Clinical trial NCT03706469
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Neurocrine Biosciences
Start date: 2018-10-18; Completion date: 2018-12-22
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the oral BA of TAK-831 T3 tablet formulation relative to TAK-831 T2 tablet formulation under fasting conditions and to assess the effect of food on the pharmacokinetics (PK) of TAK-831 T3 tablet formulation.

Detailed description:
The drug being tested in this study is called TAK-831. TAK-831 is being tested in healthy participants to evaluate the relative BA and effect of food on the PK of TAK-831 tablet formulation.

The study will enroll approximately 16 participants. Participants will be randomly assigned (by chance, like flipping a coin) to TAK-831 in 1 of the 4 treatment sequences as following:

* T2 50 mg Fasted + T3 50 mg Fasted + T3 600 mg Fasted + T2 600 mg Fasted + T3 600 mg Fed
* T3 50 mg Fasted + T2 600 mg Fasted + T2 50 mg Fasted + T3 600 mg Fasted + T3 600 mg Fed
* T2 600 mg Fasted + T3 600 mg Fasted + T3 50 mg Fasted + T2 50 mg Fasted + T3 600 mg Fed
* T3 600 mg Fasted + T2 50 mg Fasted + T2 600 mg Fasted + T3 50 mg Fasted + T3 600 mg Fed

All participants will be asked to take tablet of assigned TAK-831 on Day 1 of each treatment period.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 70 days. Participants will make multiple visits to the clinic and will be contacted by clinic approximately 14 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-831 T2 50 milligram (mg), tablet, orally, once, under fasted condition on Day 1 of Treatment Period 1, followed by TAK-831 T3 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 2, followed by TAK-831 T3 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 3, followed by TAK-831 T2 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 4, further followed by TAK-831 T3 600 mg, tablet, orally, once, under fed condition on Day 1 of Treatment Period 5. There will be a washout period of at least 7 days between study drug in-take in subsequent treatment periods. arm 2: TAK-831 T3 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 1, followed by TAK-831 T2 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 2, followed by TAK-831 T2 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 3, followed by TAK-831 T3 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 4, further followed by TAK-831 T3 600 mg, tablet, orally, once, under fed condition on Day 1 of Treatment Period 5. There will be a washout period of at least 7 days between study drug in-take in subsequent treatment periods. arm 3: TAK-831 T2 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 1, followed by TAK-831 T3 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 2, followed by TAK-831 T3 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 3, followed by TAK-831 T2 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 4, further followed by TAK-831 T3 600 mg, tablet, orally, once, under fed condition on Day 1 of Treatment Period 5. There will be a washout period of at least 7 days between study drug in-take in subsequent treatment periods. arm 4: TAK-831 T3 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 1, followed by TAK-831 T2 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 2, followed by TAK-831 T2 600 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 3, followed by TAK-831 T3 50 mg, tablet, orally, once, under fasted condition on Day 1 of Treatment Period 4, further followed by TAK-831 T3 600 mg, tablet, orally, once, under fed condition on Day 1 of Treatment Period 5. There will be a washout period of at least 7 days between study drug in-take in subsequent treatment periods.
Interventions: intervention 1: TAK-831 T2 intervention 2: TAK-831 T3
Intervention descriptions: intervention 1: TAK-831 T2 Tablets. intervention 2: TAK-831 T3 Tablets.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Open-Label, Randomized, Single Dose, 5-Period, 5-Treatment, Study to Evaluate 
the Relative Bioavailability and Effect of Food on TAK-831 Tablet Formulations in Healthy 
Subjects
NCT Number: NCT03706469
Protocol Approve Date: 28 September 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-Label, Randomized, Single Dose, 5-Period, 5-Treatment, Study to Evaluate 
the Relative Bioavailability and Effect of Food on TAK-831 Tablet Formulations in Healthy 
Subjects
Study Identifier:
TAK-831-1006
Compound:
TAK-831
Date:
28 September 2018
Version/Amendment 
Number:
Final Protocol
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................14
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................15
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................19
4.3
Benefit/Risk Profile .................................................................................................19
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................21
5.1
Hypothesis...............................................................................................................21
5.2
Trial Objectives .......................................................................................................21
5.2.1
Trial Primary Objectives ....................................................................................21
5.2.2
Trial Secondary Objective..................................................................................21
5.3
Endpoints.................................................................................................................21
5.3.1
Primary Endpoints .............................................................................................21
5.3.2
Secondary Endpoint ...........................................................................................22
5.3.3
Exploratory Endpoints .......................................................................................22
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................23
6.1
Trial Design.............................................................................................................23
6.2
Dose Escalation .......................................................................................................24
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................24
6.3.1
Rationale of Trial Design ...................................................................................24
6.3.2
Rationale for Dose .............................................................................................25
6.3.3
Rationale for Endpoints......................................................................................26
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................26
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................26
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6.5
Trial Beginning and End/Completion.......................................................................26
6.5.1
Definition of Beginning of the Trial ...................................................................26
6.5.2
Definition of End of the Trial.............................................................................26
6.5.3
Definition of Trial Completion...........................................................................26
6.5.4
Definition of Trial Discontinuation ....................................................................27
6.5.5
Criteria for Premature Termination or Suspension of the Trial............................27
6.5.6
Criteria for Premature Termination or Suspension of a Site................................27
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............28
7.1
Excluded Medications, Supplements, Dietary Products............................................28
7.2
Diet, Fluid, Activity.................................................................................................29
7.2.1
Diet and Fluid ....................................................................................................29
7.2.2
Activity..............................................................................................................30
7.3
Criteria for Discontinuation or Withdrawal of a Subject...........................................30
7.4
Procedures for Discontinuation or Withdrawal of a Subject......................................31
7.5
Subject Replacement................................................................................................31
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................32
8.1
Clinical Study Drug .................................................................................................32
8.1.1
TAK-831 T2 Tablets..........................................................................................32
8.1.2
TAK-831 T3 Tablets..........................................................................................32
8.1.3
Clinical Study Drug Labeling.............................................................................32
8.1.4
Clinical Study Drug Inventory and Storage ........................................................32
8.1.5
Clinical Study Drug Blinding.............................................................................33
8.1.6
Randomization Code Creation and Storage ........................................................33
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................33
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs...............................33
9.0
STUDY PROCEDURES...............................................................................................34
9.1
Administrative Procedures.......................................................................................34
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9.1.1
Informed Consent Procedure..............................................................................34
9.1.2
Inclusion and Exclusion .....................................................................................35
9.1.3
Medical History/Demography ............................................................................38
9.1.4
Concomitant Medications...................................................................................39
9.2
Clinical Procedures and Assessments.......................................................................39
9.2.1
Full Physical Examination..................................................................................39
9.2.2
Height and Weight .............................................................................................39
9.2.3
BMI ...................................................................................................................39
9.2.4
Vital Signs .........................................................................................................40
9.2.5
12-Lead ECG.....................................................................................................40
9.2.6
Columbia Suicidality Symptoms Rating Scale....................................................40
9.2.7
Study Drug Administration ................................................................................41
9.2.8
AE Monitoring...................................................................................................42
9.2.9
Laboratory Procedures and Assessments ............................................................42
9.3
PK Samples .............................................................................................................44
9.3.1
PK Measurements..............................................................................................45
9.3.2
Biomarker Measurements...................................................................................46
9.3.3
PGx Measurements ............................................................................................46
9.3.4
Confinement ......................................................................................................46
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions and Elements of AEs .............................................................................47
10.1.1 SAEs..................................................................................................................50
10.1.2 Special Interest AEs...........................................................................................51
10.2
AE Procedures.........................................................................................................51
10.2.1 Assigning Severity of AEs .................................................................................51
10.2.2 Assigning Causality of AEs................................................................................52
10.2.3 Start Date...........................................................................................................52
10.2.4 End Date............................................................................................................52
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10.2.5 Pattern of Adverse Event (Frequency)................................................................53
10.2.6 Action Taken With Study Treatment..................................................................53
10.2.7 Outcome ............................................................................................................53
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs............................54
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....56
11.0
STATISTICAL METHODS..........................................................................................58
11.1
Statistical and Analytical Plans ................................................................................58
11.1.1 Analysis Sets......................................................................................................58
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................58
11.1.3 PK Analysis .......................................................................................................58
11.1.4 Ratios and Confidence Intervals.........................................................................59
11.1.5 PD Analysis .......................................................................................................60
11.1.6 Safety Analysis ..................................................................................................60
11.2
Interim Analysis and Criteria for Early Termination ................................................61
11.3
Determination of Sample Size..................................................................................61
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................62
12.1
Study-Site Monitoring Visits ...................................................................................62
12.2
Protocol Deviations..................................................................................................62
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................62
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 Trial Registration Policy.................................67
13.4.1 Publication and Disclosure.................................................................................67
13.4.2 Clinical Trial Registration..................................................................................68
13.4.3 Clinical Trial Results Disclosure ........................................................................68
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13.5
Insurance and Compensation for Injury....................................................................69
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................70
14.1
Administrative Information......................................................................................70
14.1.1 Study Contact Information .................................................................................70
14.1.2 INVESTIGATOR AGREEMENT......................................................................71
14.1.3 Study-Related Responsibilities...........................................................................72
14.1.4 List of Abbreviations .........................................................................................72
15.0
DATA HANDLING AND RECORDKEEPING............................................................75
15.1
CRFs (Electronic and Paper)....................................................................................75
15.2
Record Retention .....................................................................................................76
16.0
REFERENCES..............................................................................................................77
17.0
APPENDICES...............................................................................................................79
LIST OF IN-TEXT TABLES
Table 6.a
Planned TAK-831 Doses....................................................................................24
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................29
Table 9.a
Sequence Groups ...............................................................................................34
Table 9.b
Primary Specimen Collections ...........................................................................45
Table 10.a
Takeda Medically Significant AE List................................................................51
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................79
Appendix B
Elements of the Subject Informed Consent.........................................................81
Appendix C
Investigator Consent to the Use of Personal Information ....................................85
Appendix D
Pregnancy and Contraception.............................................................................87
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1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge, Massachusetts USA 02139
Telephone: +1 (617) 679-7000
Compound:
TAK-831
Study Identifier: TAK-831-1006 (CA24822)
Phase: 1
Protocol Title: A Phase 1, Open-Label, Randomized, Single Dose, 5-Period, 5-Treatment Study to Evaluate the 
Relative Bioavailability and Effect of Food on TAK-831 Tablet Formulations in Healthy Subjects
Trial Design:
An open-label, 5-period, 5-treatment, relative bioavailability (BA) and food-effect study in 16 healthy adult subjects. 
On Day 1 of each treatment period subjects will receive a single oral dose of TAK-831. In Treatment Periods 1-4, each 
subject will receive two dose levels of the T2 formulation and two dose levels of the T3 formulation under fasted
conditions, per the randomization schedule, to assess the relative BA of the two formulations. In Treatment Period 5, 
all subjects will receive a single oral dose of T3 formulation under fed conditions, in order to assess the food effect. In 
each treatment period, serial blood samples will be collected for 72 hours postdose to determine the pharmacokinetics 
(PK) of TAK-831 in plasma following administration of different formulations and/or different feeding conditions.
There will be a washout period of at least 7 days between each dose of study drug (s).
The clinic will contact all subjects (including subjects who terminate the study early) approximately 14 days after the 
last study drug administration to determine if any adverse events have occurred since the last study visit.
Trial Primary Objectives:

To assess the oral BA of TAK-831 T3 tablet formulation relative to TAK-831 T2 tablet formulation under fasting 
conditions.

