAK-831 and 2 placebo) have completed treatment at dose levels of 100 
mg QD (T2 tablet formulation), 600 mg QD (T2 tablet formulation), 800 mg QD (oral suspension), 
or 1200 mg (oral suspension) administered first as a single dose, and then administered for up to 14 
days of multiple dosing. In addition to standard safety assessments, subjects in three of these 
cohorts underwent catheterized CSF collection for a 24 hour period starting prior to dosing on Day 
1 single dose treatment and on Day 14 of multiple dose treatment. Nausea and post-lumbar 
puncture syndrome were the most common treatment-emergent AEs; nausea in the absence of 
post-lumbar puncture syndrome was reported by one subject in each cohort. All episodes of nausea 
were mild in intensity and self-limiting. Two subjects in each of the two first cohorts met 
categorical criteria for orthostatic hypotension on at least one assessment; none of these findings 
were associated with an AE of dizziness. There were no concerning trends in laboratory, ECG, or 
vital sign data collected in these cohorts. 
After both single and multiple dosing with TAK-831, there was a notable increase in the area 
under the effect curve from time 0 to 24 hours of CSF D-serine for both the 600 mg T2 and 800 mg 
oral suspension treatment groups when compared to placebo; changes in CSF D-serine were 
noticeably higher after multiple doses of TAK-831 than after administration of a single dose of 
TAK-831. The magnitude of the increase in the area under the effect curve for CSF D-serine was 
similar for both the 600 mg T2 and 800 mg oral suspension, suggesting that the maximal PD effect 
in the CSF was achieved at drug exposures attained with the 600 mg T2 dose and 800 mg 
suspension. Following once-daily dosing, mean plasma exposures of TAK-831 were higher (Cmax: 
1.3-fold and AUC: 1.8-fold) when dosed as an oral suspension than as T2 tablets. Geometric mean 
Cmax values were 1466 and 1976 ng/mL with 600 mg QD (T2 tablet formulation) and 800 mg QD 
(oral suspension), respectively. Mean steady-state exposures (AUCt) over the 24-hour dosing 
interval were on average 4993 and 8853 ng.hr/mL for the respective 600 and 800 mg QD dosing 
cohorts. The mean 24-hour TAK-831 PK profile in CSF was parallel to that of plasma and 
observed TAK-831 CSF concentrations were well in agreement with the TAK-831 unbound 
fraction in plasma.
Overall, the emerging safety data from the TAK-831-1004 and TAK-831-1005 studies are 
consistent with the data collected in prior clinical studies and do not alter the risk profile of the 
compound. 
The safety data from healthy subjects cannot be directly generalized for patients with 
schizophrenia. However, no safety signal has manifested that would prevent additional studies in 
healthy subjects or in subjects with schizophrenia.
4.3
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 rats and it also demonstrated a positive effect on cognition and social interaction in rodent 
cognition and behavioral models. TAK-831 is under development for the treatment of cerebellar 
ataxia, and cognitive impairment associated with schizophrenia (CIAS), and negative symptoms 


TAK-831
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of schizophrenia. The proposed study is aimed at providing evidence of pharmacodynamic (PD) 
effects of TAK-831 treatment on brain function in subjects with schizophrenia.
A cross-over design was chosen for this study to minimize the potential impact of inter-subject 
variability on the ability to detect a treatment effect of TAK-831. As each subject serves as his/her 
own comparator, cross-over designs tend to have greater power to detect treatment effects 
compared to parallel designs. A placebo control is standard in the evaluation of novel therapeutics 
for neuropsychiatric disorders; as this study is an add-on to standard therapy in stable subjects the 
risk of subjects experiencing an exacerbation of their underlying condition is minimized. 
Preclinical data indicates that PD effects of TAK-831 may be apparent with single doses, 
supporting the short treatment duration period.
4.4
Benefit/Risk Profile
There is no benefit to subjects in this clinical study.
The following risk mitigation measures will be implemented in this study with TAK-831. These 
measures are based on what is known about the mechanism of action of TAK-831, nonclinical 
data, and the 2 phase 1 studies conducted to date, and general considerations in the development of 
new chemical entities. Procedures may be added during the study if necessary based on evaluation 
of any additional clinical or nonclinical safety data.

The dosing and duration of TAK-831 proposed for this study has been used 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 [15]), or who have made a suicide attempt in 
the previous 12 months, will be excluded from this study. The Columbia-Suicide Severity 
Rating Scale (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.

Emesis and diarrhea were reported in laboratory animals exposed to TAK-831 and in clinical 
studies in healthy subjects. Nausea has been observed in clinical studies in subjects taking 
TAK-831, but there has been no consistent relationship observed between frequency or 
severity of nausea and dose of TAK-831, and all reports of nausea at the highest dose 
examined in the TAK-831-1005 study were mild in severity. Subjects will be informed of these 
findings and instructed to contact the investigator for guidance in the management of these 
symptoms and possible ways to mitigate them. 

Postural hypotension and dizziness were observed in prior studies in healthy subjects. 
However, the incidence of dizziness in subjects treated with TAK-831 and placebo was 
similar. In addition, some healthy subjects who received TAK-831 met vital signs criteria 


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consistent with orthostatic hypotension without accompanying clinical symptoms, although a 
number of these observations were considered not related to TAK-831. Subjects will be 
informed of these findings and instructed to contact the investigator for guidance in the 
management of these symptoms and possible ways to mitigate them. 

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 [16]. There have been no findings of elevations in creatinine in 
clinical studies with TAK-831 summarized above; creatinine will continue to be measured in 
the clinical studies.

Study procedure–specific risks include issues relating to blood collection for safety 
assessment/ pharmacokinetic (PK) monitoring (venipuncture may cause bruising), and the 
placement of electrocardiogram (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
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Trial Objectives
5.1.1
Trial Primary Objective

To determine whether TAK-831 is superior to placebo in improving cerebellar function as 
measured with the average % of conditioned responses during the eyeblink conditioning 
(EBC) test.
5.1.2
Trial Secondary Objectives

To determine whether add-on TAK-831 compared to placebo improves sensory processing as 
measured by ERPs mismatch negativity (MMN) and p300. 

To determine whether add-on TAK-831 compared to placebo improves the auditory 
steady-state response (ASSR) to 40 Hz stimulation.

To determine whether add-on TAK-831 compared to placebo improves the composite score of 
the BACS battery.

To assess the safety and tolerability of TAK-831. 

To assess the PK of TAK-831.

To assess the PD of TAK-831 by measurement of plasma D-serine and L-serine levels, as well 
as plasma D-serine: total serine ratios. 


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5.2
Endpoints
5.2.1
Primary Endpoints

Average % of conditioned responses during the EBC test at Day 8. 
5.2.2
Secondary Endpoints 

MMN amplitude at Fz (electroencephalogram [EEG]) at Day 8. 

P300 amplitude at midline parietal electrode (Pz) (EEG) at Day 8. 

ASSR at midline central electrode (Cz) (EEG) at Day 8. 

BACS cognitive battery composite score at Day 7.

Plasma D-serine and L-serine levels, and plasma D-serine:total serine ratio at Day 8.

TAK-831 plasma concentrations.
5.2.4
Safety Endpoints

Percentage of subjects who experience at least 1 treatment-emergent adverse event (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.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This study is a randomized, double-blind, placebo-controlled, 2-period crossover phase 2 study to 
evaluate the PD effects, safety, tolerability and PK of multiple daily oral doses of TAK-831 in 
adult patients with schizophrenia. 
Approximately 32 adult male and female subjects between ages 18 and 60, inclusive, with a
current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of 
schizophrenia who are receiving stable antipsychotic therapy (no increase, no decrease >25% in 
dose in the preceding 2 months) will be randomized in to the study. Subjects will have a PANSS 
NSFS of at least 15 with no fluctuation between Screening and Baseline >25%. PANSS total score 
will not exceed 90 points with no fluctuations between Screening and Baseline >25%. Subjects 
with extrapyramidal signs or symptoms or depressive symptoms will be excluded. 
Additional screening assessments include a physical and neurological exam, clinical laboratory 
and ECG measures, a urine drug screen, and screening for suicidality and depression using the 
C-SSRS and the Calgary Depression Scale Score (CDSS), respectively. Assessment of 
extrapyramidal symptoms will be performed with the Simpson Angus Scale (SAS). The presence 
of dyskinesias will be assessed with the Abnormal Involuntary Movement Scale (AIMS).
During the pretreatment days (Days -2 and -1), subjects will participate in a baseline assessment 
with a cognitive battery, PANSS, EEG/ERP measures, and the EBC test.
Effects of up to 2 dose levels of TAK-831 or placebo will be assessed. Each treatment will be 
administered daily for a period of 8 consecutive days, separated by a 14- to 21-day washout (see 
Section 2.0 Study Schematic). 
The planned dose levels of TAK-831 to be evaluated will be 500 and 50 mg. 
The study will consist of 2 treatment periods, and visits to the clinic at the following times: 
(1) Screening Period (Days -30 to -3) covering full medical, neurological, and psychiatric 
examinations; (2) Treatment Visits and inpatient stays: On Day -2 of Periods 1 and 2, subjects will 
be admitted to the clinic for 2-night stays; on Day -2, subjects will undergo baseline clinical 
assessment procedures and cognitive battery assessment. On Day -1, subjects will receive the 
baseline EEG and EBC assessments. In Period 1, those who continue to meet all eligibility criteria 
will be randomized via an interactive response technology (IRT) system to 1 of 2 treatment 
sequences. On Day 1, subjects will undergo predose blood PK/PD samples, first dosing, and 
postdose blood draws, after which they will be discharged from the clinic to continue dosing at 
their residence. Subjects will receive double-blind treatment from Days 1 through 8 (inclusive) 
with completion of efficacy and PK/PD-related assessments on Days 7 and 8 of each treatment 
period; and (3), a washout period between Treatment Periods 1 and 2 lasting between 14 to 21 
days. 
The study schedule is detailed in Table 6.a.


