Clinical trial NCT04234672
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Neurocrine Biosciences
Start date: 2020-02-17; Completion date: 2020-04-04
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine ABA of TAK-831 following a single microdose intravenous administration of 50 microgram (μg) (approximately 1 microcurie \[μCi\]) \[14C\]TAK-831 and a single oral administration of 500 milligram (mg) TAK-831 tablets in Period 1, and to assess the mass balance, characterize the PK of TAK-831 in plasma and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single oral suspension dose of 500 mg (approximately 100 μCi) \[14C\]TAK-831 in Period 2.

Detailed description:
The drug being tested in this study is called TAK-831 (also known as luvadaxistat). The study will determine ABA in Period 1, and the absorption, metabolism, excretion, and mass balance of TAK-831 after single oral administration in Period 2 in healthy adult male participants, by collecting plasma, urine, and feces samples for drug concentration analysis, and plasma, whole blood, urine, and fecal samples for total radioactivity analysis and metabolic profiling.

The study will enroll approximately 6 participants. The study is designed to consist of 2 periods: Period 1 (ABA study period) and Period 2 (absorption, distribution, metabolism, and elimination \[ADME\] study period). In Period 1 (ABA study period), all participants will receive a single unlabelled oral dose of TAK-831 as tablet and a microdose intravenous infusion of 50 μg (approximately 1 μCi) \[14C\]TAK-831, followed by a washout period of 8 days before the dose in Period 2. In Period 2 (ADME study period), all participants will receive a single dose of 500 mg (approximately 100 μCi) \[14C\]TAK-831 as an oral suspension.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 65 days including screening period. Participants will be contacted approximately 30 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-831 500 mg, tablet, orally, once on Day 1, followed by \[14C\]TAK-831 50 micrograms (μg) \[approximately 1 microcurie (μCi)\], infusion, intravenously (IV), once on Day 1 of Treatment Period 1, followed by a washout period of 8 days, further followed by \[14C\]TAK-831 500 mg (approximately 100 μCi), suspension, orally, once under fasted state on Day 1 of Treatment Period 2.
Interventions: intervention 1: TAK-831 Oral Tablet intervention 2: [14C]TAK-831 IV Infusion intervention 3: [14C]TAK-831 Oral Suspension
Intervention descriptions: intervention 1: TAK-831 tablet. intervention 2: \[14C\]TAK-831 IV infusion. intervention 3: \[14C\]TAK-831 oral suspension.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-831 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-831 in Male Healthy 
Subjects
NCT Number: NCT04234672
Protocol Approve Date: 29 October 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (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.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1 Study to Assess Absolute Bioavailability of TAK-831 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-831 in Male Healthy 
Subjects
Study Identifier:
TAK-831-1008
Compound:
TAK-831
Date:
29 October 2019
Version/Amendment 
Number:
Final
rcial Use Only and Subject to the Applicable Terms of Use
s
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For Non-Commerc