To assess the effect of food on the PK of TAK-831 T3 tablet formulation.
Secondary Objectives:

To determine the safety and tolerability of single doses of TAK-831 T2 and T3 tablet formulations.
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Trial Subject Population: Healthy adult male and female subjects
Planned Number of Subjects:
16
Planned Number of Sites:
1
Dose Levels:
Treatment A (Reference, Fasted): 
50 mg TAK-831 T2 (2 x 25 mg T2 tablets) under fasted 
conditions
Treatment B (Test, Fasted): 
50 mg TAK-831 T3 (2 x 25 mg T3 tablets) under fasted 
conditions
Treatment C (Reference, Fasted): 
600 mg TAK-831 T2 (6 x 100 mg T2 tablets) under 
fasted conditions
Treatment D (Test, Fasted): 
600 mg TAK-831 T3 (2 x 300 mg T3 tablets) under 
fasted conditions
Treatment E (Test, Fed): 
600 mg TAK-831 T3 (2 x 300 mg T3 tablets) under fed 
conditions
Route of Administration:
Oral
Duration of Treatment:
On Day 1 of each treatment period, subject will receive 
a single oral dose of assigned TAK-831 formulation.
Planned Trial Duration:
Approximately 70 days including screening period
Main Criteria for Inclusion:
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study: 
1.
Healthy, adult, male or female, 19-55 years of age, inclusive, at screening.
2.
Body mass index (BMI) ≥18.0 and ˂ 30.0 kg/m2 at screening 
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3.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs or electrocardiographs (ECGs), as deemed by the Investigator or designee.
4.
For a female of childbearing potential, use one of the following acceptable birth control methods:

Surgical sterilization of the partner (vasectomy for 4 months minimum prior to the first dosing).

Physical barrier method (eg, condom, diaphragm) with spermicide for at least 14 days prior to the first dosing 
and throughout the study.
In addition, female subjects of childbearing potential will be advised to remain sexually inactive or to keep the 
same birth control method for at least 35 days following the last dose/dosing.
5.
For a female of non-childbearing potential, females must have undergone one of the following sterilization 
procedures at least 6 months prior to the first dosing:

hysteroscopic sterilization (with confirmation from the subject that follow-up hysterosalpingogram was 
conducted);

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and follicle-stimulating hormone 
(FSH) serum levels consistent with postmenopausal status.
6.
A non-vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse 
during the study until 95 days after the last dosing. (No restrictions are required for a vasectomized male provided 
his vasectomy has been performed 4 months or more prior to the first dosing of study drug. A male who has been 
vasectomized less than 4 months prior to study first dosing must follow the same restrictions as a 
non-vasectomized male).
7.
If male, must agree not to donate sperm from the first dosing until 95 days after the last dosing.
8.
Able to swallow multiple tablets.
9.
Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the 
protocol.
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Main Criteria for Exclusion:
Subjects must not be enrolled in the study if they meet any of the following criteria:
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the
Investigator or designee.
3.
History or presence of gastritis, gastrointestinal tract, or hepatic disorder or other clinical condition which, in the 
opinion of the Investigator or designee, may affect the absorption, distribution, metabolism, or elimination of 
study drug. 
4.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study 
or poses an additional risk to the subject by their participation in the study.
5.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
6.
History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related compounds.
7.
Smokes more than 20 cigarettes or equivalent per day within 3 months prior to the first dose and is unwilling to 
discontinue use of any tobacco- or nicotine-containing products during the confinement period(s) of the study.
8.
Has a risk of suicide according to the Investigator’s clinical judgment (eg, per Columbia–Suicide Severity Rating 
Scale [C-SSRS]), or has made a suicide attempt in the previous year prior to screening.
9.
Female subjects with a positive pregnancy test or who are lactating.
10. Positive urine drug or alcohol results at screening or first check-in.
11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or 
hepatitis C virus (HCV).
12. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
13. Seated heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening.
14. Orthostatic vital sign results with a decrease in systolic > 20 mmHg or decrease in diastolic > 10 mmHg, and 
increase in pulse of > 20 bpm.
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15. Corrected QT interval using Fridericia’s formula (QTcF) interval is >460 msec (males) or >470 msec (females) or 
ECG findings are deemed abnormal with clinical significance by the Investigator or designee at screening.
16. Estimated creatinine clearance <80 mL/min at screening.
17. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements 
within 14 days prior to the first dosing and throughout the study, including the follow-up period. Thyroid 
hormone replacement medication may be permitted if the subject has been on the same stable dose for the 
immediate 3 months prior to first study drug administration. After the first dose of study drug, ibuprofen (up 
to 1.2 g per 24 hours) may be administered at the discretion of the Investigator or designee.

Any drugs known to be significant inducers of uridine diphosphate glucuronosyltransferase (UGT) or 
sulfotransferase (SULT), including St. John’s Wort, within 28 days prior to the first dosing and throughout 
the study, including the follow-up period. Appropriate sources (eg, Flockhart TableTM) will be consulted to 
confirm lack of PK/pharmacodynamics interaction with study drug.
18. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 
30 days prior to the first dosing and throughout the study.
19. Is lactose intolerant or unable/unwilling to eat the high-fat breakfast.
20. Donation of blood or significant blood loss within 56 days prior to the first dosing.
21. Plasma donation within 7 days prior to the first dosing.
22. Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be derived 
from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of Treatment 
Period 1 of the current study.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:
The following PK parameters of TAK-831 derived after a single dose of TAK-831 on Day 1 of each treatment period:

Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration 
(AUClast)

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf)