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Table 6.a
Part 1: Study Schedule
Screening 
Period
Pretreatment
Dose 
Administration 
Period 1 (a)
Washout (b, c)
Dose 
Administration 
Period 2 (a)
Follow-Up (c)
Day -30 to -3
Period 1 
Days -2, -1, 1
Days 1 to 8
Days 9 to 22
Days 1 to 8
Period 2 Day 
20±2
(a) Subjects will be admitted to the clinic on the afternoon of Day -2 of each period for pretreatment assessments. On 
Day -2, they will receive clinical assessments and cognitive testing, and on Day -1 they will receive EBC and 
EEG/ERP assessments. On Day 1, they will receive the first dose of study medication and predose and postdose PK 
assessments. Study drug for Days 3 to 6 may be dispensed to the participant to take at their place of residence or may 
be dispensed at the clinic through a qualified member of the research team. On Day 7 in the morning, subjects will be 
admitted to the clinic for a 1 night stay. On Days 7 and 8, they will receive drug and specified study procedures.
(b) Washout duration may range from 14 to 21 days based on emerging data.
(c) A follow-up safety visit will be performed 10 to 14 days after the last dose in Period 2. Subjects may be brought 
back to the study clinic for re-evaluation at any time during the study per investigator’s discretion.
Study participants will receive daily study drug dosing until Day 8 of each period. Clinical 
assessments, laboratory tests and ECG will be repeated after dosing on Days 7 and 8 as per the 
schedule of events. Upon completion of the first dosing period, subjects will enter a washout 
period lasting between 14 to 21 days and will then return to the study site to undergo Day -2 
procedures for the next dosing period. 
Approximately 10 to 14 days after the last dose of study drug in the second dosing period, a 
follow-up safety assessment will be performed. 
In the event of a subject prematurely discontinuing the study during one of the study periods, an 
Early Termination Visit must be conducted, at which the safety, PK, plasma D- and L-serine 
assessments corresponding to a Final Visit will be performed. If a subject discontinues the study 
during the washout period, only the procedures corresponding to the follow-up safety assessment 
will be performed.
Subjects who drop out before completing 2 treatment periods of the study may be replaced at the 
discretion of the study sponsor.
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 have been screened but have exceeded the 28-day Screening Period may proceed in 
the study after a discussion with the sponsor/designee to obtain approval and to determine whether 
any screening procedures should be repeated before admission on Day -2 of Period 1.
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design and Regimen
The cross-over design was chosen to minimize potential confounding from inter-subject 
variability of baseline characteristics and PD measures, as each subject will serve as their own 


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control. PD measures were selected based on their potential as translational measures from 
preclinical TAK-831 efficacy models, due to their linkage to NMDA receptor or cerebellar 
function, or their association with relevant aspects of schizophrenia pathophysiology. The 
selection of neurocognitive measures was informed by the results of a schizophrenia clinical study 
with a weak DAO inhibitor, sodium benzoate [14]. A small Takeda team will remain unblinded for 
the purposes of conducting interim analyses. Limited treatment duration is needed for a cross-over 
design and is consistent with PD effects observed in nonclinical studies with single doses or 
multiple doses up to 14 days. 
6.2.2
Rationale for Dose 
Effects of 2 dose levels of TAK-831 or placebo will be evaluated. The proposed doses of TAK-831 
(500 and 50 mg once daily [QD]) have been selected based on PK data from the single-rising 
(SRD)/multiple-rising dose (MRD) studies (TAK-831-1001 and TAK-831-1005), brain target 
occupancy data from the positron emission tomography (PET) study (TAK-831-1003), PK and 
food effect study (TAK-831-1004), CSF D-serine data from the TAK-831-1005 study, and safety 
data from all clinical studies after oral administration of TAK-831 in healthy subjects. D-serine 
levels at 600 mg QD using T2 tablet and 800 mg suspension produced a similar level of CSF and 
plasma D-serine, suggesting that 600 mg QD produced levels of D-serine approaching maximal 
DAO inhibition in the brain. The planned dose of 500 mg QD is expected to have D-serine increase 
near the plateau. Preliminary PK/PD modeling analyses also showed that the high dose regimen 
resulted in steady-state exposures associated with mean peak target occupancy of ≥90%, while the 
lower dose regimen produced daily exposures associated with mean peak target occupancy of 
≥50%. Both doses are predicted to demonstrate D-serine (PD) effects based on preclinical efficacy 
models. These 2 dose levels may allow characterization of an exposure-response relationship with 
pharmacodynamic measures. The planned dose regimens are expected to deliver mean exposures 
within the range previously studied in study TAK-831-1001 and TAK-831-1005 that were found 
to be well tolerated. 
6.2.3
Rationale for Endpoints
6.2.3.1
Primary Endpoint
EBC Test
Disrupted cerebellar function has been hypothesized to contribute to schizophrenia 
pathophysiology by way of disruption of cortico-cerebellar-thalamic-cortical circuits. Patients 
with cerebellar lesions may display non-motor deficits such as impaired attention, language and 
executive function. In schizophrenia, cerebellar abnormalities have been found including reduced 
volume of vermis, lobules and hemispheres, and reductions in size and density of Purkinje cells. In 
addition, cerebellar abnormalities are correlated with symptoms and clinical outcomes [17]. 
EBC is highly conserved among mammalian species and is a commonly used method to 
investigate cerebellar function [18,19]. In EBC, a conditioned stimulus (CS), a tone precedes but 
coterminates with an unconditioned stimulus (US), an airpuff to the eyelid. Learning is 


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demonstrated when an eyeblink (the conditioned response [CR]) occurs prior to the onset of the 
US. Multiple studies have evaluated EBC in schizophrenia with the majority indicating deficits 
relative to control subjects [19]. Neural circuits in the cerebellum, including cerebellar cortex and 
interpositus nucleus are essential to the development and manifestation of the CR. NMDA 
receptors, in particular the GluN2 subunit, appear to play a critical role for the development of 
EBC. In preclinical studies, TAK-831 1 mg/kg per oral administration improved the rate of 
acquisition of the conditioned response relative to untreated and vehicle treated control groups. 
Furthermore, it significantly compensated the deleterious effects of scopolamine (0.3 mg/kg, sc) 
administration on the generation of conditioned eyelid responses and completely reversed 
scopolamine induced deficits at 1 mg/kg. 
As acquisition of delay EBC is impaired in schizophrenia and hypothesized to be linked to 
cerebellar-cortical circuit function, it may be subject to therapeutic intervention with TAK-831 
[18]. Of note, the EBC test has been used previously for the evaluation of experimental 
therapeutics in schizophrenia [20]. 
6.2.3.2
Secondary Endpoints
ERPs
The ERPs to be measured (via scalp EEG) include the mismatch negativity potential during the 
oddball paradigm (MMN), and the ASSR task. These tests have been linked to NMDA receptor 
function [21-24] and have demonstrated differences between subjects with schizophrenia and 
control subjects.
MMN is an ERP evoked in response to unattended changes in background stimulation. MMN is 
believed to reflect an automatic process of detecting a mismatch between a deviant stimulus and a 
sensory-memory trace. Smaller amplitudes of MMN have been consistently identified in 
schizophrenia subjects, showing promise as a quantitative clinical biomarker of the disease [25]. 
MMN amplitude is significantly reduced by ketamine [21] and is associated with 
ketamine-induced psychotic experiences [22]. Hence, MMN may index NMDA function in 
humans. Moreover, MMN is associated with cognitive and psychosocial functioning in 
schizophrenia [26]. MMN has demonstrated stability in clinical populations with high test-retest 
reliability over 1 year [27,28]. Hence, MMN represents a potentially informative probe of sensory 
processes for use in experimental medicine studies of novel therapeutics. Its association with 
NMDA receptor function suggests that it may be sensitive to modulation with TAK-831.
The P300 wave is an ERP component that is elicited by the presentation of a novel, behaviorally 
relevant target stimulus embedded among irrelevant stimuli in a manner similar to MMN, but 
requiring active listening and responding from participants. Auditory stimuli are presented in an 
oddball paradigm consisting of 1 standard tone and 1 target tone. Subjects are instructed to push a 
button as quickly as possible when they hear the target tone, but not when they hear the standard 
tone. P300 reflects allocation of attention and activation of immediate memory. P300 amplitude 
indexes brain actions when the mental representation of the stimulus environment is updated, 
while P300 latency indexes stimulus classification speed unrelated to response selection 


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processes. The P300 paradigm can therefore be used to study drug effects on the speed and 
efficiency of effortful attentional processing and working memory performance. 
ASSRs are evoked oscillatory responses that are entrained to the frequency and phase of 
temporally modulated stimuli. Individuals with schizophrenia experience subjective sensory 
anomalies and objective deficits on assessment of sensory function. These deficits can be 
produced by abnormal signaling in the sensory pathways and sensory cortex or by later-stage 
disturbances in the cognitive processing of such inputs. SSRs can be used to assess the integrity of 
sensory pathways including cortical processing. Steady state response can be maximized when 
delivered as ASSR stimuli at ~40 Hz. Schizophrenia subjects have been shown to have deficits in 
ASSR power and phase locking of approximately 0.5 vs control subjects. ASSR has demonstrated 
adequate test-retest characteristics in healthy volunteers to both evoked power and intertrial phase 
coherence when measured using both a standard EEG array [29] or using magneto 
electroencephalography [30]. Therefore, ASSR appears to be a promising surrogate measure to 
evaluate NMDA function in humans.
Cognitive Battery
Cognitive deficits are a core, enduring aspect of schizophrenia. Cognitive deficits are more 
strongly associated with functional outcomes than psychotic symptoms, yet there are no therapies 
currently approved for their treatment and represent a major unmet need in the treatment of 
schizophrenia. Multiple clinical development programs for the treatment of CIAS have not been 
able to successfully demonstrate adequate evidence of efficacy. Recently sodium benzoate, a weak 
inhibitor of DAO, showed efficacy in multiple cognitive measures in a small phase 2 study when 
used as add-on therapy in schizophrenia subjects [14]. 
D- and L-Serine
Changes in the D-serine levels or D-serine to total serine ratios have been reported in the plasma of 
patients with schizophrenia, both naive to drug treatment and under drug treatment [7-10]. 
Inhibition of DAO elevates endogenous D-serine in the cerebellum and plasma of rats. Analysis of 
changes in D-serine levels, and D-serine to total serine ratios will allow an evaluation of PD 
effects, and 
 
will allow a 
preliminary evaluation of the potential utility of these biomarkers to select for patients that may 
benefit from treatment with TAK-831. 
TAK-831 Plasma Concentrations (or PK)
TAK-831 plasma concentrations are used to measure TAK-831 PK parameters and build PK/PD 
relationship (see Section 11.1.3).


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6.2.3.4
Safety Endpoints
TAK-831 has undergone clinical assessments in previous studies. Based on the safety and 
tolerability profile observed to date, standard safety endpoints and monitoring have been included 
in the current study, including AE documentation, psychiatric assessments, laboratory tests and 
biomarker evaluation.


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6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, collecting EBC, EEG, cognition, PK, and biomarkers in subjects with 
schizophrenia are the critical procedures. 