TAK-831
Study ID TAK-831-1008
Page 2 of 79
Final Protocol 
29 October 2019
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................12
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................13
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.2
Rationale for the Proposed Study.............................................................................21
4.3
Benefit/Risk Profile .................................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Hypothesis...............................................................................................................23
5.2
Study Objectives......................................................................................................23
5.2.1
Study Primary Objectives...................................................................................23
5.2.2
Study Secondary Objectives...............................................................................23
5.2.3
Study Exploratory Objectives.............................................................................23
5.3
Endpoints.................................................................................................................23
5.3.1
Primary Endpoints .............................................................................................24
5.3.2
Secondary Endpoints..........................................................................................24
5.3.3
Exploratory Endpoints .......................................................................................24
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.2
Dose Escalation .......................................................................................................26
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................26
6.3.1
Rationale of Study Design..................................................................................26
6.3.2
Rationale for Dose .............................................................................................27
6.3.3
Critical Procedures Based on Study Objectives: Timing of Procedures...............27
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................28
6.5
Study Beginning and End/Completion .....................................................................28
6.5.1
Definition of Beginning of the Study..................................................................28
6.5.2
Definition of End of the Study ...........................................................................28
6.5.3
Definition of Study Completion .........................................................................28
6.5.4
Definition of Study Discontinuation...................................................................28
6.5.5
Criteria for Premature Termination or Suspension of the Study..........................28
6.5.6
Criteria for Premature Termination or Suspension of a Site................................29
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 3 of 79
Final Protocol 
29 October 2019
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................30
7.3
Excluded Medications, Supplements, Dietary Products............................................32
7.4
Diet, Fluid, Activity.................................................................................................33
7.4.1
Diet and Fluid ....................................................................................................33
7.4.2
Activity..............................................................................................................33
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................34
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................34
7.7
Subject Replacement................................................................................................34
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................35
8.1
Clinical Study Drug .................................................................................................35
8.1.1
TAK-831 Tablet.................................................................................................35
8.1.2
[14C]TAK-831 IV Sterile Solution......................................................................35
8.1.3
[14C]TAK-831 Oral Suspension .........................................................................35
8.1.4
Clinical Study Drug Labeling.............................................................................35
8.1.5
Clinical Study Drug Inventory and Storage ........................................................35
8.1.6
Clinical Study Drug Blinding.............................................................................36
8.1.7
Randomization Code Creation and Storage ........................................................36
8.1.8
Clinical Study Blind Maintenance/Unblinding Procedure...................................36
8.1.9
Accountability and Destruction of Sponsor-Supplied Drugs...............................36
9.0
STUDY PROCEDURES...............................................................................................37
9.1
Administrative Procedures.......................................................................................37
9.1.1
Informed Consent Procedure..............................................................................37
9.1.2
Inclusion and Exclusion .....................................................................................37
9.1.3
Medical History/Demography ............................................................................37
9.1.4
Concomitant Medications...................................................................................37
9.2
Clinical Procedures and Assessments.......................................................................37
9.2.1
Full Physical Examination..................................................................................38
9.2.2
Height and Weight .............................................................................................38
9.2.3
BMI ...................................................................................................................38
9.2.4
Vital Signs .........................................................................................................38
9.2.5
12-Lead ECG.....................................................................................................38
9.2.6
Columbia-Suicide Severity Rating Scale ............................................................39
9.2.7
Study Drug Administration ................................................................................39
9.2.8
AE Monitoring...................................................................................................40
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TAK-831
Study ID TAK-831-1008
Page 4 of 79
Final Protocol 
29 October 2019
9.2.9
Laboratory Procedures and Assessments............................................................40
9.3
PK Samples .............................................................................................................41
9.3.1
PK Measurements..............................................................................................42
9.3.2
Biomarker Measurements...................................................................................44
9.3.3
PGx Measurements............................................................................................44
9.3.4
Confinement ......................................................................................................45
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions and Elements of AEs .............................................................................47
10.1.1 SAEs..................................................................................................................49
10.1.2 Special Interest AEs...........................................................................................50
10.2
AE Procedures.........................................................................................................50
10.2.1 Assigning Severity/Intensity of AEs...................................................................50
10.2.2 Assigning Causality of AEs................................................................................50
10.2.3 Start Date...........................................................................................................51
10.2.4 End Date............................................................................................................51
10.2.5 Pattern of Adverse Event (Frequency)................................................................51
10.2.6 Action Taken With Study Treatment..................................................................51
10.2.7 Outcome ............................................................................................................51
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................52
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....54
11.0
STATISTICAL METHODS..........................................................................................55
11.1
Statistical and Analytical Plans ................................................................................55
11.1.1 Analysis Sets......................................................................................................55
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................55
11.1.3 PK Analysis .......................................................................................................55
11.1.4 Analysis of Mass Balance ..................................................................................56
11.1.5
........................................................56
11.1.6
..........................................................................................56
11.1.7 PD Analysis .......................................................................................................56
11.1.8 Safety Analysis ..................................................................................................56
11.2
Interim Analysis and Criteria for Early Termination ................................................57
11.3
Determination of Sample Size..................................................................................57
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................58
12.1
Study-Site Monitoring Visits ...................................................................................58
12.2
Protocol Deviations..................................................................................................58
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TAK-831
Study ID TAK-831-1008
Page 5 of 79
Final Protocol 
29 October 2019
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................58
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................59
13.1
IRB and/or IEC Approval ........................................................................................59
13.2
Subject Information, Informed Consent, and Subject Authorization .........................60
13.3
Subject Confidentiality ............................................................................................61
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................61
13.4.1 Publication and Disclosure.................................................................................61
13.4.2 Clinical Study Registration.................................................................................62
13.4.3 Clinical Study Results Disclosure.......................................................................62
13.5
Insurance and Compensation for Injury....................................................................62
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................63
14.1
Administrative Information......................................................................................63
14.1.1 Study Contact Information .................................................................................63
14.1.2 INVESTIGATOR AGREEMENT......................................................................64
14.1.3 Study-Related Responsibilities...........................................................................65
14.1.4 List of Abbreviations .........................................................................................65
15.0
DATA HANDLING AND RECORDKEEPING............................................................68
15.1
CRFs .......................................................................................................................68
15.2
Record Retention .....................................................................................................68
16.0
REFERENCES..............................................................................................................70
17.0
APPENDICES...............................................................................................................71
LIST OF IN-TEXT TABLES
Table 3.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-831 
(Period 1 - ABA Study Period)...........................................................................16
Table 3.b
Urine and Fecal Sampling Schedule (Period 1 – ABA Study Period)..................17
Table 3.c
Blood Collection Schedule (Period 2 - ADME Study Period).............................18
Table 3.d
Urine and Fecal Sampling Schedule (Period 2 - ADME Study Period) ...............19
Table 6.a
Planned Dose Levels of TAK-831 and [14C]TAK-831........................................26
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................33
Table 9.a
Primary Specimen Collections ...........................................................................42
Table 10.a
Takeda Medically Significant AE List................................................................50
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TAK-831
Study ID TAK-831-1008
Page 6 of 79
Final Protocol 
29 October 2019
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................71
Appendix B
Elements of the Subject Informed Consent.........................................................73
Appendix C
Investigator Consent to the Use of Personal Information ....................................76
Appendix D
Pregnancy and Contraception.............................................................................77
Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 7 of 79
Final Protocol 
29 October 2019
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-831-1008
Phase: 1
Protocol Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-831 and to Characterize Mass Balance, 
Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-831 in Male Healthy Subjects
Study Design:
This is an open-label, 2-period, single-dose study in 6 male healthy subjects. 
On Day 1 of Period 1 (absolute bioavailability [ABA] Study Period), subjects will receive a single unlabeled oral 
500 mg dose of TAK-831 as tablets. At 1.25 hours (75 minutes) post oral dosing (ie, 15 minutes prior to the median 
tmax for the oral unlabeled dose [approximately (~) 1.5 hours]), subjects will receive a 15-minute intravenous (IV) 
infusion of a microdose of 50 µg (approximately equivalent to 1 microcurie [~1 µCi]) [14C]TAK-831. Serial blood 
sampling will be performed up to Day 5 to determine the pharmacokinetics (PK) of TAK-831 in the plasma for the 
oral dose and [14C]-total radioactivity and PK of [14C]TAK-831 in the plasma for the IV dose. Urine and fecal output 
will also be collected up to the morning of Day 5 postdose to determine [14C]TAK-831 concentrations. Subjects will 
remain in the CRU and continue with urine and feces collection until one of the discharge criteria is met (ie, 80% or 
greater of the total dose of radioactivity administered is recovered in urine and fecal samples or the excretion of 
radioactivity in the urine and feces combined has declined to ≤1% of the total administered radioactivity for at least 2 
consecutive intervals where both a urine and fecal sample are collected) or up to Day 8 but no less than Day 5 for 
[14C]-total radioactivity excretion in urine and feces. 
In Period 1, subjects will be confined in the clinical research unit (CRU) for at least 5 days (until after the last PK 
sample and morning urine and fecal sample [when passed] are collected) and until one of the discharge criteria is met 
or up to Day 8. Subjects will return to the CRU on Day -1 of Period 2 for Period 2 procedures.
There will be a washout period of at least 7 days between the last dose in Period 1 and the dose in Period 2.
On Day 1 of Period 2 (absorption, distribution, metabolism, and elimination [ADME] Study Period), subjects will 
receive a single dose of 500 mg (~100 μCi) [14C]TAK-831 as an oral suspension. Serial blood sampling will be 
performed and urine and feces will be collected to determine the PK of TAK-831 in plasma and urine, and total 
radioactivity in plasma, whole blood, urine, and feces, 
 