Maximum observed plasma concentration (Cmax)
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The secondary endpoint of the study is:
!
Percentage of subjects who experience at least 1 treatment emergent adverse event (TEAE)
The exploratory endpoints of the study are:
Statistical Considerations:
Individual TAK-831 plasma concentration data and PK parameters will be listed by subject and treatment, and 
summarized by treatment (TAK-831 plasma concentrations and PK parameters) and nominal time (TAK-831 plasma 
concentrations).
An analysis of variance (ANOVA) will be performed on the natural-log (ln)-transformed AUClast, AUC0-inf and 
Cmax as follows:
!
Relative bioavailability (Treatments A-D):
The ANOVA model will include sequence, treatment, and treatment period as fixed effects, and subject nested 
within sequence as a random effect. Each ANOVA will include calculation of least square means (LSM) as well 
as the difference between treatment LSM.
!
Food Effect (Treatments D and E):
The ANOVA model will have treatment as a fixed-effect and subject as a random-effect to account for the 
correlation between the repeated measures on each subject.
Ratios of LSM will be calculated using the exponentiation of the difference between treatment LSM from the analyses 
on the ln-transformed AUClast, AUC0-inf, and Cmax. These ratios will be expressed as a percentage relative to the 
reference treatments.
Consistent with the two one-sided test, 90% confidence intervals (CIs) for the ratios will be derived by exponentiation 
of the CIs obtained for the difference between treatment LSM resulting from the analyses on the ln-transformed 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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AUClast, AUC0-inf, and Cmax. The CIs will be expressed as a percentage relative to the reference treatments.
Bioequivalence (Treatment B versus Treatment A and Treatment D versus Treatment C) will be claimed if the 
90% CIs of the ratios of LSMs of the ln-transformed PK parameters AUClast, AUC0-inf, and Cmax of TAK-831 fall 
entirely within 80.00-125.00%.
Sample Size Justification:
A total 16 subjects will be randomized into 4 sequence groups in a ratio of 1:1:1:1. Assuming there are no more than 
1 dropout in each sequence group, this will provide at least 12 observations for each of Treatments A, B, C and D. 
Based on the intra-subject variability (CV = 24.49%) of AUC from Study TAK-831-1004, this provides a two-sided 
90% CI of the central value ratios (Treatment B versus Treatment A or Treatment D versus Treatment C) of 
(0.8484, 1.1787) if the observed central value ratio is 1. If the observed central value ratio is 1.2, the 90% CI will be 
(1.0180, 1.4144).
The study design will also provide at least 12 observations for each of Treatments D and E, which will provide a 
two-sided 90% CI of the central value ratios (Treatment E versus Treatment D) of (0.8799, 1.1365) if the observed 
central value ratio is 1. If the observed central value ratio is 1.6, the two-sided 90% CI will be (1.4078, 1.8184).
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2.0
STUDY SCHEMATIC
Pretreatment
Treatment Periods 1-5
Study Exit (a)
Follow up (b)
Screening
Predose 
Assessments
Dosing and
Study Assessments
Safety and PK 
Assessments
Within 
28 days prior 
to first dosing
Day -1
Day 1
Day 1-2 
Days 3-4
Day 4 of 
Treatment 
Period 5
14 (±2) days 
after last dose
Outpatient 
Visit
Confinement (a) (c)
Outpatient Visits
(a) At all times, a subject may be required to remain at the clinical research unit for longer at the discretion of the
Investigator or designee.
(b) The clinic will contact all subjects (including subjects who terminate the study early) approximately 14 days after 
the last study drug administration to determine if any adverse events have occurred since the last study visit.
(c) Subjects will start the confinement on Day -1 and be released from confinement after Day 2 study assessments are 
complete and will return to the study site on Day 3 and Day 4 for subsequent safety and PK assessments; There 
will be a washout period of at least 7 days between each dose.
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3.0
SCHEDULE OF STUDY PROCEDURES 
Study Procedures a
S b
Study Days in Each Treatment Period c
ET d
FU 
e
Days →
-1
1
2
3
4
Hours →
C-I f
P
0
0.25 0.5
1
1.5
2
3
4
5
6
8
10
12
24
48
72
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X g
Medical History
X
Safety Evaluations
Full Physical Examination h
X
Height
X
Weight
X
X i
12-Lead Safety ECG
X
X j
X
X
X
X
Vital Signs (heart rate and blood pressure)
X
X j
X
X
X
X
Orthostatic Vital Signs (heart rate and blood pressure)
X
Vital Signs (respiratory rate and temperature)
X
Hematology, Serum Chemistry k, and Urinalysis
X
X
X
X
Serum Pregnancy Test (females only)
X
X
X l
X 
Serum FSH (postmenopausal females only)
X
Urine Drug and Alcohol Screen
X
X
HIV/Hepatitis Screen
X
C-SSRS Questionnaire m
X
X
X
X
AE Monitoring
X
Concomitant Medication Monitoring
X
X
Study Drug Administration / Pharmacokinetics
TAK-831 Administration
X
Blood for TAK-831 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Procedures
Confinement in the CRU n
X
Visit and Return Visits
X
X
X
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a
For details on Procedures, refer to Section 9.2.
b
Within 28 days prior to the first study drug administration.
c
There will be a washout period of at least 7 days between doses.
d
To be performed prior to early termination from the study.
e
The clinic will contact all subjects (including subjects who terminate the study early) approximately 14 days after the last study drug administration to 
determine if any adverse events have occurred since the last study visit.
f
Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU. If the CRU decides to confine the subjects throughout the study, some safety 
events at check-in (eg, clinical laboratory tests, urine drug and alcohol screen, serum pregnancy test, vital signs, and ECGs) may not be performed at the
Investigator’s discretion.
g
To be performed in Treatment Period 1 only.
h
Symptom-driven physical examination may be performed at other times, at the Investigator’s or designee’s discretion.
i
If screening assessment was conducted within 4-7 days prior to dosing (Day 1), weight assessment will be conducted at check-in only if in the opinion of the
Investigator there is no reason to believe they have substantially changed.
j
To be performed within 24 hours prior to dosing.
k
Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 
8 hours prior to the serum chemistry sample being taken. Coagulation tests (PT/INR) will be performed if subjects has on-study aspartate aminotransferase or 
alanine aminotransferase elevated ≥3x the upper limit of normal.
l
To be performed at the end of Treatment Period 5 only.
m
At screening the C-SSRS Baseline/Screening version will be administered; at all other time points, the Since Last Visit version will be administered.
n
As per site preference, subjects may be confined throughout the washout period.
Abbreviations: AE = Adverse events, C-I = Check-in, C-SSRS = Columbia Suicidality Symptoms Rating Scale, CRU = Clinical research unit, 
ECG = Electrocardiogram, ET = Early termination, FU = Follow-up, HIV = Human immunodeficiency virus, P = Predose,
PK = Pharmacokinetics, 
PT/INR = Prothrombin time/International normalized ratio, S = Screening.
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4.0
INTRODUCTION
4.1
Background
Ataxia constitutes a neurological sign consisting of a lack of voluntary coordination of muscle 
movements. It is a nonspecific clinical manifestation implying dysfunction of the parts of the 
central nervous system that coordinate movement, such as the cerebellum [1]. The most common 
hereditary ataxia (approximately 50% of cases) is Friedreich ataxia (FRDA), a debilitating, 
life-shortening, and degenerative multiple system disorder [2,3]. Patients with FRDA has a 
guanine-adenine-adenine trinucleotide repeat expansion mutation in intron 1 of the frataxin gene 
and suffer from drastically reduced levels of the frataxin protein [4, 5], which in turn leads to 
neurodegeneration, cardiomyopathy, diabetes mellitus and skeletal deformities [3]. The sensory 
ataxia component of FRDA involves progressive loss of coordination and muscle strength leads to 
motor incapacitation However, there is currently no cure or approved effective treatment for any of 
the hereditary ataxias [1]. Thus, there is a great need to identify and develop effective therapies for 
patient populations with ataxia.
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and 
behaves, including hallucinations, delusions, psychosis (positive symptoms), lack of motivation 
and reduced social interaction (negative symptoms), and poor information processing, impaired 
ability to focus on objectives, and abnormalities of working memory and learning (cognitive 
symptoms) [7]. 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 [8]. 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 [9-12]. D-serine has been demonstrated to be a co-agonist of NMDA glutamate 
receptors that, along with glutamate, mediates NMDA receptor transmission, synaptic plasticity 
and other physiologic functions. D-serine is also a known endogenous ligand for the δ2 glutamate 
receptor which has been implicated in synaptic plasticity and long-term depression [1]. Adding to 
the above evidence of a potential role of D-amino acid oxidase (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 
[713].
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TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase, a peroxisomal 
enzyme active toward neutral D-amino acids and associated with the metabolism of D-serine. 
TAK-831 was shown to increase D-serine levels in the cerebellum of normal mice and to be 
efficacious in a mouse model of FRDA. 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 FRDA, cognitive impairment associated with schizophrenia, and negative 
symptoms of schizophrenia [14].
Pharmacokinetics
Four phase 1 clinical studies have been conducted in healthy subjects. TAK-831 was rapidly 
absorbed following both single-dose (10 to 750 mg) and multiple-dose (30 to 1200 mg) oral 
administration of suspension or tablet formulation under fasting conditions. TAK-831 plasma 
concentration generally reached maximal levels within median 0.25 to 2 hours after dosing. 
Exposure was generally dose dependent with mean t½ values ranging from 6 to 23 hours across the 
dose range studied. Accumulation was negligible, and steady-state was attained by the fourth day 
of daily dosing.
The effect of food on the PK profile of two TAK-831 tablet formulations (T1 and T2) was 
investigated. Under fasting conditions, TAK-831 mean Cmax and AUC values following oral 
administration of a single 100 mg dose of the T1 tablet formulation were lower  approximately 
64% and 50%, respectively, when compared to those of the oral suspension. Coadministration of 
TAK-831 T1 tablet with a standard Food and Drug Administration (FDA) high-calorie high-fat 
breakfast increase mean Cmax and AUC0-inf values by approximately 2-fold. The exposure of 
TAK-831 is similar between T2 and T1 tablet under fasting conditions. The relative bioavailability 
estimates of TAK-831 T2 tablet 400 mg under fed (nutrition drink) versus fasted conditions 
showed that nutrition drink had minimal effect on TAK-831 exposure. 
Safety
To date, TAK-831 has been administered to a total of 117 healthy subjects in 3 completed phase 1 
studies (TAK-831-1001, TAK-831-1003, and TAK-831-1004); 88 subjects received single doses 
ranging from 10 to 750 mg and 29 subjects received multiple doses ranging from 30 to 400 mg for 
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up to 13 days. TAK-831 or placebo have been administered to an additional 33 healthy subjects 
across 4 cohorts in the ongoing blinded TAK-831-1005 study at doses ranging from 100 to 
1200 mg once daily (QD) for 14 days.
TAK-831 was considered safe and well tolerated after multiple oral doses administered to healthy 
subjects up to and including 1200 mg QD (conclusions for doses of 600 to 1200 mg QD are based 
on preliminary blinded AE data reported by the Investigator and blinded safety endpoint data). 
Headache and nausea were the most commonly reported TEAE potentially related to treatment; 
AEs that were mild to moderate in intensity and generally self-limiting. Postural dizziness was also 
reported, however, the rate of postural dizziness in TAK-831–treated subjects did not markedly 
differ from the rate observed in placebo-treated patients. There were no concerning trends in 
laboratory, ECG, or vital sign data.
Refer to the Investigator’s Brochure (IB) for detailed background information on TAK-831 [14].
4.2
Rationale for the Proposed Study
The ongoing Phase 2 proof of concept studies in patients with schizophrenia or Friedrich ataxia 
currently use the T2 tablet formulation of TAK-831. The newly developed T3 tablet formulation 
will be used in the planned Phase 3 studies of TAK-831. The purpose of this study is to compare 
the PK of TAK-831 following a single oral dose of the T3 and T2 tablet formulations under fasting 
conditions. In addition, the effect of food on TAK-831 PK will be investigated for the T3 
formulation.
4.3
Benefit/Risk Profile
The dose of study drug administered in this study is not anticipated to induce any potential risk or
benefit to subjects participating in this study, as it is a single dose administered according to the 
dosing recommendations found in the IB [14].
The safety monitoring practices employed by this protocol (ie, 12-lead ECG, vital signs, C-SSRS, 
clinical laboratory tests, AE questioning, and physical examination) are adequate to protect the 
subjects’ safety and should detect all expected TEAEs.
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There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
NA
5.2
Trial Objectives
5.2.1
Trial Primary Objectives

To assess the oral BA of TAK-831 T3 tablet formulation relative to TAK-831 T2 tablet 
formulation under fasting conditions.

To assess the effect of food on the PK of TAK-831 T3 tablet formulation.
5.2.2
Trial Secondary Objective

To determine the safety and tolerability of single doses of TAK-831 T2 and T3 tablet 
formulations.
5.3
Endpoints
5.3.1
Primary Endpoints
The primary endpoint of the study is:
The following PK parameters of TAK-831 derived after a single dose of TAK-831 on Day 1 of 
each treatment period:

AUClast

AUC0-inf

Cmax
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5.3.2
Secondary Endpoint
The secondary endpoint will be assessed through evaluation of the following parameters:
!
Percentage of subjects who experience at least 1 TEAE.
5.3.3
Exploratory Endpoints
The exploratory endpoints of the study are:
CCI
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Page 23 of 90
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
An open-label, 5-period, 5-treatment, relative BA and food-effect study in 16 healthy adult 
subjects. 
Screening of subjects will occur within 28 days prior to the first dosing
On Day 1 of each treatment period, subjects will receive a single dose of study drug. In Treatment 
Periods 1-4, each subject will receive two dose levels of the T2 formulation and two doses of the 
T3 formulation under fasted, per the randomization schedule, to assess the relative BA of the two 
formulations. In Treatment Period 5, all subjects will receive a single oral dose of T3 formulation 
under fed conditions, in order to assess the food effect. In each treatment period, serial blood
samples will be collected for 72 hours postdose to determine the PK of TAK-831 in plasma 
following administration of different formulations and/or different feeding conditions.
There will be a washout period of at least 7 days between each dose of study drug.
The clinic will contact all subjects (including subjects who terminate the study early) 
approximately 14 days after the last study drug administration to determine if any adverse events 
have occurred since the last study visit.
Please refer to Section 2.0 for study schematics.
The planned dose levels of TAK-831 to be evaluated are outlined in Table 6.a.
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Study ID TAK-831-1006
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Final Protocol 
28 September 2018
Table 6.a
Planned TAK-831 Doses
Formulation
Dose
Treatment/meal condition (a)
Treatment A
T2
50 (2 x 25 mg tablets)
Fasted (b)
Treatment B
T3
50 (2 x 25 mg tablets)
Fasted (b)
Treatment C
T2
600 (6 x 100 mg tablets)
Fasted (b)
Treatment D
T3
600 (2 x 300 mg tablets)
Fasted (b)
Treatment E
T3
600 (2 x 300 mg tablets)
Fed (c)
(a) All study drugs will be administered orally with approximately 240 mL of water. 
(b) In Treatments A, B, C, and D, subjects will fast overnight for at least 10 hours prior to each study drug 
administration (see Section 7.2.1).
(c) In Treatment E, subjects will fast overnight for at least 10 hours until 30 minutes prior to their scheduled morning 
dose, when they will be given a high-fat breakfast which will be entirely consumed within 30 minutes (see Section 
7.2.1).
6.2
Dose Escalation
NA
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design 
Subjects in the study will receive a single dose of TAK-831 on Day 1 of each of the 5 treatment 
periods. Treatment Periods 1-4 will assess the bioavailability of TAK-831. A single-dose fasting 
study design using the highest strength of product is recommended as per the FDA’s draft 
Guidance for Industry on Bioavailability and Bioequivalence Studies Submitted in NDAs or 
IND - General Considerations [15]. 
 
 
 The TAK-831 T3 tablet is available as 25 mg or 300 mg
CCI
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ition
ion (a)
(
Ter
(b)
(b)
ble
Fasted
asted (b)
(
Fas
F
)
40 mL of
mL 
ight 
ht for
for
least 10
ast 10 h
fastst whic
wh
bjejeje
for
or Tria
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eri
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Gu


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tablets. 
 