On Day -2, a baseline cognitive assessment will be conducted. On Day -1, baseline EBC, and 
EEG based measures will be conducted. Postbaseline EBC test, EEG, and cognitive testing 
will be performed sequentially on Days 7 and 8, with EBC tested approximately 1 hour 
postdose.

At any postdose time point, the critical assessments need to be collected as close to the exact 
time point as possible.

All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.

The order of assessments can be changed during the study with joint agreement of the 
investigator and the sponsor. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 2 study to explore assessment of PD profile of TAK-831 in humans. Some 
alterations from the currently outlined dose and/or dosing regimen may be permitted based on 
newly available data.

In order to accommodate potential unanticipated disruptions to the planned schedule of events, 
subjects will be provided with 10 days of drug supply for each treatment period. In case of 
subject unavailability to participate in study procedures, rescheduling the subject to attend the 
site up to 1 day earlier or later will not be considered a protocol deviation.

The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, 
safety laboratory tests) and washout currently outlined in the protocol may be modified during 
the study based on newly available safety, tolerability, PK, or PD/biomarker data. These 
changes will not increase the number of study procedures for a given subject during his/her 
participation in the entire study. 

Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatine kinase to serum chemistry panel that was 
already drawn). 
It is understood that the current study may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the study objectives must be detailed by the sponsor in 
a letter to the Study File and forwarded to the investigator for retention. The letter may be 
forwarded to the institutional review board (IRB)/independent ethics committee (IEC) at the 
discretion of the investigator.


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6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.4.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit, discontinues from the study or is lost to follow-up 
(ie, the investigator is unable to contact the subject).
6.4.3
Definition of Study Completion
The primary objective of this phase 2 study is to assess if cerebellar function can be improved by 
add-on TAK-831 therapy compared to placebo based on the EBC in subjects with schizophrenia.
It is possible that study subjects may not receive all dose levels specified in the protocol, or that the 
study may be stopped before all planned subjects are enrolled if this objective is achieved early in 
this study. This is not considered an early termination of the study, but rather an earlier than 
anticipated achievement of the study objective(s) or study completion. 
6.4.4
Definition of Study Discontinuation
Study discontinuation due to non-safety reasons, such as:

A finding (eg, PK, PD, biologic targets, etc) from another preclinical or clinical study using the 
study treatment(s) results in the study being stopped for a non-safety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a non-safety-related reason. 

The study is stopped due to non-scientific and non-safety reasons, such as slow enrollment.
Study discontinuation due to safety reasons: 

Early study termination due to unanticipated concerns of safety to the study subjects arising 
from clinical or preclinical studies with the study treatment(s), comparator(s), drug(s) of the 
same class, or methodology(ies) used in this study.
6.4.5
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 medication 
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.


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6.4.5.1
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.
6.4.5.2
Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Site(s)
In the event that the sponsor, an IRB/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 randomization or first dose.
7.1
Inclusion Criteria 
In order to be eligible for participation in this study, the subject or caregiver must:
1. Understand the study procedures and agree to participate by providing written informed
consent.
2. Be willing and able to comply with all study procedures and restrictions (see Sections 7.3 and 
7.4 for a summary of restrictions).
3. Be male or a female aged 18 to 60 years, inclusive, at the Screening Visit. 
4. Have a body BMI ≥18.5 and ≤40.0 (kg/m2) at the Screening Visit.
5. Be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign 
measurements performed at the Screening Visit and prior to administration of the initial dose 
of study drug/invasive procedure.
6. Meet the following birth control requirements:
–
Is a male subject who is sterile or agrees to use a barrier method of contraception 
(eg, condom with or without spermicide) from study drug administration on the first day of 
the first dose until 95 days after the last dose of study drug administration. No restrictions 
are required for a vasectomized male subject provided the subject is at least 1 year 
post-bilateral vasectomy procedure prior to study drug administration on first day of the 
first dose. A male subject whose vasectomy procedure was performed less than 4 months 
prior to study drug administration on the first day of the first dose must follow the same 
restrictions as a nonvasectomized male. Appropriate documentation of surgical procedure 
should be provided.
–
Is a male subject who agrees to not donate sperm from study drug administration on the 
first day of the first dose until 95 days after the last dose of study drug administration.
–
Is a female subject with no childbearing potential, defined by at least 1 of the following 
criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years, 6 months of spontaneous amenorrhea in females aged >45 years with serum 
FSH levels >40 mIU/mL). Appropriate documentation of FSH levels is required.
b) Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
c) Had a tubal ligation with appropriate documentation of surgical procedure. 
d) Has a congenital condition resulting in no uterus.


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–
Is a female subject with child-bearing potential must have the following criteria:
a) A negative pregnancy test at Screening and Baseline.
b) Agrees to use a highly effective method of contraception from signing of informed 
consent throughout the duration of the study and for 35 days after the last dose. (see 
Appendix D for definitions of highly effective contraception).
c) Is not breastfeeding.
7. Meets a current DSM-5 diagnosis of schizophrenia.
8. PANSS NSFS ≥15, stable screening and baseline PANSS NSFS (<25% change).
9. PANSS total score ≤90; stable screening and baseline PANSS total score (<20% change). 
10. Receiving stable (no increase, no decrease >25% in dose in the preceding 2 months) 
antipsychotic medication at doses not to exceed risperidone 6 mg or its equivalent. 
Concomitant treatment with a subtherapeutic dose of a second antipsychotic may be permitted 
with sponsor or designee approval if used as a hypnotic (maximum of quetiapine 300 mg or its 
equivalent once daily at bedtime) and subject does not show morning sedation as per the 
investigator opinion, but not if it is used for refractory positive psychosis symptoms. Under 
this exception, the total daily dose the second antipsychotic will not have to be included in the 
calculation of the 6 mg/day risperidone-equivalent limit.
11. Able to swallow study drug in tablet form.
12. Should a patient require a caregiver to accompany him/her during the study, the caregiver 
should be available for the full duration of the study.
7.2
Exclusion Criteria
The subject must be excluded from participating in the study if the subject: 
1. Has participated in another investigational study within 30 days prior to the prestudy 
(screening) visit or <5 half-lives prior to the first dose. The 30 days window will be derived 
from the date of the last study procedure and/or AE related to the study procedure in the 
previous study to the prestudy/Screening Visit of the current study. 
2. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the study 
site personnel or of the Sponsor.
3. Has a history of cancer (malignancy) excluding treated basal cell carcinoma or treated 
stage 0 (in situ) cervical carcinoma.
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
5. Subject has a QT interval with Fridericia’s correction method (QTcF) >450 ms (males) or 
>470 ms (females) confirmed with one repeat testing, at the Screening Visit or Check-in.


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6. Has a positive alcohol or drug screen for disallowed substances, including amphetamines, 
barbiturates, cocaine, marijuana, methadone, methamphetamine, 
3,4-methylenedioxymethamphetamine, 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 patient may either be 
re-screened after a sufficient washout period or may continue screening process and a drug 
screen must be performed on Baseline Day -2 of each treatment period and at all subsequent 
outpatient 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.
7. Has a positive pregnancy test or plan to become pregnant during the study (female subjects 
only).
8. Is positive for HBsAg, hepatitis C antibodies, or has HIV by history (confirmatory testing is 
allowed; most sensitive test should take precedence).
9. Had major surgery, donated or lost 250 mL of blood within 4 weeks prior to the prestudy 
(screening) visit. 
10. Use of disallowed concomitant medications.
11. Is unable to refrain from or anticipates the use of any medication (except those prescribed), 
including prescription and nonprescription drugs or herbal remedies beginning approximately 
7 days prior to administration of the initial dose of study drug, throughout the study (including 
washout intervals between treatment periods), until the poststudy visit. There may be certain 
medications that are permitted, see Section 7.3.
12. Unwilling or unable to comply with the requirements of the protocol. 
13. Subject has a known hypersensitivity to any component of the formulation of TAK-831.
14. If male, the subject intends to donate sperm during the course of this study or before 95 days 
have elapsed since the last dose of study drug. 
15. Subject has a history of significant skin reactions (hypersensitivity) to adhesives, metals or 
plastic.
16. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, 
others, or property, or subjects who within the past year prior to Screening have attempted 
suicide. Subjects who have positive answers on item 4 or 5 on the C-SSRS (based on the past 
year) prior to randomization are excluded.


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17. Ongoing disability, medical, neurological, or psychiatric history, cognitive impairment or 
conditions that, in the opinion of the investigator, may interfere with study conduct or clinical 
assessments. 
18. The subject has a recent (within the last 6 months) diagnosis of panic disorder, depressive 
episode, or other comorbid psychiatric conditions requiring clinical attention based on the 
DSM-5 and the general psychiatric evaluation.
19. The subject has a diagnosis of substance use disorder (with the exception of nicotine 
dependence) within the preceding 6 months based on DSM-5 and the general psychiatric 
evaluation.
20. 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.
21. The subject has evidence of depression as measured by a CDSS >11 at Screening. Subjects 
with a CDSS score of 9 to 11 must be discussed with the sponsor and will also be excluded if 
the item scores are determined to reflect the presence of depression rather than schizophrenia 
negative symptoms.
22. Hearing deficits that in the investigator’s opinion prevent participation in event related 
potential testing.
23. History of brain trauma associated with loss of consciousness for >15 minutes. 
7.3
Excluded Medications, Supplements, Dietary Products
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 
excluded/allowed medications may be provided in separate reference documentation provided to 
study sites.


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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)
Chronic Use
Episodic Use
Comments or Exceptions
Any investigational drug
X
X
<30 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
Maximum dose of chronic anticholinergic 
treatment is 2 mg/day of benztropine or 
equivalent. 
Antithrombic agents and anticoagulants 
(excluding warfarin, which is excluded)
X
Anticonvulsants 
X
X
Exception: gabapentin and pregabalin are 
permitted if they are prescribed at a stable 
dose for ≥2 months prior to Screening and 
throughout study treatment. Subjects taking 
other anticonvulsants should not be 
considered for participation in the study, as 
their discontinuation could lead to symptom 
instability.
Antidepressants (excluding tricyclic 
antidepressants, MAOIs, and 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.
Antihistamines
X
X
Except loratadine, desloratadine, cetirizine, 
levocetirizine, mizolastine, and 
fexofenadine.
Antihypertensives
Clonidine NOT allowed.
Antipsoriatic agents
X
X
Topical agents are allowed.
Antipsychotics
X
Clozapine is excluded; all other treatments 
must adhere to requirements outlined in the 
study entry criteria.
As an exception, occasional use of an 
additional dose of the background 
antipsychotic may be permitted with sponsor 
or designee approval. 
Footnotes are on last table page.