. Complete urinary and fecal output will be collected during the confinement period until 
discharge criteria are met (anticipated to be 10 days postdose or less).
In Period 2, subjects will be confined in the CRU for at least 5 days postdose (ie, Day 6) and until 90% or greater of the 
total dose of radioactivity administered is recovered in urine and fecal samples. If less than 90% of the total dose of 
radioactivity administered is recovered in urine and fecal samples within 10 days postdose (ie, Day 11), the subject 
will continue to stay at the CRU until 80% or greater of the total dose of radioactivity administered is recovered in 
urine and fecal samples or the excretion of radioactivity in the urine and feces combined has declined to ≤1% of the 
total administered radioactivity for at least 2 consecutive intervals where both a urine and fecal sample are collected, 
whichever occurs first, or until Day 14. If neither one of the 2 discharge criteria is met by Day 14, at the discretion of 
the Sponsor, the subject may be required to return to the CRU for urine and fecal sample collection in two 24-hour 
periods at approximately 7 and 14 days after discharge from the CRU (eg, Days 21 and 22 and Days 28 and 29).
Subjects will be confined in the CRU for these 24-hour sample collection periods.
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, actual subject release 
from the CRU may occur 1 day after discharge criteria are met.
In both Periods 1 and 2, any subject who experiences emesis within 3 hours post oral dosing will be excluded in the 
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TAK-831
Study ID TAK-831-1008
Page 8 of 79
Final Protocol 
29 October 2019
final data analysis and may be replaced with a new subject. For a subject who drops out in Period 2, the replacement 
subject will be required to complete Period 2 only. If a subject experiences emesis after dosing in Period 2, vomitus 
will be collected throughout the study and assayed for total radioactivity.
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days after the last study 
drug administration to determine if any adverse events (AEs) have occurred since the last study visit.
Study Primary Objectives:
Period 1 (ABA)