 
 Additionally, some deviation from linearity in TAK-831 
exposures have been previously observed when administered as an oral suspension over the dose 
range of 10 to 750 mg. Consequently, the oral bioavailability of both strengths of the T3 tablet 
(50 mg as 2x 25 mg tablets and 600 mg as 2x 300 mg tablets) will be assessed relative to the 
existing 25 mg and 100 mg strengths of the T2 tablet formulation across the clinical dose range of 
TAK-831.
Furthermore, because co-administration with food increased TAK-831 systemic exposure in 
healthy subjects (TAK-831-1001), the effect of food on the PK of the new T3 tablet formulation 
will be assessed at the highest dose of TAK-831 expected to be used in clinical settings in 
accordance with FDA BA Food Effect Guidance for Industry.
In Treatment Periods 1-4, subjects will be randomized to treatment sequences to minimize 
assignment bias for the BA comparison of T3 versus T2 formulation. A crossover design is used to 
reduce the residual variability as every subject acts as their own control. In Treatment Period 5, the 
effect of food on the BA of the T3 formulation will be assessed in all subjects.
TAK-831 has an apparent mean terminal half-life (t½) of approximately 6 to 23 hours in human. 
Therefore, a minimum 7-day washout interval between the doses is sufficient to ensure that there is 
no drug carryover effect.
6.3.2
Rationale for Dose 
Two single dose levels (50 and 600 mg) have been selected for this study as they represent the 
therapeutic dose range currently tested in Phase 2 studies of TAK-831.
The highest dose of TAK-831 tested in healthy subjects was 1200 mg in oral suspension and was 
found to be safe and well tolerated. The exposure (both Cmax and AUC0-inf) of TAK-831 at this 
dose reached more than 2-fold exposure of 600 mg T2 tablet under the fasting condition and will 
provide adequate safety margin for the expected increase in systemic exposure for the 600 mg dose 
administered under fed condition.
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Te
TAK
A -83
over the
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of t
f he
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sessed 
essed r
the clini
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Term


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6.3.3
Rationale for Endpoints
NA
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this study, the blood collection for plasma TAK-831 concentrations is the critical procedure
and needs to be collected as close to the exact time point as possible.
6.4
Trial 
Design/Dosing/Procedures 
Modifications 
Permitted 
Within 
Protocol 
Parameters
The dose and administration of the study drug to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 6.5.5.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The beginning of the trial will be defined as the beginning of screening (ie, signing of the ICF) of 
the first subject.
6.5.2
Definition of End of the Trial
The end of study is defined as the date of the last scheduled study procedure (ie, follow-up phone 
call) as outlined in the Schedule of Study Procedures (Section 3.0).
6.5.3
Definition of Trial Completion
The end of the study is scheduled after completion of the evaluations in the follow-up phone call 
for the last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up.
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6.5.4
Definition of Trial Discontinuation
Celerion reserves the right to terminate the study in the interest of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.5.5
Criteria for Premature Termination or Suspension of the Trial
Celerion reserves the right to terminate the study in the interest of subject welfare.
Sponsor reserves the right to suspend or terminate the study at any time.
6.5.6
Criteria for Premature Termination or Suspension of a Site
NA
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 9.1.2.2. 
After the first dose of study drug, ibuprofen (up to 1.2 g per 24 hours) may be administered at the 
discretion of the Investigator or designee. Thyroid hormone replacement medication may be 
permitted if the subject has been on the same stable dose for the immediate 3 months prior to first 
study drug administration.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case-by-case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or nonprescription) or dietary products is outlined in Table
7.a.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Randomization 
(within 28 days prior to predose [Day 1])
Post-Randomization (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to dosing
Prohibited from 48 hours prior to 
dosing in each treatment period and 
throughout the period of PK sample 
collection.
Xanthine and/or caffeine
Prohibited from 24 hours prior to dosing (a)
Prohibited from 24 hours prior to 
dosing in each treatment period and 
throughout the period of PK sample 
collection (a).
Medications
See Section 7.1
See Section 7.1
Nicotine
Prohibited from check-in
Prohibited throughout confinement
Food substance
Poppy seeds
Prohibited from 96 days prior to dosing
Prohibited
Grapefruit/Seville orange
Prohibited from 14 days prior to dosing
Prohibited
(a) small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction.
7.2
Diet, Fluid, Activity 
7.2.1
Diet and Fluid
Water (except water provided with each oral dosing) will be restricted 1 hour prior to and 1 hour 
after each study drug administration, but will be allowed ad libitum at all other times. Other fluids 
may be given as part of meals and snacks but will be restricted at all other times throughout the 
confinement period.
In Treatments A, B, C, and D, subjects will fast overnight for at least 10 hours prior to each study 
drug administration and will continue to fast for at least 4 hours postdose.
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In Treatment E, subjects will fast overnight for at least 10 hours until 30 minutes prior to their 
scheduled morning dose, when they will be given a high-fat breakfast which will be entirely 
consumed within 30 minutes. Subjects will fast for at least 4 hours postdose on this day. If a meal 
is not fully consumed, the percentage of meal not consumed will be recorded.
An example of high-fat breakfast would be 2 slices of buttered toast, 2 eggs fried in butter, 2 strips 
of bacon, 4 ounces of hash brown potatoes, and 240 mL of whole milk. The clinical site may make 
minor modifications to the high-fat, high-calorie meal as long as the same meal is served to all 
subjects and the meal meets the high-fat, high-calorie criteria (~ 800-1000 calories with at least 
50% from fat) together with comparable meal volume and viscosity. The clinical site will 
document the amount of protein, carbohydrate, and fat and total calorie content of the test meal for 
the study file and provide a copy to the sponsor.
Each meal and/or snacks served at the clinical research unit (CRU) will be standardized and will be 
similar in caloric content and composition (except for the breakfast served as part of Treatment E) 
and will be taken at approximately the same time in each treatment period.
7.2.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when they 
are supine or semi-reclined for study procedures.
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the study.
Subjects will be prohibited from smoking during their confinement.
7.3
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the Investigator or designee for the 
following reasons:

AEs.
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
Difficulties in blood collection.

Positive drug or alcohol screen

Positive pregnancy test.
Any subject who experiences emesis within 2 hours postdose may be discontinued, excluded from 
the final data analysis, and may be replaced with a new subject.
A subject may be withdrawn by the Investigator (or designee) or the Sponsor if enrollment into the 
study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.
7.4
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 7.3. 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 as described in Section 3.0.
7.5
Subject Replacement
Discontinued subjects may be replaced at the discretion of the Sponsor and the Investigator.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
8.1.1
TAK-831 T2 Tablets
A single dose of 50 mg (2 x 25 mg tablets) or 600 mg (6 x 100 mg tablets) of TAK-831 T2 tablets 
will be administered in Treatments A and C of the study. 
TAK-831 T2 25 mg and 100 mg tablets are nonsterile, oral, tablet dosage forms, containing 25 mg 
and 100 mg (as freebase) of TAK-831, respectively. 
8.1.2
TAK-831 T3 Tablets
A single dose of (2 x 25 mg tablets) or 600 mg (2 x 300 mg tablets) of TAK-831 T3 tablets will be 
administered in Treatments B, D, and E of the study.
TAK-831 T3 25 mg and 300 mg tablets are nonsterile, oral, tablet dosage form, containing 25 mg 
and 300 mg (as freebase) of TAK-831, respectively.
8.1.3
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.4
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-831 products to allow completion of this 
study. 
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied. All TAK-831 products will be prepared and labeled by licensed pharmacy staff 
according to the procedures outlined in the pharmacy manual.
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8.1.5
Clinical Study Drug Blinding
This is an open-label study.
8.1.6
Randomization Code Creation and Storage 
Subjects will be randomized to 1 of 4 Treatment sequences in a 1:1:1:1 ratio (see Section 9.1.1.1) 
according to a randomization schedule will be generated by Celerion.
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure
NA
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs
At the conclusion of the study, any unused TAK-831 study drug will be retained by Celerion, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies 
remain, this fact will be documented in the pharmacy product accountability records.
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9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date an 
ICF summarizing the discussion prior to screening, and will be assured that they may withdraw 
from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique randomization identification number at the time of the first dosing, different from the 
screening number, and will receive the corresponding product.
Subjects will be randomized to 1 of 4 Treatment sequences in a 1:1:1:1 ratio. The sequences to be 
used in the randomization are detailed in Table 9.a below. Subjects will receive each treatment on 
one occasion.
Table 9.a
Sequence Groups
Sequences
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Treatment 
Period 4
Treatment 
Period 5
1 (n=4)
A
B
D
C
E
2 (n=4)
B
C
A
D
E
3 (n=4)
C
D
B
A
E
4 (n=4)
D
A
C
B
E
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
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9.1.1.2
Study Drug Assignment
This is a 5-period, 5-treatment crossover study. All subjects will receive each of the treatments on 
one occasion as detailed in Section 6.1.
9.1.2
Inclusion and Exclusion 
9.1.2.1
Inclusion Criteria
Subjects must fulfill all the following inclusion criteria to be eligible for participation in the study:
1. Healthy, adult, male or female, 19-55 years of age, inclusive, at screening.
2. Body mass index (BMI) ≥18.0 and ˂ 30.0 kg/m2 at screening. 
3. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee.
4. For a female of childbearing potential, use one of the following acceptable birth control 
methods:

Surgical sterilization of the partner (vasectomy for 4 months minimum prior to the first 
dosing).

Physical barrier method (eg, condom, diaphragm) with spermicide for at least 14 days prior 
to the first dosing and throughout the study.
In addition, female subjects of childbearing potential will be advised to remain sexually 
inactive or to keep the same birth control method for at least 35 days following the last 
dose/dosing.
5. For a female of non-childbearing potential, females must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dosing:

hysteroscopic sterilization (with confirmation from the subject that follow-up 
hysterosalpingogram was conducted);
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
bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and FSH 
serum levels consistent with postmenopausal status.
6. A non-vasectomized, male subject must agree to use a condom with spermicide or abstain from 
sexual intercourse during the study until 95 days after the last dosing. (No restrictions are 
required for a vasectomized male provided his vasectomy has been performed 4 months or 
more prior to the first dosing of study drug. A male who has been vasectomized less than 
4 months prior to study first dosing must follow the same restrictions as a non-vasectomized 
male).
7. If male, must agree not to donate sperm from the first dosing until 95 days after the last dosing.
8. Able to swallow multiple tablets.
9. Understands the study procedures in the ICF, and be willing and able to comply with the 
protocol.
9.1.2.2
Exclusion Criteria
Subjects must not be enrolled in the study if they meet any of the following criteria:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History or presence of gastritis, gastrointestinal tract, or hepatic disorder or other clinical 
condition which, in the opinion of the Investigator or designee, may affect the absorption, 
distribution, metabolism, or elimination of study drug. 
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4. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the study.
5. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related 
compounds.
7. Smoke more than 20 cigarettes or equivalent per day within 3 months prior to the first dose and 
is unwilling to discontinue use of any tobacco- or nicotine-containing products during the 
confinement period(s) of the study.
8. Has a risk of suicide according to the Investigator’s clinical judgment (eg, per C-SSRS), or has 
made a suicide attempt in the previous year prior to screening.
9. Female subjects with a positive pregnancy test or who are lactating.
10. Positive urine drug or alcohol results at screening or first check-in.
11. Positive results at screening for HIV, HBsAg, or HCV.
12. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
13. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
14. Orthostatic vital sign results with a decrease in systolic > 20 mmHg or decrease in diastolic 
> 10 mmHg, and increase in pulse of > 20 bpm.
15. QTcF interval is >460 msec (males) or >470 msec (females) or ECG findings are deemed 
abnormal with clinical significance by the Investigator or designee at screening.
16. Estimated creatinine clearance <80 mL/min at screening.
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17. Unable to refrain from or anticipates the use of:
Any drug, including prescription and non-prescription medications, herbal remedies, or 
vitamin supplements within 14 days prior to the first dosing and throughout the study, 
including the follow-up period. Thyroid hormone replacement medication may be 
permitted if the subject has been on the same stable dose for the immediate 3 months prior 
to first study drug administration. After the first dose of study drug, ibuprofen (up to 1.2 g 
per 24 hours) may be administered at the discretion of the Investigator or designee.
Any drugs known to be significant inducers of UGT or SULT, including St. John’s Wort, 
within 28 days prior to the first dosing and throughout the study, including the follow-up 
period. Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack of 
PK/pharmacodynamics interaction with study drug.
18. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to the first dosing and throughout the study.
19. Is lactose intolerant or unable/unwilling to eat the high-fat breakfast. 
20. Donation of blood or significant blood loss within 56 days prior to the first dosing.
21. Plasma donation within 7 days prior to the first dosing.
22. Participation in another clinical study within 30 days prior to the first dosing. The 30-day 
window will be derived from the date of the last blood collection or dosing, whichever is later, 
in the previous study to Day 1 of Treatment Period 1 of the current study
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use (including number of cigarettes smoked per day) will be reported.
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9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.1. All 
medications taken by subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to subject safety.
For this study, the collection of blood for plasma TAK-831 concentrations is the critical parameter 
and needs to be collected as close to the exact time point as possible. All other procedures should 
be completed as close to the prescribed/scheduled time as possible, but can be performed prior or 
after the prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Full Physical Examination
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
BMI
BMI will be calculated based on the height and weight measured at screening.
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9.2.4
Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Blood pressure and heart rate measurements will be performed with subjects in a seated position, 
except when they are supine or semi-reclined because of study procedures and/or AEs (eg, nausea, 
dizziness) or if deemed necessary by the Investigator or designee.
Blood pressure and heart rate will be measured within 24 hours prior to Day 1 dosing of each 
treatment period for the predose time point. When scheduled postdose, vital signs will be 
performed within approximately 15 minutes of the scheduled time point. 
For orthostatic vital signs (heart rate and blood pressure), subjects should be seated and then stand 
upright prior to measurement of orthostatic vital signs, as per Celerion standard operating 
procedures.
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the
Investigator or designee.
ECGs will be performed with subjects in a supine position. All ECG tracings will be reviewed by 
the Investigator or designee.
ECGs will be measured within 24 hours prior to Day 1 dosing of each treatment period for the 
predose time point. When scheduled postdose, ECGs will be performed within approximately 
20 minutes of the scheduled time point.
9.2.6
Columbia Suicidality Symptoms Rating Scale
The C-SSRS is a questionnaire scale to detect emergent suicide symptoms (suicidal ideation or 
actual suicidal behavior) during the course of this study. Assessments will be performed according 
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to the Schedule of Study Procedures (Section 3.0). Additional C-SSRS assessment may be 
performed at other times if deemed necessary. The C-SSRS is to be administered at the site by an 
appropriately qualified/trained individual and a copy of the questionnaire to be used will be kept in 
the study binder. In addition, subjects who at any time during this study spontaneously report AEs
of suicidal ideation or suicidal behavior, either as an outpatient or during visit interviews, must be 
assessed by the Investigator or designee and referred for further mental health evaluation as 
clinically indicated.
9.2.7
Study Drug Administration
TAK-831 T2 and T3 tablets will be provided as described in Section 8.1.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject, as appropriate.
All doses of TAK-831 will be administered with approximately 240 mL of water. 
The exact clock time of oral dosing will be recorded.
Subjects will be instructed not to crush, split or chew the TAK-831 tablets.
Treatments are as follows:
Treatment A 
(Reference, Fasted)
50 mg TAK-831 T2 (2 x 25 mg T2 tablets) administered at Hour 0 on 
Day 1 following an overnight fast of at least 10 hours.
Treatment B 
(Test, Fasted)
50 mg TAK-831 T3 (2 x 25 mg T3 tablets) administered at Hour 0 on 
Day 1 following an overnight fast of at least 10 hours.
Treatment C 
(Reference, Fasted)
600 mg TAK-831 T2 (6 x 100 mg T2 tablets administered at Hour 0 on 
Day 1 following an overnight fast of at least 10 hours.
Treatment D 
(Test, Fasted)
600 mg TAK-831 T3 (2 x 300 mg T3 tablets) administered at Hour 0 on 
Day 1 following an overnight fast of at least 10 hours.
Treatment E
(Test, Fed)
600 mg TAK-831 T3 (2 x 300 mg T3 tablets) administered at Hour 0, 
30 minutes after the start of a high-fat breakfast on Day 1.
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9.2.8
AE Monitoring
Subjects will be monitored throughout confinement for adverse reactions to the study formulations 
and/or procedures. Prior to release, subjects will be asked how they are feeling. At the beginning of 
subsequent treatment period subjects will be queried with an open-ended question such as: ‘How 
have you been feeling since your last visit?’ 
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test value(s) 
will be evaluated by the Investigator or designee and treated and/or followed up until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the Investigator or 
designee. 
Treatment of serious adverse events (SAEs) will be performed by a physician, either at Celerion or 
at a nearby hospital emergency room. Where appropriate, medical test(s) and/or examination(s) 
will be performed to document resolution of event(s). Outcome may be classified as resolved, 
improved, unchanged, worse, fatal, or unknown (lost to follow-up).
9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures (Section 
3.0). In addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the Investigator or designee.
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9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample is taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Blood Urea Nitrogen
Sodium
Bilirubin (total and direct)
Potassium
Alkaline phosphatase
Chloride
Aspartate aminotransferase (AST)
Glucose 
Alanine aminotransferase (ALT)
Creatinine *
Albumin
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
Coagulation
Coagulation tests will be performed if subjects has on-study ALT or AST elevated ≥3x the upper 
limit of normal (ULN).
Coagulation evaluations will consist of the following tests:
Prothrombin time
International normalized ratio (INR)
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Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination 
(for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
Other 
HIV test
Urine drug screen

Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)

Amphetamines

Barbiturates

Benzodiazepines

Cocaine

Cannabinoids
HBsAg
HCV (if antibody positive, confirm RNA negative)
Urine alcohol screen
FSH (for postmenopausal females only)
Serum pregnancy test (for females only)
9.3
PK Samples
Primary specimen collection parameters are provided in Table 9.b.
For all subjects, blood samples for the determination of plasma TAK-831 will be collected in 4 mL 
blood collection tubes containing the appropriate anticoagulant at scheduled time points as 
delineated in the Schedule of Study Procedures (Section 3.0). The actual time of sample collection 
will be recorded on the source document in the case report form (CRF).
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately.
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Table 9.b
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma for TAK-831 PK
Plasma
PK analysis
Mandatory
9.3.1
PK Measurements 
9.3.1.1
Plasma PK Measurements
PK parameters for plasma TAK-831 concentrations will be calculated as follows, as appropriate, 
following oral administration:
AUClast:
The area under the concentration versus time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method.
AUC0-inf:
The area under the concentration versus time curve, from time 0 
extrapolated to infinity. AUC0-inf is calculated as AUClast plus the ratio of 
the last measurable plasma concentration to the elimination rate constant.
AUC%extrap:
Percent of AUC0-inf extrapolated, represented as 
(1 – AUClast/AUC0-inf)*100.
Cmax:
Maximum observed concentration.
Tmax:
Time to reach Cmax. If the maximum value occurs at more than one time 
point, Tmax is defined as the first time point with this value.
Kel:
Apparent first-order terminal elimination rate constant calculated from a 
semilog plot of the blood concentration versus time curve. The parameter 
will be calculated by linear least-squares regression analysis using the 
maximum number of points in the terminal log-linear phase (eg, three or 
more non-zero blood concentrations).
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t½:
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel.
No value for Kel, AUC0-inf, AUC%extrap, or t½ will be reported for cases that do not exhibit a 
terminal log-linear phase in the concentration versus time profile.
No PK parameters will be calculated for subjects with detectable concentrations at 2 or fewer 
consecutive time points.
Individual and mean plasma concentration-time curves (both linear and log-linear) will be 
included in the final report.
9.3.2
Biomarker Measurements 
NA
9.3.3
PGx Measurements 
NA
9.3.4
Confinement
In each treatment period, subjects will be housed on Day -1, at the time indicated by the CRU until 
after the 24-hour blood draw and/or study procedures. Subjects will return for study procedures as 
indicated in the Schedule of Study Procedures (Section 3.0).
At all times, a subject may be required to remain at the CRU for longer at the discretion of the
Investigator or designee.
The clinic will contact all subjects (including subjects who terminate the study early) 
approximately 14 days after the last study drug administration to determine if any adverse events 
have occurred since the last study visit.
As per site preference, subjects may be confined throughout the washout period.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the Investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the Investigator
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
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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 
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). Investigator(s) 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, Investigator(s) should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, Investigator(s) 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. Investigator(s) should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
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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 (electronic [e]) case report form, in order to capture this important safety 
information consistently in the database. AEs associated with an overdose will be documented 
on AE CRF(s) according to Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
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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 Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
NA
10.2
AE Procedures
10.2.1 Assigning Severity 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.
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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.
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.
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10.2.5 Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

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.
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 treatment 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 
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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, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and Abnormal LFTs) will commence at the time the subject 
signs the informed consent. Routine collection of AEs will continue until the follow-up phone call 
on Day 14 (± 2 days), approximately 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. Non-serious 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 
changes observed. All AEs will be documented in the AE page of the CRF, whether or not the 
Investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:
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
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 
Section 14.1.1.
Any SAE spontaneously reported to the Investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
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Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
Investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs
NA
10.2.8.5 Reporting of Abnormal Liver Function Tests
If a subject has elevated ALT ≥3x ULN with concurrent elevated total bilirubin >2× ULN or
elevated INR >1.5x ULN, contact the sponsor’s medical monitor within 24 hours. 
For any subject with ALT ≥3x ULN and total bilirubin >2x ULN or INR >1.5x ULN for which an 
alternative etiology has not been found, report the event as an SAE (Section 10.2.8.3) and contact 
the sponsor immediately.
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, Investigator(s) and 
Institutional Review Boards (IRBs) or Independent Ethics Committees (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 
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assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared and finalized before 
database lock. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives. Additional statistical analyses 
other than those described in this section may be performed if deemed appropriate.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
All subjects who received at least one dose of the study drug(s) will be included in the safety 
evaluations.
11.1.1.2 PK Set
Samples from all subjects will be assayed even if the subjects do not complete the study. All 
subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) will 
be included in the statistical analyses.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3 PK Analysis
Descriptive statistics will be provided for the plasma TAK-831 concentrations using appropriate 
summary statistics to be fully specified in the SAP.
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PK parameters for plasma TAK-831 concentrations will be calculated as described in Section 
9.3.1.1.
An ANOVA will be performed on the ln-transformed AUClast, AUC0-inf and Cmax as follows:

Relative BA (Treatments A-D):
The ANOVA model will include sequence, treatment, and treatment period as fixed effects, 
and subject nested within sequence as a random effect. Each ANOVA will include calculation 
of LSM as well as the difference between treatment LSM.