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Table 7.a
Excluded Medications and Dietary Products (continued)
Drug Class
Disallowed (X) During the Study
(sections without [X] indicate no restriction)
Chronic Use
Episodic Use
Comments or Exceptions
Herbal remedies, which are psychoactive (eg, St 
John’s Wort, kava, valerian, ginkgo biloba, 
melatonin)
X
X
Must be discontinued ≥14 days prior to 
randomization.
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 for the treatment of anxiety or agitation 
as needed is permitted up to 2 mg/day 
lorazepam (or the equivalent dose of another 
benzodiazepine) up to 3 times per week, but 
cannot be taken within 8 hours of the 
administration of study assessments.
Insulin
X
X
Mood stabilizers 
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.
UGT enzyme inhibitors (probenecid and valproic 
acid)
Not within 14 days of dosing.
BZ=benzodiazepine, MAOI=monoamine oxidase inhibitor, RIMA=reversible inhibitor of monoamine oxidase type A, 
UGT=uridine 5'-diphosphate-glucuronosyltransferase.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Study drug can be taken with water or milk. Subjects should avoid drinking juices 1 hour before 
and 1 hour after taking study drug. 
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc) from the Screening Visit until the poststudy visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. The subject experiences an AE that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health or the subject is unwilling to continue 


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because of the AE. The primary reason for discontinuation or withdrawal of the subject form 
the study or study drug should be recorded in the electronic case report form (eCRF).
2. Drug-Induced Liver Injury (DILI).
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status), if any of the following circumstances occur at any time during 
study medication treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit 
of normal (ULN), or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or INR 
>1.5.
3. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health. Subject inability to adhere to medication 
intake or study procedures may also be considered a reason for early subject discontinuation.
4. Lost to follow-up. The subject did not return to the unit and multiple attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
6. Study termination. The sponsor, IRB/independent ethics committee, or regulatory agency 
terminates the study.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
7.7
Subject Replacement
If a subject discontinues from the study, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and Sponsor. The study site should contact the IRT for the 
replacement subject’s treatment assignment and identification number.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Details regarding the dosage form description and strengths, or composition for the 
extemporaneous preparation, of the active drug and placebo, can be found in the pharmacy manual 
or in the referenced compounding manual when applicable. Study drug will be packaged to 
support enrollment and replacement subjects as required.
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and remain in the original container until dispensed. The temperature 
excursion information can be found in the pharmacy manual or in the referenced compounding 
manual when applicable. Receipt and dispensing of study drug must be recorded by authorized 
personnel at the study site.
8.1.3
Clinical Study Drug Blinding
The study drug blind will be maintained using the IRT.
8.1.4
Randomization Code Creation and Storage 
IRT system will generate the randomization schedule. All randomization information will be 
stored in a secured area, accessible only by authorized personnel.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
The study drug blind will be maintained using the IRT.
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. If possible, the medical monitor 
should be contacted before the blind is broken. Unblinding will be performed per the standard 
operating procedures of the study site.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the study drug received from the 
sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the end of the study. For all study sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for study drug 
accountability, return, and destruction.


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8.1.7
Ancillary Supplies
All ancillary supplies will be provided by either the study site or the sponsor or designee, based 
upon availability. The list of ancillary supplies and source information can be found in the 
pharmacy manual or in the referenced compounding manual when applicable. If provided by the 
sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the sponsor 
or designee.


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9.0
STUDY PROCEDURES
The following sections describe the study procedures and data to be collected as indicated in the 
Schedule of Study Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained 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. 
 informed consent is a component of the overall study informed 
consent. The requirements of informed consent are described in Section 13.2. 
When subjects have performed screening assessments prior to study, the data from screening using 
a generic screening consent form can be used in this study for those who were subsequently 
enrolled, as long as the procedure was performed within the protocol screening to enrollment 
window.
 
9.1.1.1
Assignment of Screening and Randomization Numbers 
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to randomization or allocation. Screening numbers must 
not be re-used for different subjects. Any subject who is screened multiple times will be assigned a 
new screening number for each screening event.
All eligible subjects will be randomized by contacting the IRT for treatment assignment. The 
randomization number will be assigned to each subject; however, it will not be provided to the site 
or entered into the eCRF. The subject identification (ID) number will be the number that identifies 
the subjects for all procedures. Once a randomization number is assigned to a subject, it can never 
be reassigned to another subject. A single subject cannot be assigned more than 1 randomization 
number.
9.1.1.2
Clinical Study Drug Assignment
At the first and subsequent drug-dispensing visits, the investigator or designee will access the IRT 
to request study drug for a subject. The medication ID number of the study drug to be dispensed 
will be provided by the IRT.


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9.1.2
Inclusion and Exclusion Criteria 
Each subject is assessed through randomization, according to the eligibility criteria provided in 
Section 7.0.
9.1.3
Medical History/Demographics
Qualified site personnel are to collect subject significant medical history (past and ongoing) per 
the site’s standard of care and appropriate clinical judgment as well as subject demographics. 
9.1.4
Prior and Concomitant Medication Review
Medications are defined as prescription and over-the-counter drugs, vitamin supplements, 
nutraceuticals, and oral herbal preparations. Qualified site personnel are to review subject 
medication use.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
Qualified site personnel will conduct full physical including neurological examinations. 
9.2.2
Psychiatric Examination
The presence of extrapyramidal symptoms will be determined using the SAS. The presence of 
dyskinesias will be documented with the AIMS.
9.2.2.1
SAS
The SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 10 
items. Items are anchor-based, rated on a 5-point scale, and address rigidity, gait (bradykinesia), 
tremor, glabellar tap, and salivation [36]. The SAS will be administered by a qualified rater at the 
site.
9.2.2.2
AIMS
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive 
observation of the subject at rest (with shoes removed) and several questions or instructions 
directed toward the subject. Using a severity scale ranging from 0 (none) to 4 (severe), clinicians 
rate dyskinesia in several body regions, including the facial area, extremities, and trunk. There are 
two items related to dental status, as well as three global impression items assessing overall 
severity, incapacitation, and the subject’s awareness of abnormal movements [37,38]. The AIMS 
raters will be required to meet specific credential and educational criteria before they are certified 
to rate for this study. The AIMS will be administered by a qualified rater at the site.
9.2.3
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.


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9.2.4
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed. 
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 round down and 0.5 to 0.9 round up.
9.2.5
Vitals (Body Temperature, Heart Rate, Blood Pressure)
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes prior to having vital sign 
measurements obtained. Vital signs will include heart rate (HR) and systolic and diastolic blood 
pressure. The same method (eg, same size cuff, manual or automated) must be used for all 
measurements for each individual subject and should be the same for all subjects. 
9.2.6
12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry prior to lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bra. 
Subjects should be resting in a semirecumbent position for at least 5 minutes prior to each ECG 
measurement.
QTcF will be used to calculate QT intervals in this study.
Prior to each treatment period/cohort, a predose ECG will be obtained on Day -2. This 
measurement will be used as the baseline. The principal investigator should arrange to have a 
study cardiologist available as needed to review ECG tracings with abnormalities.
During each treatment period, if a subject demonstrates an increase in QTcF interval ≥40 msec 
compared with a predose baseline measurement, the ECG will be repeated within 5 minutes. The 
average value of the QTcF interval from the 2 ECGs will represent the value at that time point. If 
the average QTcF interval increase from Baseline for any postdose time point is ≥40 msec, the 
subject will continue to be monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours 
or until the QTcF is within 40 msec of the baseline value. If prolongation of the QTcF interval 
≥40 msec persists, a consultation with a study cardiologist may be appropriate and the Sponsor 
should be notified.
If the QTcF interval is 500 msec on repeat measurements, the Sponsor should be notified and the 
ECGs should be reviewed by a cardiologist. The subject should be monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted, the 
subject should be immediately transferred to an acute care setting for definitive therapy. 


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If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: HR, PR-interval, QRS-duration, QT-interval, 
QTcF-interval, and the interpretation of the ECG profile by the principal investigator.
9.2.7
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. The C-SSRS is composed of 3 questions addressing suicidal behavior and 
5 questions addressing suicidal ideation, with subquestions assessing the severity. The tool is 
administered via an interview with the subject.
Suicidality will be assessed by the use of the C-SSRS, a 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 (actually, interrupted, and aborted attempts at suicide). Two versions of the 
C-SSRS will be used in this study: the Screening/Baseline C-SSRS Lifetime and the 
Since-Last-Visit C-SSRS. 
9.2.8
CDSS
The CDSS was developed to assess symptoms of major depressive disorder in patients with 
schizophrenia, and specifically designed to assess comorbid depressive symptoms. The CDSS 
consists of nine 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.
9.2.9
PANSS
The PANSS is an interview-based measure of the severity of psychopathology in adults with 
psychotic disorders. The measure is comprised of 30 items and 3 scales: the Positive scale assesses 
hallucinations, delusions, and related symptoms; the Negative scale assesses emotional 
withdrawal, lack of motivation, and similar symptoms; and the General Psychopathology scale 
addresses other symptoms such as anxiety, somatic concern, and disorientation. An anchored 
Likert scale from 1 to 7, where values of 2 and above indicate the presence of progressively more 
severe symptoms, is used to score each item. Individual items are then summed to determine 
scores for the 3 scales, as well as a total score. A Composite scale score (Positive scale score minus 
Negative scale score) can also be calculated to show the relative valence of positive and negative 
symptoms. Total time required for the PANSS interview and scoring is approximately 30 to 
40 minutes [39-41]. PANSS raters will be required to meet specific training and education criteria 


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before they are certified to rate for this study. In addition, raters will receive specific training and 
education regarding all of the assessments prior to study initiation.
9.2.10 Study Drug Administration
This is a double-blind study; therefore, TAK-831 or matching placebo will be administered orally, 
once a day for 8 days in a blinded fashion.
9.2.10.1 Monitoring Subject Treatment Compliance
Compliance will be assessed via study drug count and subject or informant report. Subjects will 
also be required to bring study medication containers to each clinic visit, regardless of whether the 
study medication container is empty.
All subjects who are noncompliant 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. Subjects will be required to bring study medication 
containers/unused medications to the site visit during the study.
9.2.11 Cognitive Assessments
In order to obtain early estimates of potential treatment effects of TAK-831 on cognitive function, 
the BACS battery will be included in this study [42]. These neurocognitive domains may be 
potentially improved by TAK-831 based on preclinical efficacy data as well as the results of the 
phase 2 sodium benzoate study [14]. 
The set of tests is of approximately 35 to 40 minutes duration and may be conducted using either 
paper and pencil or a comparable version delivered electronically [43]. 
9.2.12 ERPs
This test takes approximately 45 minutes.
The ERPs to be measured (via scalp EEG) include the MMN potential during the oddball paradigm 
(MMN), the P300 wave during the oddball task, and the ASSR task. These tests have been linked 
to NMDA receptor function [21-24] and have demonstrated differences between subjects with 
schizophrenia and control subjects. Further details will be provided in the manual of procedure 
(MOP) for event related potentials and EEG based measures.
Frequency analysis during resting state will be recorded as quantitative electroencephalogram as 
indicated in the Schedule of Study Procedures (Section 3.0).
9.2.13 Delay EBC Test
EBC enables evaluation of cerebellar-dependent learning and is the primary endpoint in this study. 
Briefly, the procedure involves an initial set of 8 unconditioned stimuli (unconditioned stimulus: 
corneal air puff, 50 msec, 10 psi at source) presented with an intertrial interval of 15 seconds. The 
acquisition phase will then follow, consisting of 5 blocks of trials (mean intertrial interval = 
15 seconds; range = 10 to 20 seconds). Each block will contain 18 trials in which the conditioned 