To determine ABA of TAK-831 following a single microdose IV administration of 50 µg (~1 µCi) 
[14C]TAK-831 and a single oral administration of 500 mg TAK-831 tablets.
Period 2 (ADME)

To assess the mass balance (ie, cumulative excretion of total radioactivity in urine and feces) following a single 
oral administration of 500 mg (~100 µCi) [14C]TAK-831 suspension.

To characterize the PK of TAK-831 in plasma and urine, and total radioactivity concentration equivalents in 
plasma and whole blood following a single oral suspension dose of 500 mg (~100 µCi) [14C]TAK-831.
Study Secondary Objectives:
Period 1 (ABA)

To determine the PK of [14C]TAK-831 following a single IV administration of 50 µg [14C]TAK-831 and the PK 
of TAK-831 following a single oral administration of 500 mg TAK-831 tablets.
Periods 1 (ABA) and 2 (ADME)

To assess the safety of TAK-831 during the ABA and ADME study periods.
Study Exploratory Objectives:
Study Subject Population: Healthy adult male subjects
Planned Number of Subjects:
6
Planned Number of Sites:
1
Dose Levels:
Period 1:
500 mg of TAK-831
50 µg (1 µCi) [14C]TAK-831
Period 2:
500 mg (~100 µCi) [14C]TAK-831
Route of Administration:
Period 1:
Oral (tablets)
IV infusion
Period 2:
Oral (suspension)
Duration of Treatment:
Period 1:
On Day 1, subject will receive a single oral dose of 
TAK-831 (tablets) followed by a 15-minute IV dose of 
[14C]TAK-831 at 1.25 hours (75 minutes) post oral 
dose.
Planned Study Duration:
Approximately 65 days including the Screening Period
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Commercial Use 