Food Effect (Treatments D and E):
The ANOVA model will have treatment as a fixed-effect and subject as a random-effect to 
account for the correlation between the repeated measures on each subject. 
Each ANOVA will include calculation of LSM as well as the difference between treatment LSM.
11.1.4 Ratios and Confidence Intervals
Ratios of LSM will be calculated using the exponentiation of the difference between treatment 
LSM from the analyses on the ln-transformed AUClast, AUC0-inf, and Cmax. These ratios will be 
expressed as a percentage relative to the reference treatments (ie, Treatments A and C for the 
relative BA assessment, and Treatment D for the food-effect assessment, as detailed below).
Consistent with the two one-sided test [16], 90% CIs for the ratios will be derived by 
exponentiation of the CIs obtained for the difference between treatment LSM resulting from the 
analyses on the ln-transformed AUClast, AUC0-inf, and Cmax. The CIs will be expressed as a 
percentage relative to the reference treatments (ie, Treatments A and B for the relative BA 
assessment, and Treatment D for the food-effect assessment, as detailed below).
Bioequivalence (Treatment B versus Treatment A and Treatment D versus Treatment C) will be 
claimed if the 90% CIs of the ratios of LSMs of the ln-transformed PK parameters AUClast, 
AUC0-inf, and Cmax of TAK-831 fall entirely within 80.00-125.00%.
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The comparisons of interest are as follows:
Relative Bioavailability:

Treatment B compared with Treatment A

Treatment D compared with Treatment C
Food Effect:

Treatment E compared with Treatment D
11.1.5 PD Analysis 
NA
11.1.6 Safety Analysis
All safety data will be populated in the individual CRFs. 
Dosing dates and times will be listed by subject.
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics.
11.1.6.1 AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by treatment for the number and percentage of 
subjects reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing 
including verbatim term, coded term, treatment, severity, and relationship to treatment will be 
provided.
11.1.6.2 Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by treatment and point of time of collection and a 
shift table describing out of normal range shifts will be provided.
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11.1.6.3 Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
11.1.6.4 Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs will be summarized by treatment and point of time of collection.
C-SSRS findings will be presented in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
A total 16 subjects will be randomized into 4 sequence groups as indicated in Table 9.a in a ratio of 
1:1:1:1. Assuming there are no more than 1 dropout in each sequence group, this will provide at 
least 12 observations for each of Treatments A, B, C and D. Based on the intra-subject variability 
(CV = 24.49%) of AUC from Study TAK-831-1004, this provides a two-sided 90% confidence 
interval of the central value ratios (Treatment B versus Treatment A or Treatment D versus 
Treatment C) of (0.8484, 1.1787) if the observed central value ratio is 1. If the observed central 
value ratio is 1.2, the 90% CI will be (1.0180, 1.4144).
The study design will also provide at least 12 observations for each of Treatments D and E, which 
will provide a two-sided 90% confidence interval of the central value ratios (Treatment E versus 
Treatment D) of (0.8799, 1.1365) if the observed central value ratio is 1. If the observed central 
value ratio is 1.6, the two-sided 90% CI will be (1.4078, 1.8184).
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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 CRFs. 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 and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, trial drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the Investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
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addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the 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 Council for Harmonisation (ICH) Harmonised Tripartite Guideline 
for Good Clinical Practice (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 American 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 IB, a copy of the ICF, 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, ICF) 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 
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trial. Until the site receives drug/notification no protocol activities, including screening, may 
occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, 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.
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 ICF, 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 ICF 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 ICF 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 ICF
and, if applicable, the subject authorization form. The ICF, 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 ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
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must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the Investigator (or designee) to explain the detailed elements of the ICF, 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 ICF 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 ICF 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 ICF, 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 ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs 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 ICF.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
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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 CRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study Investigator s 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 
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any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with Investigator’s city, state (for American Investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive Investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
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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
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda 
Development 
Center 
Americas, 
Inc.
Fax: 224-554-1052
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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 Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4 List of Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC%extrap
Percent of AUC0-inf extrapolated 
AUClast
Area under the concentration-time curve, from time 0 to the last observed 
non-zero concentration
AUC0-inf
Area under the concentration-time curve, from time 0 extrapolated to 
infinity
BA
Bioavailability
BMI
Body mass index
bpm
Beats per minute
C-SSRS
Columbia-Suicidality Symptoms Rating Scale
CFR
Code of Federal Regulations
CI
Confidence interval
cm
Centimeter
Cmax
Maximum observed concentration 
CRF
Case report form
CRU
Clinical Research Unit
CV
Intra-subject variability
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DAO
D-amino acid oxidase
ECG
Electrocardiogram
FDA
Food and Drug Administration
FRDA
Friedreich ataxia
FSH
Follicle-stimulating hormone
g
Gram(s)
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
Kel
Apparent first-order terminal elimination rate constant
kg
Kilogram
LFT
Liver function test(s)
ln
Natural log
INR
International normalized ratio
LSM
Least-squares
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
mL
Milliliter
mmHg
Millimeter of mercury
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msec
Millisecond
n
Sample size
NA
Not applicable
NMDA
N-methyl-D-aspartate
oz
Ounce
PK
Pharmacokinetic(s)
PT
Prothrombin time
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SULT
Sulfotransferase
SUSAR
Suspected unexpected serious adverse reactions
t½
Apparent first-order terminal elimination half-life
TEAE
Treatment-emergent adverse event
Tmax
Time to reach maximum observed concentration [Cmax]
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal
US
United States
USA
United States of America
WHO
World Health Organization
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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 Medical Dictionary for 
Regulatory Activities (MedDRA®). Drugs will be coded using the World Health Organization 
Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed CRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the CRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. CRFs must be completed in English. Data are transcribed directly onto CRFs.
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 CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the Investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs is made by Clinical Data Management through the Database Unlock Process after 
approval is granted by the Sponsor to Unlock the Database. The Investigator must review the data 
change for completeness and accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
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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 CRFs. The completed CRFs 
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 ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of CRFs, 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 documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the Investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the Investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The Investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.0
REFERENCES
1. Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, et al. D-serine 
regulates cerebellar LTD and motor coordination through the delta2 glutamate receptor. Nat 
Neurosci 2011;14(5):603-11 
2. Pandolfo M. Friedreich’s ataxia. In: Wells RD, Ashizawa T, editors. Genetic Instabilities &
Neurological Diseases. Burlington, Massachusetts: Academic Press; 2006; Chapter 17, 
p.277-96.
3. Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol 2009;256 Suppl 1:3-8.
4. Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, et al.
Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat
expansion. Science 1996;271(5254):1423-7.
5. Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, et al. Frataxin is
reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum
Mol Genet 1997;6(11):1771-80
6. Akbar U, Ashizawa T, Ataxia. Neurol Clin. 2015;33(1):225-48.
7. van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
8. Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor 
antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift 
in medication development. Psychopharmacology (Berl) 2003;169(3-4):215-33.
9. Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, et al. Plasma
levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 
2012;142(1-3):83-7.
10. Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, et al. Changes in plasma 
glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms 
improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog 
Neuropsychopharmacol Biol Psychiatry 2008;32(8):1905-12.
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11. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. Decreased 
serum levels of D-serine in patients with schizophrenia: evidence in support of the 
N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen 
Psychiatry 2003;60(6):572-6.
12. Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M. Reduced D-serine to 
total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog 
Neuropsychopharmacol Biol Psychiatry 2005;29(5):767-9.
13. Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of
benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino 
acid oxidase inhibitor. JAMA Psychiatry 2013;70(12):1267-75TAK-831.
14. Takeda Pharmaceuticals, Inc. Global Investigator Brochure. Edition 4.0, July 2018.
15. Food and Drug Administration, Draft Guidance for Industry on Bioavailability and 
Bioequivalence Studies Submitted in NDAs or IND – General Considerations, Mar 2014.
16. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach 
for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 
1987;15: 657-680.
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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.
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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 ICF 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 ICF 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 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The Investigator should 
contact and receive written approval from the Sponsor before disposing of any such 
documents.
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 ICF, the subject or the subject’s 
legally acceptable representative is authorizing such access.
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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 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the ICF 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 o
clinical research and safety reporting 
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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.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 
{5 half-lives PLUS 30 days} after the last dose of study drug. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study drug will be discontinued and the Investigator will 
offer the subject the choice to receive unblinded treatment information. 
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26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for {5 half-lives 
PLUS 90 days} after the last dose of study drug. If the partner or wife of the subject is found to 
be pregnant during the study, the Investigator will offer the subject the choice to receive 
unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of Investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting Investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
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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 spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. 
Female Subjects and Their Male Partners
Female subjects of childbearing potential* who are sexually active with a nonsterilized male 
partner** must use a method of contraception as described below.
* A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysteroscopic sterilization (with confirmation from the subject that follow-up 
hysterosalpingogram was conducted), bilateral tubal ligation or bilateral salpingectomy, 
hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high follicle stimulating hormone (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 4 month 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. In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are: 
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
Non-Hormonal Methods: 
–
Physical barrier method (eg, condom, diaphragm) with spermicide for at least 14 days 
prior to the first dosing and for at least 35 days following the last dose of study 
drug(s).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. 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.

Temporary sexual abstinence is NOT an acceptable method of contraception.
3. Subjects will be provided with information on 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.
4. During the course of the study, regular serum human chorionic gonadotropin (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:
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Study ID TAK-831-1006
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Final Protocol 
28 September 2018
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?
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?
5.
In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative serum hCG pregnancy test at each check-in prior to receiving any 
dose of study medication.
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?
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Study ID TAK-831-1006
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Final Protocol 
28 September 2018
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-831) 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. 
If the female subject agrees to the primary care physician being informed, the Investigator should 
notify the primary care physician that the female subject was participating in a clinical study at the 
time she became pregnant and provide details of the study drug the subject received (blinded or 
unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) will be followed up to final outcome, using the pregnancy 
form. Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-Label, Randomized, Single Dose, 5-Period, 5-Treatment, Study to Evaluate the 
Relative Bioavailability and Effect of Food on TAK-831 Tablet Formulations in Healthy Subjects
NCT Number: NCT03706469 
SAP Approve Date: 19 December 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-831-1006
CELERION STUDY NUMBER: CA24822
A Phase 1, Open-Label, Randomized, Single Dose, 5-Period, 5-Treatment, Study to 
Evaluate the Relative Bioavailability and Effect of Food on TAK-831 Tablet Formulations 
in Healthy Subjects
PHASE 1
Version: Final
Date: 19 December 2018
Prepared by:
Based on:
Protocol Dated: 26 September 2018
PPD
Property of Takeda: For n
otocol
tocol D
l
Dec
Decem
cial use only and subject to the applicable Terms of Use
od, 5
d, 5-Tr
-T
n TAK
n TAK-8
on:n: Fina
Fin
9
non-commerci
ty of Ta


TAK-831-1006
Celerion Study Number CA24822
Page 2 of 18
Statistical Analysis Plan Final
19 December 2018
1.1
Approval Signatures
Study Title:
A Phase 1, Open-Label, Randomized, Single Dose, 5-Period, 5-Treatment, 
Study to Evaluate the Relative Bioavailability and Effect of Food on 
TAK-831 Tablet Formulations in Healthy Subjects
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ent,
nt,
a: For non-commercial use only and subject to the applicabl