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stimulus (1 KHz tone; 400 msec; sound pressure level: 80 dB) will be paired with the 
unconditioned stimulus and 2 trials in which the conditioned stimulus will be presented alone. In 
trials in which the conditioned and unconditioned stimuli are paired, the unconditioned stimulus 
air puff will be coterminated with the conditioned stimulus tone. The overall duration of this task is 
between 30 to 60 minutes. Further details will be provided in the MOP for EBC test (including 
modifications for administration at the Screening Visit).
9.2.14 AE Monitoring
AE monitoring begins following signing of informed consent. Changes in subject health status 
from baseline assessment to trial drug administration should be captured in the subject’s medical 
history. A complete description of AE collections and procedures is provided in Section 10.0.
9.2.15 Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken on the days stipulated in the Schedule of Study Procedures (Section 3.0).
9.2.15.1 Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute 
differential
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cell/high-power field, white blood cell/high-power field, and casts.


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Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase 
ALT
AST
Blood urea nitrogen 
Calcium
Carbon dioxide
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase 
Sodium
Potassium
Bilirubin (total), if above ULN total bilirubin will be 
fractionated
Protein (total)
9.2.15.2 Diagnostic Screening
Serum
Serum diagnostic evaluations will include the following tests:
β-hCG (females only)
FSH (females only)
Hepatitis Screen (HBsAg, HCV antibody)
Urine
A urine drug screen will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine 
Barbiturates
Methadone / Metabolite
Benzodiazepines
Opiates
Buprenorphine / Metabolite
Oxycodone / Oxymorphone
Cannabinoids
Phencyclidine
Cocaine / Metabolites
9.3
Biomarker, PK, PD, and 
, Samples
Samples for PK and PD (D- and L-serine) will be collected as specified in the Schedule of Study 
Procedures (Section 3.0). Please refer to the Laboratory Manual for information on the collection, 
processing, and shipment of samples to the Central Laboratory.
The decision as to which plasma and/or urine samples collected will be assayed for evaluation of 
PK/biomarkers will be determined by the Sponsor (eg, samples at lower doses may not be assayed 
if samples at higher doses reveal undetectable drug concentrations). If indicated, these samples 


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may also be assayed and/or pooled for assay in an exploratory manner for metabolites and/or 
additional biomarkers.
It is anticipated that the total blood volume drawn for the study will be approximately 220 ml. 
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Blood sample for PK
Blood
Plasma
Plasma sample for PK analysis
Blood sample for PD assessment (D-
and L-serine)
Blood
Plasma
Plasma sample for PD analysis
9.3.1
PK Measurements 
9.3.1.1
PK Sample Collection
Serial blood samples (one 4-mL sample per scheduled time) for PK analysis of TAK-831 plasma 
concentrations will be collected into chilled Vacutainers containing the anticoagulant potassium 
ethylenediamine tetraacetic acid (K2EDTA), as specified in Schedule of Study Procedures (See 
Section 3.0).
The actual date and time of each PK sample collection as well as the date and time of study drug 
dosing for the most recent dose will be recorded accurately in the eCRF.
Instructions for sample collection, processing and shipment are provided in the laboratory manual.
9.3.1.2
Bioanalytical Methods
Plasma concentrations of TAK-831 will be measured by a validated high-performance liquid 
chromatography (HPLC) with tandem mass spectrometry.
9.3.2
Biomarker Measurements 
9.3.2.1
PD Sample Collection
Serial blood samples (one 6-mL sample per scheduled time) for PD (D-serine and L-serine) 
analysis of TAK-831 will be collected into chilled Vacutainers containing the anticoagulant 
K2EDTA, according to the schedule shown in in Schedule of Study Procedures (See Section 3.0).


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The actual time of sample collection, time since last dose was administered, and time since last 
meal will be recorded on the source document and eCRF.
Instructions for sample processing and shipment are provided in the laboratory manual.
9.3.2.2
PD Analysis
Plasma concentrations of D- and L-serine will be measured by a validated HPLC with tandem 
mass spectrometry. Additional D- and L- amino acids may also be analyzed, including but not 
limited to alanine.
9.3.2.3
PD Parameters
PD parameters will be determined for all evaluable subjects. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times. The PD 
parameters of plasma D- and L-serine, and the ratio of D-serine to total serine in plasma will be 
assessed. Individual PD data may be combined with other study data and analyzed using a 
population PK/PD modeling approach.


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9.3.4
Confinement
The study will include 2 inpatient stays at the clinic in each period. The first will be 2 days 
(including night stays on Days -2 to -1) and the second will be on Days 7 to 8 (including a night 
stay on Day 7). In between these stays, subjects will report to the study site as and when required 
per schedule of assessments.


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


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


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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.2.8.3).
10.1.2 Special Interest AEs
No AEs of special interest have been identified for this compound.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event 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 adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.


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


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10.2.7 Outcome 

Recovered/resolved - subject returned to first assessment status with respect to the AE.

Recovering/resolving - the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved - there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae - the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal - an AE that is considered as the cause of death.

Unknown - the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and DILI
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and DILI) will commence at the time the 
subject signs the informed consent. Routine collection of AEs will continue until the follow-up 
visit 10 to 14 days after the last dose of investigational product. For subjects who discontinue prior 
to the administration of study medication, AEs will be followed until the subject discontinues 
study participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 


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changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Appendix 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 


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fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs 
No AEs of special interest have been identified for TAK-831.
10.2.8.5 Reporting of DILI
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, a DILI 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 elevated >3 × ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, a DILI eCRF must be completed providing 
additional information on relevant recent history, risk factors, clinical signs and symptoms and 
results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.15 must also be 
performed. In addition, a DILI eCRF must be completed and transmitted with the Takeda SAE 
form (as per Section 10.2.9). 
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (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. In cases of 
inconsistencies between the protocol and the SAP in regard to data analysis, the SAP is to take 
precedence over the protocol. Due to this clear understanding of precedence, the statistical analysis 
section will not necessarily be updated to match the SAP when the protocol is amended.
A targeted 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.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The Safety Set will include all randomized subjects who receive at least 1 dose of double-blind study 
medication. Subjects in this analysis set will be used for demographic, baseline characteristics, and 
safety summaries.
11.1.1.2 PK Set
The PK Set will include all randomized subjects who receive at least one dose of double-blind study 
medication and who have any available plasma concentration data.
11.1.1.3 PD Set
The PD set will consist of all subjects who receive at least 1 dose of study drug and have at least 1 
postdose PD result.
11.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics including age, gender, race, body mass index, and 
medical history will be listed and summarized by randomized treatment sequence and overall 
based on the Safety Set.
Baseline values for selected PD assessments will also be summarized by treatment sequence and 
overall based on the Safety Set.
11.1.3 PK Analysis
Plasma concentrations of TAK-831 will be listed for each subject and summarized by each time 
point for each dose and period 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 


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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 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 may be reported separately.
11.1.4 PD Analysis 
11.1.4.1 Analysis of Primary PD Endpoint 
Pairwise comparisons between active treatments and placebo will be generated within the 
framework of analysis of variance (ANOVA), with treatment sequence, period, and treatment as 
fixed effects. Subject nested within sequence is included as a random effect. The dependent 
variable is the change in response from the period baseline assessment to the final treatment day 
for each period. The analysis will be performed using observed data. Potential carryover effects 
will be investigated. P-values and confidence intervals will be reported.
A frequentist analysis will be done for the full data set, using simulations to adjust for the effect of 
the interim analysis on the type I error rates. The results of the primary endpoint will be considered 
statistically significant at either of the 2 doses (as applicable) if the one-sided p<0.05, without 
adjustment for multiplicity (ie, the type I error rate will be separately controlled for each dose). 
In addition, the primary endpoint will be analyzed using a Bayesian normal linear model with 
treatment sequence, period, and treatment as fixed effects and subject within sequence as a 
repeated factor. The dependent variable is the change in response from the period baseline 
assessment to the final treatment day for each period. The response data will be logit transformed 
before the change is calculated. A diffuse normal distribution will be used as a prior for the 
regression coefficients and a diffuse inverse gamma for the residual variance. The Bayesian model 
will be used to estimate the posterior distribution of the treatment effect from each dose (as 
applicable). 
11.1.4.2 Analysis of Other PD Endpoints 
The secondary EEG endpoints will be analyzed using an ANOVA model as described in 
Section 11.1.4.1. 
The cognitive battery composite score, the BACS, will be analyzed as follows. The primary 
measure from each test is standardized by creating z-scores whereby the mean of the test session of 
a healthy participant is set to 0 and the standard deviation set to 1 [44]. A composite score will be 
calculated by averaging the 4 measures from the BACS used in the study, and then calculating a
z-score of the composite. The composite z-score indicates how much higher or lower the 
participant’s cognition is compared to a healthy person. An ANOVA will be performed on the 
change from baseline for the composite BACS score, using a similar model to that used for 
primary endpoint.