TAK-831
Study ID TAK-831-1008
Page 9 of 79
Final Protocol 
29 October 2019
Period 2:
On Day 1, subject will receive a single oral dose of 
[14C]TAK-831 (suspension).
Main Criteria for Inclusion:
In order to be eligible for study participation, subjects must: 
1.
Healthy, adult, male, 19-55 years of age, inclusive, at screening.
2.
Weighs at least 45 kg and body mass index (BMI) ≥18.0 and ˂32.0 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.
Subjects who are sexually active with a female partner of childbearing potential must use a highly effective 
method of contraception as indicated in Appendix D or true sexual abstinence, only if this is in line with the 
preferred and usual lifestyle of the subject. True abstinence is defined for male subjects as refraining from 
heterosexual intercourse during the entire period of the study, from 1 month prior to the first dose until 95 days 
after the last dosing.
5.
Must agree not to donate sperm from the first dosing until 95 days after the last dosing.
6.
Is able to swallow multiple tablets.
7.
Understands the study procedures and agrees to participate by providing written informed consent, and be willing 
and able to comply with all study procedures and restrictions.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
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, gastric bypass surgery, 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 alcohol 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 C-SSRS), or has made a suicide 
attempt in the previous year prior to screening.
9.
Positive urine drug or alcohol results at screening or first check-in.
10. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
11. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
12. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
13. Orthostatic vital sign results with a decrease in systolic >20 mmHg or decrease in diastolic >10 mmHg, and 
increase in pulse of >20 bpm at screening.
14. QTcF interval is >460 msec or ECG findings are deemed abnormal with clinical significance by the Investigator 
or designee at screening. 
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TAK-831
Study ID TAK-831-1008
Page 10 of 79
Final Protocol 
29 October 2019
15. Estimated creatinine clearance <80 mL/min at screening.
16. Has tattoo(s) or scarring at or near the site of IV infusion or any other condition which may interfere with infusion 
site examination, in the opinion of the Investigator.
17. Has infrequent bowel movements (less than approximately once per day) within 30 days prior to first dosing.
18. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, within 2 weeks 
prior to first dosing.
19. Has received radiolabeled substances or has been exposed to radiation sources within 12 months of first dosing or 
is likely to receive radiation exposure or radioisotopes within 12 months of first dosing such that participation in 
this study would increase their total exposure beyond the recommended levels considered safe (ie, weighted 
annual limit recommended by the ICRP of 3000 mrem).
20. 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. Milk of 
Magnesia (ie, magnesium hydroxide) (≤60 mL per day) may be administered approximately on Day 4 
(Period 1) or Day 8 (Period 2) to ensure defecation, with agreement between the study Investigator and 
Sponsor Physician. Additional administration of milk of Magnesia may be needed on other days at discretion 
of the Investigator and Sponsor Physician.

Any drugs known to be significant inducers of uridine diphosphate glucuronosyltransferase or 
sulfotransferase, 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 Table™) will be consulted to confirm 
lack of PK/pharmacodynamic interaction with study drug(s).

Alcohol, as defined in Table 7.a.
21. 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.
22. Donation of blood or significant blood loss within 56 days prior to the first dosing.
23. Plasma donation within 7 days prior to the first dosing.
24. 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 Period 1 
of the current study.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are:
Period 1 (ABA):

Absolute bioavailability (F) as percent F (%F) for TAK-831.
Period 2 (ADME):

Percent of total radioactivity recovered in urine (Cum%Dose[UR]) and feces (Cum%Dose[FE]) relative to 
the administered radioactive dose (Combined Cum%Dose).

Total radioactive recovery in urine (Ae[UR]) and feces (Ae[FE]) and the percent of the radioactive dose 
excreted in the urine (%Dose[UR]) and feces (%Dose[FE]).

PK parameters Cmax, tmax, t1/2z, AUC∞, and AUClast for TAK-831 in plasma. 

PK parameters Cmax, tmax, t1/2z, AUC∞, and AUClast for total radioactivity concentration equivalents in plasma
and whole blood.

PK parameters for renal clearance (CLR) for TAK-831 in urine.
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TAK-831
Study ID TAK-831-1008
Page 11 of 79
Final Protocol 
29 October 2019
The secondary endpoints will be assessed through evaluation of the following parameters: 
Period 1 (ABA):

PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUClast, and t1/2z for TAK-831, and 
[14C]TAK-831 in plasma.
Periods 1 (ABA) and 2 (ADME):