TAK-831-1006
Celerion Study Number CA24822
Page 3 of 18
Statistical Analysis Plan Final
19 December 2018
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 .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objective..................................................................................................7
4.3
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Secondary Endpoint...................................................................................................9
5.3
Exploratory Endpoints ...............................................................................................9
5.3.1
Safety Endpoints..................................................................................................9
5.3.2
PK Endpoints.......................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
7.1
General Principles....................................................................................................10
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.2
Analysis Sets ...........................................................................................................12
7.3
Disposition of Subjects ............................................................................................12
7.4
Demographic and Other Baseline Characteristics.....................................................12
7.5
Medical History and Concurrent Medical Conditions...............................................13
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................13
7.8
Efficacy Analysis.....................................................................................................13
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................13
7.9.1
Pharmacokinetic Analysis ..................................................................................13
7.9.2
Pharmacodynamic Analysis ...............................................................................15
7.10
Other Outcomes.......................................................................................................15
7.11
Safety Analysis........................................................................................................15
7.11.1 Adverse Events ..................................................................................................16
7.11.2 Clinical Laboratory Evaluations .........................................................................16
7.11.3 Vital Signs .........................................................................................................17
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Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
7.11.4 12-Lead ECGs ...................................................................................................17
7.11.5 Physical Exams..................................................................................................17
7.11.6 Columbia Suicidality Symptoms Rating Scale (C-SSRS) ...................................17
7.11.7 Overdose............................................................................................................18
7.12
Interim Analysis ......................................................................................................18
7.13
Preliminary Analysis................................................................................................18
7.14
Changes in the Statistical Analysis Plan...................................................................18
8.0
REFERENCES..............................................................................................................18
LIST OF IN-TEXT TABLES
Table 4.a
Summary of Treatments.......................................................................................7
Table 4.b
Treatment Sequences ...........................................................................................8
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................14
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................8
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Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
3.0
LIST OF ABBREVIATIONS
AE
adverse event
AUC
area under the curve
AUC0-inf
area under the plasmaconcentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the 
last quantifiable concentration.
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
Cmax
maximum observed plasma concentration
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CS
clinically significant
CSR
clinical study report
CV
coefficient of variation
ECG
electrocardiogram
eCRF
electronic case report form
Geom CV
geometric coefficient of variation
Geom Mean
geometric mean
ICF
informed consent form
ICH
International Conference on Harmonisation
ln
natural log
LSM
least-square means
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
PI
Principal Investigator
PK
pharmacokinetics
SAE
serious adverse event
SD
standard deviation
SEM
standard error of the mean
SOC
system organ class
t½
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tables, figures and listings
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Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
Tmax
time to first occurrence of Cmax
WHO
World Health Organisation
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Celerion Study Number CA24822
Page 7 of 18
Statistical Analysis Plan Final
19 December 2018
4.0
OBJECTIVES
4.1
Primary Objectives

To assess the oral bioavailability (BA) of TAK-831 T3 tablet formulation relative to
TAK-831 T2 tablet formulation under fasting conditions.

To assess the effect of food on the pharmacokinetics (PK) of TAK-831 T3 tablet formulation.
4.2
Secondary Objective
To determine the safety and tolerability of single doses of TAK-831 T2 and T3 tablet 
formulations.
4.3
Study Design
This is an open-label, 5-period, 5-treatment, relative BA and food-effect study in 16 healthy 
adult subjects. On Day 1 of each treatment period, subjects will receive a single dose of study 
drug. In Treatment Periods 1 – 4, each subject will receive 2 dose levels of the T2 formulation 
and 2 doses of the T3 formulation under fasted, per the randomization schedule, to assess the 
relative BA of the 2 formulations. In Treatment Period 5, all subjects will receive a single oral 
dose of T3 formulation under fed conditions, in order to assess the food effect. There will be a 
washout period of at least 7 days between each dose.
A summary of the treatments is presented in Table 4.a.
Table 4.a
Summary of Treatments
Treatment 
Formulation
TAK-831 Dose
Treatment/meal condition (a)
A
T2
50 (2 x 25 mg tablets)
Fasted (b)
B
T3
50 (2 x 25 mg tablets)
Fasted (b)
C
T2
600 (6 x 100 mg tablets)
Fasted (b)
D
T3
600 (2 x 300 mg tablets)
Fasted (b)
E
T3
600 (2 x 300 mg tablets)
Fed (c)
(a) All study drugs will be administered orally with approximately 240 mL of water. (b) In Treatments A, B, C, and
D, subjects will fast overnight for at least 10 hours prior to each study drug administration. (c) In Treatment E,
subjects will fast overnight for at least 10 hours until 30 minutes prior to their scheduled morning dose, when they
will be given a high-fat breakfast to be entirely consumed within 30 minutes.
Sixteen subjects will be randomized to 1 of 4 treatment sequences in a 1:1:1:1 ratio. The 
sequences used in the randomization are detailed in Table 4.b below. Subjects will receive each 
treatment on one occasion. 
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Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
Table 4.b
Treatment Sequences
Sequences
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Treatment 
Period 4
Treatment 
Period 5
1 (n=4)
A
B
D
C
E
2 (n=4)
B
C
A
D
E
3 (n=4)
C
D
B
A
E
4 (n=4)
D
A
C
B
E
Subjects were screened up to 28 days prior to dosing, to determine eligibility before 
randomization. Eligible subjects returned to the clinic at Check-in (Day -1). 
A schematic of the study design is included as Figure 4.a.
Figure 4.a
Schematic of Study Design
Pretreatment
Screening
Treatment Periods 1-5
Study Exit (a)
Follow up (b)
Predose 
Assessments
Dosing and
Study Assessments
Safety and PK 
Assessments
Within 
28 days prior 
to first dosing
Day -1
Day 1
Day 1-2
Days 3-4
Day 4 of 
Treatment 
Period 5
14 (±2) days 
after last dose
Outpatient 
Visit
Confinement (a) (c)
Outpatient Visits
(a) At all times, a subject may be required to remain at the clinical research unit for longer at the discretion of the 
Investigator or designee.
(b) The clinic will contact all subjects (including subjects who terminate the study early) approximately 14 days 
after the last study drug administration to determine if any adverse events have occurred since the last study visit.
(c) Subjects will start the confinement on Day -1 and be released from confinement after Day 2 study assessments 
are complete and will return to the study site on Day 3 and Day 4 for subsequent safety and PK assessments. 
Subjects for all treatment sequences will be kept in the study unit from Day -1 Check-in until at 
least 24 hours after dosing (Day 2) for safety and PK assessments before discharge. The 
minimum confinement will be 2 nights (Days -1 to 2, inclusively). Subjects will return to the 
study unit on Day 3 and Day 4 for PK and safety assessments. The clinic will contact all subjects 
(including subjects who terminate the study early) approximately 14 days after the last study 
drug administration to determine if any adverse events (AEs) have occurred since the last study 
visit. 
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Statistical Analysis Plan Final
19 December 2018
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The following plasma PK parameters will be analyzed following a single dose of TAK-831 on 
Day 1 of each treatment period:
!
Area under the plasma concentration-time curve (AUC) from time 0 to time of the last 
quantifiable concentration (AUClast).
!
AUC from time 0 to infinity (AUC0-inf).
!
Maximum observed plasma concentration (Cmax).
5.2
Secondary Endpoint
The following safety variable will be used to characterize the safety and tolerability of TAK-831:
!
Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).
5.3
Exploratory Endpoints
5.3.1
Safety Endpoints
5.3.2
PK Endpoints
CCI
CCI
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 on
 on
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as
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afety y an
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ent-em
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omme
keda: For non-com


TAK-831-1006
Celerion Study Number CA24822
Page 10 of 18
Statistical Analysis Plan Final
19 December 2018
6.0
DETERMINATION OF SAMPLE SIZE
A total of 16 subjects was randomized into 4 sequences in a ratio of 1:1:1:1. Assuming there 
were no more than 1 dropout in each sequence group, this would provide at least 12 observations 
for each of Treatments A, B, C, and D. Based on the intra-subject variability (CV = 24.49%) of 
AUC from Study TAK-831-1004, this provided a 2-sided 90% CI of the central value ratios 
(Treatment B versus Treatment A or Treatment D versus Treatment C) of (0.8484, 1.1787) if the 
observed central value ratio was 1. If the observed central value ratio was 1.2, the 90% CI would 
be (1.0180, 1.4144).
The study design provided at least 12 observations for each of Treatments D and E, which would 
provide a 2-sided 90% CI of the central value ratios (Treatment E versus Treatment D) of 
(0.8799, 1.1365) if the observed central value ratio was 1. If the observed central value ratio was 
1.6, the 2-sided 90% CI would be (1.4078, 1.8184).
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using Phoenix® WinNonlin® Version 7.0, or higher. All 
statistical analyses will be conducted using SAS® Version 9.3, or higher.
Arithmetic mean (mean), median, and geometric mean (Geom Mean) values will be presented to 
1 more level of precision than the individual values. Standard deviation (SD) and standard error 
of the mean (SEM) will be presented to 2 more levels of precision than the individual values. 
Minimum and maximum values will be presented to the same precision as the individual values. 
Arithmetic percent coefficient of variation (CV%) and geometric percent coefficient of variation 
(Geom CV%) will be presented to 1 decimal place. 
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
recorded data. Geometric LSMs are least-squares means derived from the analysis of variance 
(ANOVA) model for the analyses of ln-transformed AUClast, AUC0-inf, and Cmax which have 
been exponentiated to provide estimates on the original scale. The difference in the LSM on the 
ln-scale and associated 90% confidence intervals (CIs) will be exponentiated to produce 
geometric mean ratios of GMRs (presented as a %) and 90% CIs around the ratio and will be 
reported using 2 decimal places. These ratios will be expressed as a percentage relative to the 
reference treatment (i.e., Treatments A and C for relative BA assessment, and Treatment D for 
the food-effect assessment).
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. BLQ values will be treated as zero for the 
calculation of summary statistics, the generation of concentration plots, and the calculation of PK 
parameters, unless they are obvious outliers (e.g. BLQ value between 2 measurable values), in 
which case they will be treated as missing.
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
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Statistical Analysis Plan Final
19 December 2018
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical evaluation if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that subject’s Cmax value in that period.

A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist).

A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist).
See Clinical Pharmacology Analysis Plan (CPAP) for details on the PK parameter calculations 
and data presentation including specifics on the following:

Insufficient data to determine a reliable t½ value and other terminal elimination rate constant 
dependent parameters.

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables.

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables.

Concentration data file used for PK analysis.

PK parameter WinNonlin® output file used to generate the tables, figures, and listings 
(TFLs).

Dose-normalized PK parameters (DN_AUClast, DN_AUC0-inf, and DN_Cmax) will be 
determined by dividing each PK parameter with the treatment dose received. 

ANOVA results presented in in-text and end-of-text tables.

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures.