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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 of each dose 
level 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 
(high dose, low dose 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 statistical analysis plan.
There will be no adjustment for the multiplicity of secondary endpoints.
Analysis of exploratory PD endpoints will be described in the SAP.
11.1.5 Safety Analysis
The Safety Set will be used for all summaries of safety parameters. These summaries will be 
presented by cohort for placebo, each TAK-831 dose level, and TAK-831 overall (as appropriate). 
11.1.5.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). TEAEs with onset occurring within 30 days 
(onset date – last date of dose +1≤30) after study drug administration will be included in the 
summary tables. All AEs will be in the listings. TEAEs will be summarized by SOC and PT. The 
following summary tables will be included in the report: summary of TEAEs and drug-related 
AEs, relationship of AEs to study drug (related vs not related), severity of AEs, and related AEs. 
Data listings will be provided for all AEs including TEAEs, AEs leading to study drug 
discontinuation, and SAEs.
11.1.5.2 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal criteria will be summarized and provided in the data listings. 
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized. All 
clinical laboratory data will be provided in the data listings.
11.1.5.3 Vital Signs
Individual results of vital signs that meet Takeda’s markedly abnormal criteria will be summarized 
and provided in the data listings. Baseline, postdose, and changes from Baseline in vital sign 
measurements will be summarized. All vital sign data will be provided in the data listings.
11.1.5.4 ECGs
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria will be summarized and provided in the data listings. 
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized. Shift tables will be generated to show the investigator’s ECG interpretations at each 
postdose collection by the interpretation at Baseline.


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All ECG data will be provided in the data listings.
11.1.5.5 Other Safety Parameters
Physical examination findings will be presented in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
A planned unblinded interim analysis of the primary PD endpoints will be conducted when 
approximately 14 patients have been completed the primary endpoint. The site will be allowed to 
continue enrollment to the high/placebo comparison, with the goal that approximately 16 patients 
will be randomized by the time the interim analysis is complete. (The additional 
approximately 2 subjects will be included in the final analysis but not the interim analysis.) The 
purpose of the interim PD analysis will be to determine whether to continue enrolling subjects to 
the high-dose/placebo comparison, switch enrollment to the low-dose/placebo comparison, or 
discontinue enrollment. The decision rule will be specified in an interim analysis plan before the 
data are unblinded for the interim analysis. In addition, a decision to switch to the low dose may be 
made based on safety or tolerability of the high dose.
11.3
Determination of Sample Size
Up to approximately 32 subjects will be enrolled into this 2-period crossover study. Initially 
16 subjects will be randomized to 1 of 2 sequences comparing the high dose to placebo. Based on 
the results of an interim analysis, an additional 16 subjects may be randomized as before or to 1 of 
the 2 sequences comparing the low dose to placebo. 
The expected effect size, defined as the ratio between the mean difference between treatment and 
placebo divided by the standard deviation of this difference, is 0.6 for the primary endpoint. This 
effect size is a conservative estimate based on data from [20], which showed an effect size of 0.74 
for EBC at 24 hours after initiation of treatment with secretin. In this study of a schizophrenic 
population, subjects on secretin showed a 24% higher rate of correct responses compared to 
subjects on placebo (70% vs 46%).
The sample sizes of 16 or 32 subjects have been selected to enable Bayesian analyses to inform 
dose selection and future drug development under the expected effect size as well as other 
plausible effect sizes.


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


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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki are 
addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members 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 (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.


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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor 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 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
 
 Notify 
Sponsor of consent withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 


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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical Study Registration 
In order to ensure that information on clinical studies 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 studies 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 investigators in the United States), 
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 study 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
SAE and pregnancy reporting
Takeda Pharmacovigilance
Takeda Development Center Americas, Inc 
Fax: 224-554-1052
Email: PVSafetyAmericas@tpna.com


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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the Sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
14.1.3 Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.


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14.1.4 List of Abbreviations
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
AST
aspartate aminotransferase
ASSR
auditory steady-state response
ANOVA
analysis of variance
BACS
Brief Assessment of Cognition in Schizophrenia
beta-hCG
beta human chorionic gonadotropin
BMI
body mass index
CDSS
Calgary Depression Scale Score
CIAS
cognitive impairment in schizophrenia
CRO
contract research organization
CR
conditioned response
CS
conditioned stimulus
C-SSRS
Columbia Suicide Severity Rating Scale 
Cz
midline central electrode
DAO
D-amino acid oxidase
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EBC
eyeblink conditioning
ECG
electrocardiogram
eCRF
electronic case report form
EEG
electroencephalography
EDS
extra-dimensional set shifting
ERP
event related potential
FDA
Food and Drug Administration of the United States
FSH
follicle stimulating hormone 
Fz
midline frontal electrode
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HPLC
high performance liquid chromatography
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation
IDS
intra-dimensional shift
IEC
Independent Ethics Committee
IRB
institutional review board
IRT
interactive response technology


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K2EDTA
Potassium ethylenediaminetetraacetic acid
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MMN
mismatch negativity
MOP
manual of procedure
MRD
multiple-rising dose
NMDA
N-methyl-D-aspartate
NSFS
negative symptom factor score
PANSS
Positive and Negative Symptom Scale
PCP
phencyclidine
PD
pharmacodynamics
PET
positron emission tomography
PK
pharmacokinetic
PT
preferred term
Pz
midline parietal electrode
QD
once daily
QTcF
QT interval with Frederica correction method
RNA
ribonucleic acid
Rs
resting state
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Simpson Angus Scale
SBP
systolic blood pressure
SOC
system organ class
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
unconditioned response
WBC
white blood cell


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


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


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16.0
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13. Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, et al. D-serine 
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26. Light GA, Swerdlow NR. Future clinical uses of neurophysiological biomarkers to predict and 
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41. Perkins DO, Stroup TS, Lieberman JA. Psychotic disorders measures. In: Handbook of 
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of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard 
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 


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


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


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


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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 
35 days after the last dose of study drug. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. If a subject is found to be pregnant 
during study, study drug will be discontinued and the investigator will offer the subject the 
choice to receive unblinded treatment information. 
26. Male subjects must use a barrier method of contraception (eg, condom with or without 
spermicide) as defined in the informed consent from signing the informed consent throughout 
the duration of the study and for 95 days after the last dose of study drug. If the partner or wife 
of the subject is found to be pregnant during the study, the investigator will offer the subject the 
choice to receive unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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


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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 95 days after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with or without spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. Females 
of childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception below.
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 a highly effective/effective method of contraception (from 
the list below). 
For studies in which teratogenicity/genotoxicity/embryotoxicity has been demonstrated 
(investigational medicinal product or comparator or background medication), or there is a lack of 
adequate reproductive toxicity data, female subjects should be instructed to use two highly 
effective methods of contraception/one highly effective and one effective method (from the list 
below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming post-menopausal 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 FSH level in the postmenopausal 
range (FSH >40 IU/L) may be used to confirm a post-menopausal state in younger women (eg, 
those <45 year old) or women who are not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 


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correctly). In this study, where medications and devices containing hormones are excluded, the 
only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
the entire period of the study, from 1 month prior to the first dose until 35 days after last 
dose.
2. Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
4. Subjects will be provided with information on effective methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study.
5. During the course of the study, regular serum hCG pregnancy tests will be performed only for 
women of childbearing potential and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) Assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?


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ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
6. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative serum hCG pregnancy test at predose on Day 1 prior to receiving 
any dose of study medication. In addition, subjects must also have a negative serum/urine hCG 
pregnancy test at any time during the study, if requested by the clinical site.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (ie, condom) in males with pregnant partners.

assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
Pregnancy
Women of childbearing potential will be included in this study.
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug and should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 95 days after the last dose should also be recorded 
following authorization from the subject’s partner. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed. 
If the female subject or female partner of a male subject agrees to the primary care physician being 
informed, the investigator should notify the primary care physician that the female subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of the study drug the subject received (blinded or unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) will be followed up to final outcome, using the pregnancy 


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form. Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.


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Appendix E
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 06 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Updated entry criteria.
The primary changes occur in Section 7.0 SELECTION AND 
DISCONTINUATION/WITHDRAWAL OF SUBJECTS
Initial 
wording:
7.1 Inclusion Criteria
...
3. Be male or a female aged 18 to 50 years, inclusive, at the Screening Visit.
.....
Amended 
or new
wording:
7.1 Inclusion Criteria
.....
3. Be male or a female aged 18 to 60 years, inclusive, at the Screening Visit.
....
Rationale for change: Inclusion criterion 03 revised to increase the maximum subject age from 
50 to 60 years, which will allow for increasing patient recruitment. 
The following sections also contain this change:

Section 1.0 STUDY SUMMARY

Section 6.1 Study Design and Description


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680cbc3f1
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate Pharmacodynamic
Effects, Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adult Subjects With
Schizophrenia

SAP_001.pdf: 
1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-831-2001
A Phase 2 Randomized, Investigator-Blind, Placebo-Controlled, Cross-Over Study to 
Evaluate Pharmacodynamic Effects, Safety, Tolerability, and Pharmacokinetics of 
Multiple Oral Doses of TAK-831 in Adult Subjects With Schizophrenia
PHASE 2
Version: Amendment 2
Date: 05 February 2021
Prepared by:
Based on:
Protocol Version: 06
Protocol Date: 14 January 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.
NCT03359785


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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 Objective......................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1.1
Primary Endpoints .............................................................................................8
5.1.2
Secondary Endpoints .........................................................................................8
5.1.4
Safety Endpoints................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.........................................................................9
7.0
METHODS OF ANALYSIS AND PRESENTATION.....................................................9
7.1
General Principles......................................................................................................9
7.1.1 Study Definitions........................................................................................................10
7.1.2 Definition of Study Days ............................................................................................10
7.1.3 Definition of Study Visit Windows..............................................................................10
7.1.4 Conventions for Missing Adverse Event Dates ...........................................................10
7.1.5 Conventions for Missing Concomitant Medication Dates............................................11
7.2
Analysis Sets ...........................................................................................................11
7.3
Disposition of Subjects ............................................................................................11
7.4
Demographic and Other Baseline Characteristics.....................................................12
7.5
Medical History and Concurrent Medical Conditions...............................................12
7.6
Medication History and Concomitant Medications...................................................12
7.7
Study Drug Exposure and Compliance.....................................................................13
7.8
PD Analysis.............................................................................................................13
7.8.1
Primary PD Endpoint.......................................................................................13
7.8.2
Secondary PD Endpoint(s)...............................................................................14
7.9
Pharmacokinetic Analysis........................................................................................15
7.10
Other Outcomes.......................................................................................................16


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7.11
Safety Analysis........................................................................................................16
7.11.1
Adverse Events................................................................................................16
7.11.2
Clinical Laboratory Evaluations.......................................................................17
7.11.3
Vital Signs.......................................................................................................18
7.11.4
12-Lead ECGs.................................................................................................18
7.11.5
Other Observations Related to Safety...............................................................18
7.12
Interim Analysis ......................................................................................................19
7.13
Changes in the Statistical Analysis Plan...................................................................19
8.0
REFERENCES..............................................................................................................19


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
ASL
arterial spin labeling
AST
aspartate aminotransferase
ASSR
auditory steady state response
ANOVA
analysis of variance
ANCOVA
Analysis of covariance 
BACS
Brief Assessment of Cognition in Schizophrenia
CDSS
Calgary Depression Scale Score
C-SSRS
Columbia Suicide Severity Rating Scale 
Cz
midline central electrode
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EBC
eyeblink conditioning
ECG
Electrocardiogram
eCRF
electronic case report form
EEG
electroencephalography
ERP
event related potential
Fz
midline frontal electrode
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MID
monetary incentive delay
MMRM
mixed model for repeated measurements
MMN
mismatch negativity
MRI
magnetic resonance imaging
PD
Pharmacodynamics
PK
Pharmacokinetic
PT
preferred term
Pz
midline parietal electrode
QTcF
QT interval with Frederica correction method
RNA
ribonucleic acid
SAE
serious adverse event
SAS
Simpson Angus Scale
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell


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4.0
OBJECTIVES
4.1
Primary Objective

To determine whether TAK-831 is superior to placebo in improving cerebellar function as 
measured with the average % of conditioned responses during the eyeblink conditioning 
(EBC) test.
4.2
Secondary Objectives

To determine whether add-on TAK-831 compared to placebo improves sensory processing as 
measured by event related potentials (ERPs) mismatch negativity (MMN) and p300.

To determine whether add-on TAK-831 compared to placebo improves the auditory 
steady-state response (ASSR) to 40 Hz stimulation.

To determine whether add-on TAK-831 compared to placebo improves the composite score 
of the BACS battery.

To assess the safety and tolerability of TAK-831.

To assess the pharmacokinetics (PK) of TAK-831.

To assess the pharmacodynamics (PD) of TAK-831 by measurement of plasma D-serine and 
L-serine levels, as well as plasma D-serine: total serine ratios.


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4.4
Study Design
This study is a randomized, double-blind, placebo-controlled, 2-period crossover phase 2 study 
to evaluate the PD effects, safety, tolerability and PK of multiple daily oral doses of TAK-831 in 
adult patients with schizophrenia. 
Approximately 32 adult male and female subjects between ages 18 and 50, inclusive, with a 
current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis 
of schizophrenia who are receiving stable antipsychotic therapy (no increase, no decrease >25% 
in dose in the preceding 2 months) will be randomized in to the study. Subjects will have a 
 
 Subjects with 
extrapyramidal signs or symptoms or depressive symptoms will be excluded. 
Additional screening assessments include a physical and neurological exam, clinical laboratory 
and ECG measures, a urine drug screen, and screening for suicidality and depression using the 
Columbia Suicide Severity Rating Scale (C-SSRS) and the Calgary Depression Scale Score 
(CDSS), respectively. Assessment of extrapyramidal symptoms will be performed with the 
Simpson Angus Scale (SAS). The presence of dyskinesias will be assessed with the Abnormal 
Involuntary Movement Scale (AIMS).
During the pretreatment days (Days -2 and -1), subjects will participate in a baseline assessment 
with a cognitive battery, 
 EEG/ERP measures, and the EBC.
Effects of up to 2 dose levels of TAK-831 or placebo will be assessed. Each treatment will be 
administered daily for a period of 8 consecutive days, separated by a 14 to 21 days washout.
The planned dose levels of TAK-831 to be evaluated will be 500 and 50 mg. 
The study will consist of 2 treatment periods, and visits to the clinic at the following times: 
(1) Screening Period (Days -30 to -3) covering full medical, neurological, and psychiatric
examinations; (2) Treatment Visits and in patient stays: On Day -2 of Periods 1 and 2, subjects
will be admitted to the clinic for 2-night stays; on Day -2 subjects will undergo baseline clinical
assessment procedures and cognitive battery assessment. On Day -1, subjects will receive the
baseline EEG and EBC assessments. In Period 1, those who continue to meet all eligibility
criteria will be randomized via an interactive response technology (IRT) system to 1 of 2
treatment sequences. On Day 1, subjects will undergo predose blood PK/PD samples, first dosing,
and postdose blood draws, after which they will be discharged from the clinic to continue dosing
at their residence. Subjects will receive double-blind treatment from Days 1 through 8 (inclusive)
with completion of efficacy and PK/PD-related assessments on Days 7 and 8 of each treatment
period; and (3), a washout period between Treatment Periods 1 and 2 lasting between 14 to 21
days.
Study participants will receive daily study drug dosing until Day 8 of each period. Clinical 
assessments, laboratory tests and ECG will be repeated after dosing on Days 7 and 8 as per the 
schedule of events. Upon completion of the first dosing period, subjects will enter a wash-out 


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period lasting between 14 to 21 days and will then return to the study site to undergo Day -2
procedures for the next dosing period. 
Approximately 10 to 14 days after the last dose of study drug in the second dosing period, a 
follow-up safety assessment will be performed. 
In the event of a subject prematurely discontinuing the study during one of the study periods, an 
Early Termination Visit must be conducted, at which the safety, PK, plasma D- and L-serine
assessments corresponding to a Final Visit will be performed. If a subject discontinues the study 
during the washout period, only the procedures corresponding to the follow-up safety assessment 
will be performed.
Subjects who drop out before completing 2 treatment periods of the study may be replaced at the 
discretion of the study sponsor.
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 have been screened but have exceeded the 28-day Screening Period may proceed 
in the study after a discussion with the sponsor/designee to obtain approval and to determine 
whether any screening procedures should be repeated before admission on Day -2 of Period 1.
5.0
ANALYSIS ENDPOINTS
5.1.1
Primary Endpoints

Average % of conditioned responses during the EBC test at Day 8. 
5.1.2
Secondary Endpoints 

MMN amplitude at Fz (electroencephalogram [EEG]) at Day 8. 

P300 amplitude at midline parietal electrode (Pz) (EEG) at Day 8. 

ASSR at midline central electrode (Cz) (EEG) at Day 8.

BACS cognitive battery composite score at Day 7.

Plasma D-serine and L-serine levels, and plasma D-serine:total serine ratio at Day 8.

TAK-831 plasma concentrations.


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5.1.4
Safety Endpoints

Percentage of subjects who experience at least 1 treatment-emergent adverse event (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.
6.0
DETERMINATION OF SAMPLE SIZE
Up to approximately 32 subjects will be enrolled into this 2-period crossover study. Initially 
16 subjects will be randomized to 1 of 2 sequences comparing the high dose to placebo. Based 
on the results of an interim analysis, an additional 16 subjects may be randomized as before or to 
1 of the 2 sequences comparing the low dose to placebo. 
The expected effect size, defined as the ratio between the mean difference between treatment and 
placebo divided by the standard deviation of this difference, is 0.6 for the primary endpoint. This 
effect size is a conservative estimate based on data from [1], which showed an effect size of 
0.74 for EBC at 24 hours after initiation of treatment with secretin. In this study of a 
schizophrenic population, subjects on secretin showed a 24% higher rate of correct responses 
compared to subjects on placebo (70% vs 46%).
The sample sizes of 16 or 32 subjects have been selected to enable Bayesian analyses to inform 
dose selection and future drug development under the expected effect size as well as other 
plausible effect sizes.
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
within each study period. 
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.10 significance level unless otherwise stated. P-values will be rounded to 
3 decimal places prior to assessment of statistical significance.


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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. For transformed and derived data, summary statistics 
will be presented to appropriate decimal places.
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.
For summaries by treatment sequence, the TAK-831 dose level will be summarized separately if 
the low dose is used.
7.1.1 Study Definitions
7.1.2 Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication within each study period. 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.
7.13 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.
7.1.4 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 a 
given Period. All references to first dose in this section should be understood relative to each 
treatment Period. 
Incomplete AE dates will be presented as they are in the listings.
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, then the first day of the month will be used for the start date. If only 


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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 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 or the stop date is prior to the first dose, then January 1st will be used for the 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 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 the above instructions indicate conflicting start dates for an AE, then the earliest date indicated 
shall be used.
7.1.5 Conventions for Missing Concomitant Medication Dates
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly. Also see Section 7.6.
7.2
Analysis Sets
7.2.1.1
Safety Set
The Safety Set will include all randomized subjects who receive at least 1 dose of double-blind study 
medication. Subjects in this analysis set will be used for demographic, baseline characteristics, 
and safety summaries. Subjects will be analyzed according to the actual treatment received.
7.2.1.2
PK Set
The PK Set will include all randomized subjects who receive at least one dose of double-blind study 
medication and who have any available plasma concentration data. Subjects will be analyzed 
according to the actual treatment received.
7.2.1.3
PD Set
The PD set will consist of all subjects who receive at least 1 dose of study drug and have at least 
1 postdose PD result. Subjects will be analyzed according to the randomized treatment.
7.3
Disposition of Subjects
Study Information, including date first subject signed ICF, date of last subject’s last visit/contact, 
date of last subject’s last procedure for collection of data for primary endpoint, MedDRA 
Version, WHODrug Version, SAS Version, will be listed.
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data.
Disposition of all randomized subjects will be tabulated: 

All subjects received at least one dose of study drug (denominator).


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
Subjects who completed the study.

Subjects who prematurely discontinued study.
Primary reasons for discontinuation of study as entered on the electronic case report form 
(eCRF), will be tabulated. Reasons for discontinuation include adverse event, liver function test,
significant protocol deviation, lost to follow-up, voluntary withdrawal, study termination, and 
other. The date of first dose, date of last dose, duration of treatment and the reason for premature 
discontinuation of study drug/study visit will be presented for each subject in listings. 
Disposition of screen failure subjects will be summarized descriptively. Primary reasons for 
failure will be summarized and will be presented in a data listing.
Significant protocol deviations will be summarized and listed.
All summaries will be presented by treatment sequence and overall. 
7.4
Demographic and Other Baseline Characteristics
Demographics and baseline characteristics including age, gender, race, and body mass index will 
be listed and summarized by randomized treatment sequence and overall based on the Safety Set.
Baseline values for primary and secondary PD assessments (including average % of conditioned 
responses during the EBC test at Day 8, MMN amplitude at Fz at Day 8, P300 amplitude at Pz at 
Day 8, ASSR at Cz at Day 8, BACS cognitive battery composite score at Day 7, plasma D-serine, 
L-serine levels and the ratio of the two at Day 8) will also be summarized by treatment sequence 
and overall based on the Safety Set.
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 18 or higher) coding system. Ongoing 
conditions are considered concurrent medical conditions.
All medical history and concurrent medical condition data will be listed by site (study center) 
and subject number. The listing will contain subject identifier, treatment sequence, system organ 
class (SOC), preferred term (PT), whether there was any medical history or concurrent condition, 
and, if yes, a detail of the medical history or concurrent condition. 
Medical history and concurrent medical conditions will be listed and summarized by each 
treatment sequence and overall based on the Safety Set.
7.6
Medication History and Concomitant Medications
All medication history and concomitant medications will be listed by site (study center) and 
subject number. The listings will contain subject identifier, treatment, World Health 
Organization Drug Dictionary (WHODrug) preferred medication name, dose, unit, frequency, 
route, start date, stop date, whether the medication was ongoing, and reason for use. No 
inferential statistics will be presented. 