Individual concentration-time figures presented in Appendix 16.2.6.
For demographic data where appropriate, variables will be summarized descriptively by 
treatment sequence and overall. For the categorical variables, the count and proportions of each 
possible value will be tabulated by treatment sequence, and overall, where applicable. 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, SD, minimum, median, and maximum values will be tabulated.
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Statistical Analysis Plan Final
19 December 2018
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Day 1 for the study is defined as the date on which a subject is administered their first dose of the 
study drug(s) in Period 1. Other study days are defined relative to Day 1 with Day -1 being the 
day prior to Day 1 of Period 1. Study day prior to the first dose in Period 1 will be calculated as: 
date of assessment/event-date of treatment; study day on or after the date of first dose will be
calculated as: date of assessment/event-date of treatment +1.
Day 1 for each period is defined as the date on which a subject is administered their first dose of 
the study drug(s) in each period. Other study days are defined relative to Day 1 with Day -1 
being the day prior to Day 1 of each period. Study day prior to the first dose of each treatment 
will be calculated as: date of assessment/event-date of treatment; study day on or after the date of 
first dose will be calculated as: date of assessment/event-date of treatment +1.
7.2
Analysis Sets
Safety Set:
All subjects who received at least one dose of the study drug(s) will be included in the safety
evaluations. Subjects in this analysis set will be used for demographic, baseline characteristics 
and safety summaries.
PK Set:
Samples from all subjects will be assayed even if the subjects did not complete the study. All 
subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg,
exposure to treatment, availability of measurements and absence of major protocol violations) 
will be included in the statistical analyses. In terms of criteria for evaluable subjects, please see 
CPAP.
7.3
Disposition of Subjects
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized for each treatment sequence and 
overall. Study completion status, including reason for discontinuation, will also be listed by 
subject. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment sequence and overall. 
Summary statistics (number of subjects [n], mean, SD, minimum, median, and maximum) will 
be generated for continuous variables (age [calculated from the date of signed Informed Consent 
Form [ICF], weight, height and body mass index [BMI]) and the number and percentage of 
subjects within each category will be presented for categorical variables (sex, race, and 
ethnicity). For height the screening measurement will be reported but for weight and BMI the 
baseline value, which is the last observation prior to dosing, will be reported. The demographics 
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TAK-831-1006
Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
listing will also include protocol version and date, ICF version and date, the date of each signed 
the ICF. 
7.5
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing the 
ICF. Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing the ICF. Each subject’s medical history and concurrent medical conditions will 
be listed. Any medical condition started after taking the study drug will be classified as an 
adverse event. The medical history listing will include whether the event was medical or 
surgical, the body system or organ class involved, start date (if known) and end date or whether 
the condition was ongoing, and a description of the condition or event. There will be no 
statistical analysis of medical history.
7.6
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and
efficacy/safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant 
medication includes any medication other than study drug taken at any time between time of 
signing the ICF through the end of the study (including follow-up visit). All medication history 
and concomitant medications recorded during the study will be coded with the World Health 
Organization (WHO) Dictionary Version 01-Sep-2018 and listed. The listing will include the 
medication name, dosage, route of administration, start date and time (if known), end date and 
time, or whether it continued after study completion, and indication for use. 
7.7
Study Drug Exposure and Compliance
Not applicable.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Blood samples (one 4 mL sample per scheduled time) for PK analysis of TAK-831 will be 
collected as specified in Table 7.a following administration of different formulations and/or 
different feeding conditions.
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TAK-831-1006
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Page 14 of 18
Statistical Analysis Plan Final
19 December 2018
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-831
Plasma
1
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours after 
Day 1 dosing (a).
(a) If a subject experiences a serious adverse event (SAE), a blood sample for PK analysis should also be obtained at 
the unscheduled visit. PK samples will be collected at Early Termination at the discretion of the investigator.
The actual date and time of sample collection will be recorded on the source document and 
electronic case report form (eCRF).
The PK parameters of TAK-831 listed in the CPAP for this study will be determined from the 
concentration-time profiles for subjects in the PK set using a noncompartmental analysis method. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. If actual sample times are missing, nominal times may be used.
Concentrations will be listed and summarized descriptively by PK sampling time. Summary will 
be done by treatment using the summary statistics listed in the CPAP. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive summary statistics. Individual subject and arithmetic mean 
profiles of the concentration-time data will be plotted by treatment on linear (with and without 
SD) and semi-log scales. For summary statistics and arithmetic mean plots by sampling time, the 
nominal PK sampling time will be used, for individual subject plots by time, the actual PK 
sampling time will be used. 
PK parameters will be summarized descriptively by treatment using the summary statistics listed 
in the CPAP. Excluded parameters will be presented and footnoted as such in the PK parameter 
table listings, and those values will be excluded from the descriptive summary statistics. 
Relative Bioavailability (Treatments A-D)
Natural log (ln)-transformed AUClast, AUC0-inf, and Cmax will be analyzed using an ANOVA 
model. The model will include sequence, treatment, and treatment period as fixed effects, and 
subject nested within sequence as a random effect. Each ANOVA will include calculation of 
least-squares means (LSM) as well as the difference between treatment LSM. Geometric LSM 
ratios will be calculated using the exponentiation of the difference between treatment LSM from 
the analyses on the ln-transformed AUClast, AUC0-inf, and Cmax. These ratios will be 
expressed as a percentage relative to the reference treatments (ie, Treatments A and C for the 
relative BA assessment). The following SAS® code will be used for the analysis:
PROC MIXED DATA=XXXX;
CLASS Sequence Treatment Period Subject;
MODEL <PK_Parameter> = Sequence Treatment Period / DDFM=KR;
RANDOM Subject(Sequence);
ESTIMATE ‘Treatment B vs A ’ Treatment -1 1 0 0 / CL ALPHA = 0.10 E;
ESTIMATE ‘Treatment D vs C ’ Treatment 0 0 -1 1 / CL ALPHA = 0.10 E;
LSMEANS Treatment;
Run;
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Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
Consistent with the two one-sided test, 90% confidence intervals (CIs) for the ratios will be 
derived by exponentiation of the CIs obtained for the difference between treatment LSM 
resulting from the analyses on the ln-transformed AUClast, AUC0-inf, and Cmax. The CIs will 
be expressed as a percentage relative to the reference treatments (ie, Treatments A and C for the 
relative BA assessment). Bioequivalence (Treatment B versus Treatment A and Treatment D 
versus Treatment C) will be claimed if the 90% CIs of the ratios of geometric LSMs of PK 
parameters AUClast, AUC0-inf, and Cmax of TAK-831 fall entirely within 80.00-125.00%.
Food Effect (Treatments D and E)
Ln-transformed AUClast, AUC0-inf, and Cmax will be analyzed using an ANOVA model. The 
model will have treatment as a fixed-effect and subject as a random-effect to account for the 
correlation between the repeated measures on each subject. Each ANOVA will include 
calculation of LSM as well as the difference between treatment LSM. Ratios of geometric LSM 
will be calculated using the exponentiation of the difference between treatment LSM from the 
analyses on the ln-transformed AUClast, AUC0-inf, and Cmax. These ratios and associated 90% 
CI will be expressed as a percentage relative to Treatment D. The following SAS® code will be 
used for the analysis:
PROC MIXED DATA=XXXX;
CLASS Sequence Treatment Subject;
MODEL <PK_Parameter> = Sequence Treatment / DDFM=KR;
RANDOM Subject(Sequence);
ESTIMATE ‘Treatment E vs D ’ Treatment -1 1 / CL ALPHA = 0.10 E;
LSMEANS Treatment;
Run;
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and type of TEAEs, changes from 
baseline in the subjects’ clinical laboratory results, vital signs, and ECG’s using the safety set. 
Reasons for discontinuation will be tabulated. All clinical safety data will be listed by subject 
and assessment time points, including rechecks, unscheduled assessments, and early termination, 
chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
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Statistical Analysis Plan Final
19 December 2018
7.11.1 Adverse Events
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate or severe), relationship to study drug (related or not 
related) and action relative to the study drug. All AEs occurring during this study will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA®), Version 21.1. However, 
only TEAEs occurring after administration of the first dose of study drug and through the end of 
the study (approximately 14 (± 2) days after the last dose of investigational product 
administration) will be summarized. 
A TEAE is defined as an AE that is starting or worsening at the time of or after study drug 
administration. If an AE increases in severity, that AE will be given a resolution date and time, 
and a new AE will be entered with the new severity. If the severity of an AE remains the same or 
decreases, the AE will be kept open through to resolution.
For each treatment, TEAEs will be coded using MedDRA® Version 21.1 and tabulated by 
System Organ Class (SOC) and Preferred Term. Summary tables will include number of subjects 
reporting the AE and as percent of safety set by treatment. The most commonly reported TEAEs 
(i.e., those events reported by >5% of all subjects in each treatment group or at least 2 subjects, 
excluding SAEs) will also be summarized. For the list of all AE summary table see CPAP.
In addition, TEAEs will be summarized as number of AEs and percentage of AEs for each 
treatment for the overview of TEAEs. 
Additional TEAE summary tables will be presented by severity and relationship to study drug. If 
a subject has multiple AEs with different severity levels within the same term, the subject will be 
counted in the most severe category only. If a subject has both related and unrelated AEs with 
the same term, the subject will be counted as having related TEAEs.
Should any SAEs occur they will be summarized the same way as TEAE. All AEs will be 
displayed in the data listings and TEAEs will be discussed in the text of the study report.
7.11.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1) 
and Day 4 (hour 72) postdose in each period, or upon early termination. In addition, laboratory 
safety tests may be performed at various unscheduled time points, if deemed necessary by the 
Principal Investigator (PI).
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time 
points. Change from baseline will be summarized. Baseline is defined as the last assessment 
including rechecks taken prior to dosing in each period. 
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
treatment baseline (above normal (H), normal (N), or below normal (L)) with those postdose 
time points for each regimen. For urinalysis tests, the categories are normal (N) and abnormal 
(A). Out-of-range values and corresponding recheck results will be listed. 
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Statistical Analysis Plan Final
19 December 2018
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a clinically significant (CS) range. If the value falls within the CS 
range, it will be noted as “N” for not clinical significant. If the value fails the CS range, it will be 
flagged with a “Y” which prompts the PI to determine how the out-of-range value should be 
followed using 4 Investigator flags: "N", not clinically significant, "R", requesting a recheck, "^", 
checking at the next scheduled visit, or "Y", clinically significant. All clinically significant lab 
tests and the corresponding values will be listed by subject. All clinical laboratory data will be 
presented in by-subject data listings.
7.11.3 Vital Signs
Single measurements of heart rate and blood pressure will be obtained at screening, check-in 
(Day -1), Day 1 predose, Day 1 Hour 1, Days 2, and Day 4 in each period, or upon early 
termination. Respiration rate, temperature, and orthostatic vital signs are collected at screening 
only. Additional unscheduled vital signs measurements may be taken at other times, if deemed 
necessary by the PI.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results and change from baseline by treatment and time point of collection. Baseline is 
defined as the last assessment including rechecks taken prior to dosing in each period. Vital signs 
will also be displayed in a data listing by subject.
7.11.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded at screening, check-in (Day -1), Day 1 predose; 
postdose at Hours 1 and 4, and Day 4 (Hour 72) in each period or upon early termination. 
Additional unscheduled ECGs may be recorded at other times if deemed necessary by the PI. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by treatment and time point of collection. Baseline is defined as 
the last assessment including rechecks taken prior to dosing in each period. ECG data will also 
be displayed in a data listing by subject.
7.11.5 Physical Exams
A full physical exam will be performed at screening. Symptom driven physical exams may be 
performed at other times at the discretion of the PI. Physical exam findings will be presented in a 
data listing by subject. Reproductive system findings will also be listed by subject.
7.11.6 Columbia Suicidality Symptoms Rating Scale (C-SSRS)
The C-SSRS questionnaire will be administered at screening, check-in, and Day 4 (hour 72) in 
each period or upon early termination. At screening the C-SSRS Baseline/Screening version will 
be administered; at all other time points, the Since Last Visit version will be administered. 
C-SSRS findings will be presented in the data listings by subject.
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Celerion Study Number CA24822
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Statistical Analysis Plan Final
19 December 2018
7.11.7 Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs. 
7.12
Interim Analysis
No interim analysis was performed.
7.13
Preliminary Analysis
Analysis will be completed as described in the CPAP and Section 7.9.1 of the SAP, with the 
following changes: 1) QCed data will be used (not QAed); 2) nominal times will be used for the 
calculation of PK parameters (not actual sampling times); 3) tables and figures will be created 
using Phoenix® WinNonlin® Version 7.0.
7.14
Changes in the Statistical Analysis Plan 
Although not outlined in the protocol, dose-normalized PK parameters will also be determined 
by dividing the PK parameters AUClast, AUC0-inf, and Cmax by the treatment dose received, 
and descriptive statistics for each PK parameter will be summarized. 
In the analysis of food effects a sequence fixed-effects was added to the statistical model to 
account for period-to-period variation. 
There are no other changes in the statistical analysis plan.
8.0
REFERENCES
Not applicable.
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