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Medication history and concomitant medications will be coded using the WHODrug Version 
01March 2017 or higher.
7.7
Study Drug Exposure and Compliance
The duration of exposure will be summarized as a continuous variable. 
The percentage of study drug compliance will be defined as {(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 
(<80%, 80 to 120%, and >120%) 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).
7.8
PD Analysis
7.8.1
Primary PD Endpoint
The primary endpoint is the average % of conditioned responses in the EBC task at Day 8. 
The primary endpoint will be summarized for baseline, post-dose, and change from baseline by 
treatment. 
Pairwise comparisons between active treatments and placebo will be generated within the 
framework of analysis of variance (ANOVA), with treatment sequence, period, and treatment as 
fixed effects. Subject nested within sequence is included as a random effect. The dependent 
variable is the change in response from the period baseline assessment to the final treatment day 
for each period, and the response data will be logit transformed before the change is calculated. 
The analysis will be performed using observed data. Potential carryover effects will be 
investigated. P-values and confidence intervals will be reported. The following SAS code may be 
used:
proc mixed data=XXXX; 
class sequence treatment period subject;
model response = sequence treatment period / ddfm=kr;
random subject (sequence);
estimate 'Treatment Difference' treatment -1 1 / al alpha = 0.10 E;
lsmeans treatment;
run;
The primary endpoint will be tested individually for each of the two doses against 5% (one-sided) 
level of significance.


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As a supplementary analysis, an ANCOVA (analysis of covariance) model will be applied to the 
primary endpoint with (period) baseline as a covariate, treatment sequence, period, treatment 
effect, baseline-by-treatment as fixed effects, and subject as a random effect. The dependent 
variable is the change in response from the period baseline assessment to the final treatment day 
for each period, and the response data will be logit transformed before the change is calculated.
Based on a missing at random assumption, this analysis will be performed using observed data 
only. P-values and confidence intervals for this model will be provided.
In addition, as a supporting analysis and in the interim analysis (see Section 7.12), the primary 
endpoint will be analyzed using a Bayesian normal linear model with treatment sequence, period, 
and treatment as fixed effects, subject within sequence as a repeated factor, and (period) baseline
as a covariate. The dependent variable is the change in response from the period baseline 
assessment to the final treatment day for each period. The response data will be logit transformed 
before the change is calculated. A diffuse normal distribution will be used as a prior for the 
regression coefficients and a diffuse inverse gamma for the residual variance. The Bayesian 
model will be used to estimate the posterior distribution of the treatment effect from each dose 
(as applicable). The posterior mean, standard deviation and the 90% credible interval (highest 
posterior density interval) for each treatment, along with the posterior mean treatment difference, 
corresponding standard deviation and 90% credible interval (highest posterior density interval)
will be reported. The following SAS code may be used for the analysis:
proc genmod data = XXXX;
class Sequence Period Treatment Subject;
model Response = Sequence Period Treatment Subject Baseline / dist = Normal link=identity
alpha=0.1;
bayes seed = 666 coeffprior=normal dispersionprior = igamma(shape=0.001, scale=0.001)
nbi=2000 nmc=10000 maxit=2000 outpost=post diagnostics=all stats=all;
lsmeans Treatment / pdiff alpha = 0.1;
run;
7.8.2
Secondary PD Endpoint(s)
The secondary EEG endpoints will be analyzed using an ANOVA model similar to that used for 
the primary endpoint, as described in Section 7.8.1.
The cognitive battery composite score, the BACS, will be analyzed as follows. The primary 
measure from each test is standardized by creating z-scores whereby the mean of the test session 
of a healthy participant is set to 0 and the standard deviation set to 1 [2]. A composite score will 
be calculated by averaging the 4 measures from the BACS used in the study, and then calculating 
a z-score of the composite. The composite z-score indicates how much higher or lower the 
participant’s cognition is compared to a healthy person. An ANOVA will be performed on the 
change from baseline for the composite BACS score, using a similar model to that used for 
primary endpoint.


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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 of 
each dose level using descriptive statistics. In addition, a mixed model for repeated measures 
(MMRM) will be used on the change from baseline in these concentrations, with sequence, 
period, treatment and visit as fixed effects, and subject nested within sequence as a random effect. 
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 subject is allowed to vary freely and an 
unstructured covariance matrix is assumed. If the model does not converge, other covariance 
structures will be considered. Pairwise comparisons between the test regimens (high dose, low 
dose and placebo) will be made and the CIs for the difference in the LS means will be 
constructed for Day 8 assessments. 
There will be no adjustment for the multiplicity of secondary endpoints.
All secondary PD endpoints will be summarized for baseline, post-dose, and change from 
baseline by treatment.
7.9
Pharmacokinetic Analysis
Plasma concentrations of TAK-831 will be listed for each subject and summarized by each time 
point for each dose and period 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 will be explored. As appropriate, historical data may be used in 


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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 may be reported separately.
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
The Safety Set will be used for all summaries of safety parameters. These summaries will be 
presented by placebo, each TAK-831 dose level, and TAK-831 overall (as appropriate). 
7.11.1
Adverse Events
Verbatim terms will be coded by SOC and PT using MedDRA (version 20.0 or later).
TEAEs will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occur after the first dose of study drugs. TEAEs with onset 
occurring within 30 days (onset date – last date of dose +1≤30) after study drug administration 
will be included in the summary tables. All AEs will be included in the listings.
TEAEs will be summarized by treatment. TEAE will only be included for the treatment 
administered in the Period of its start date, unless it increases in intensity in the following Period, 
in which case will be handled as a new TEAE on the second treatment.
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary. An exception to the previous rule is if the TEAE begins in Period 1 but increases 
in intensity in Period 2, in which case it will be summarized as separate TEAEs.
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, including 
number of subjects and events.

Treatment-Emergent Adverse Events by Preferred Term.


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
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term, 
including number of subjects and events.

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term.

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.

Drug-Related Treatment-Emergent Adverse Events by Preferred Term.

Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.

Pretreatment Adverse Events by System Organ Class and Preferred Term.

Most Frequent (>5% ) Non-Serious Adverse Events by System Organ Class and Preferred 
Term.

Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term.
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for pretreatment AEs, TEAEs, TEAEs leading to study drug 
discontinuation, liver function abnormalities, serious adverse events (SAEs), and AEs that 
resulted in death. AEs happened after 31 days post the last dose of the study drug will be listed as 
well.
7.11.2
Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. Refer to Protocol 
Section 9.2.17 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. For test results 
not in SI units, the conversion to SI units will be done in the derived SDTM and ADaM datasets 
using the known conversion factors. If necessary, SI units from the central laboratory may be 
converted to Takeda’s preferred SI units in the derived SDTM and ADaM datasets. All 
summaries and analyses will be based on the values using these preferred SI units.
Only observations within 3 days of the last dose of study drug will be included in the tables, with 
the exception of observations from the Early Termination Visit. 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 by treatment. Baseline from each period 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 


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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 by treatment. 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.
Also, the elevated hepatic parameters will be summarized by treatment.
Listings of all clinical safety laboratory data will be provided in Appendix 16.2 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 sequence, 
study period/visit, and sample collection date.
7.11.3
Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Summaries will be by treatment. Baseline from each period will be 
used for change from baseline. Only observations within 3 days of the study drug will be 
included in the tables, with the exception of observations from the Early Termination Visit.
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 by treatment. 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 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 sequence, study period/visit, and sample collection date.
7.11.4
12-Lead ECGs
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria will be summarized by treatment and provided in the data 
listings. Baseline from each period will be used for change from baseline. 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.
7.11.5
Other Observations Related to Safety
Physical examination findings will be presented in the data listings. C-SSRS will be summarized 
by treatment.


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7.12
Interim Analysis
A planned unblinded interim analysis of the primary PD endpoints will be conducted when 
approximately 14 patients have been completed the primary endpoint. The site will be allowed to 
continue enrollment to the high/placebo comparison, with the goal that approximately 16 patients 
will be randomized by the time the interim analysis is complete. (The additional approximately 
2 subjects will be included in the final analysis but not the interim analysis.) The interim PD 
analysis will be to determine whether to continue enrolling subjects to the high-dose/placebo 
comparison or switch enrollment to the low-dose/placebo comparison.
The Bayesian normal linear model described in Section 7.8.1 will be performed for the primary 
endpoint. “Success Stop criteria” at interim analysis is 70% posterior probability (or greater) of a 
difference between 500 mg TAK-831 and placebo >0.6 (on logit scale), and a decision of 
switching to the low dose will be made when “Success Stop criteria” are met. “Futility Stop 
criteria” will be met if the posterior probability of a difference between 500 mg TAK-831 and 
placebo >0.1 (on logit scale) is less than 30%, and a decision of switching to the low dose will be 
made. If none of the aforementioned criteria are met, a decision of continuing enrolling high-
dose/placebo subjects (“Continue” decision) will be made.
In addition, a decision to switch to the low dose may be made based on the safety or tolerability 
of the high dose.
7.13
Changes in the Statistical Analysis Plan 
The primary endpoint will be tested individually for each of the two doses against 5% (one-sided) 
level of significance.
The summaries of safety parameters will be presented by placebo, each TAK-831 dose level, and 
TAK-831 overall (as appropriate), rather than by cohort as stated in the protocol.
To increase statistical efficiency, baseline will be used as a covariate in the Bayesian normal 
linear model described in Section 7.8.1.
8.0
REFERENCES
[1] A. R. Bolbecker, W. P. Hetrick, J. K. Johannesen, B. F. O'Donnell, J. E. Steinmetz and A. S. 
Shekhar, "Secretin effects on cerebellar-dependent motor learning in schizophrenia," Am J 
Psychiatry, vol. 166, no. 4, pp. 460-6, 2009. 
[2] R. S. Keefe, P. D. Harvey, T. E. Goldberg, J. M. Gold, T. M. Walker, C. Kennel and K. 
Hawkins, "Norms and standardization of the Brief Assessment of Cognition in Schizophrenia 
(BACS)," Schizophr Res, vol. 102 , no. 1-3, pp. 108-115, 2008. 


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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 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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