Tabulated treatment-emergent AEs (TEAEs) and summary statistics for clinically relevant 12-lead ECGs, 
vital signs, and clinical laboratory tests results.
Statistical Considerations:
Descriptive statistics will be provided for the total radioactivity (whole blood, plasma, urine, feces, and if applicable, 
emesis), plasma TAK-831 concentrations and PK parameters, and [14C]TAK-831 plasma and urine radioactivity 
concentration equivalent, using appropriate summary statistics to be fully specified in the statistical analysis plan 
(SAP).
ABA of TAK-831 will be estimated using a ninety percent (90%) confidence interval (CI) constructed for the 
difference in least-squares (LS) mean on the log scale for dose normalized AUC∞between a single oral dose and the 
IV microdose. Exponentiating the log-scale 90% CI will provide a 90% CI for the dose normalized AUC∞geometric 
mean ratio (TAK-831 administered as oral dose / [14C]TAK-831 administered as IV microdose). AUClast and Cmax will 
be analyzed in a similar fashion. 
Mass balance will be calculated as a sum of the percent of the total radioactivity recovered in urine and feces plus any 
radioactivity dose due to emesis (if any occurred) relative to the administered radioactivity dose.
Sample Size Justification:
The sample size of 6 male healthy subjects was selected without statistical considerations and is deemed adequate to 
meet the study objectives. In addition, this sample size is limited based on clinical considerations for this type of study 
and in order to limit exposure to radioactivity.
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TAK-831
Study ID TAK-831-1008
Page 12 of 79
Final Protocol 
29 October 2019
2.0
STUDY SCHEMATIC
Screening
Period 1 a
Within 28 days of first 
dosing in Period 1 
Day -1
Day 1
Days 2 - 8
Check-in
Oral Dosing 
at Hour 0
IV Dosing at 
Hour 1.25
(75 minutes
post oral 
dosing)
Plasma, urine, and fecal sampling for ABA and safety monitoring for at least 
96 hours post oral dose b
<- - - - - - - - - - - - confinement b - - - - - - - - - - - - >
a There will be a washout period of at least 7 days between the last dose in Period 1 and the dose in Period 2.
b Subjects will be confined in the CRU for at least 5 days (until after the last PK sample and morning urine and fecal 
sample [when passed] are collected) and until one of the discharge criteria is met (ie, 80% or greater of the total dose 
of radioactivity administered is recovered in urine and fecal samples or the excretion of radioactivity in the urine 
and feces combined has declined to ≤1% of the total administered radioactivity for at least 2 consecutive intervals 
where both a urine and fecal sample is collected) or up to Day 8.
Period 2 a
Follow-up
Day -1 b
Day 1
Days 2 - 6
Days 7 - 14
Days 21 - 22
Days 28 - 29
30 ± 2
days after 
last 
dosing
Check-in
Oral 
Dosing at 
Hour 0
Whole blood, plasma, urine, and fecal sampling for 
TAK-831 (plasma and urine), total radioactivity
(plasma, whole blood, urine, and feces), 
 
and safety 
monitoring (as applicable) up to approximately 
240 hours postdose
24-hour urine and fecal sampling for 
TAK-831 (urine only), total 
radioactivity, 
 
<- - - - - - confinement c - - - - - >
<confinement c >
<confinement c>
<confinement c>
a There will be a washout period of at least 7 days between the last dose in Period 1 and the dose in Period 2.
b Day -1 of Period 2 will be the same day as Day 8 of Period 1 if the washout is exactly 7 days between doses in 
Periods 1 and 2.
c Subjects will be confined in the CRU for at least 5 days postdose (ie, Day 6) and until 90% or greater of the total 
dose of radioactivity administered is recovered in urine and fecal samples. If less than 90% of the total dose of 
radioactivity administered is recovered in urine and fecal samples within 10 days postdose (ie, Day 11), the subject 
will continue to stay at the CRU until 80% or greater of the total dose of radioactivity administered is recovered in 
urine and fecal samples or the excretion of radioactivity in the urine and feces combined has declined to ≤1% of the 
total administered radioactivity for at least 2 consecutive intervals where both a urine and fecal sample are collected, 
whichever occurs first, or until Day 14. If neither one of the 2 discharge criteria is met by Day 14, at the discretion 
of the Sponsor, the subject may be required to return to the CRU for urine and fecal samples collection in two 
24-hour periods at approximately 7 and 14 days after discharge from the CRU (eg, Days 21 and 22 and Days 28 and 
29). Subjects will be confined in the CRU for these 24-hour sample collection periods. Since up to an approximate 
24-hour time lag is anticipated for radioactivity counting of samples, actual subject release from the CRU may occur 
1 day after discharge criteria are met.
CCI
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TAK-831
Study ID TAK-831-1008
Page 13 of 79
Final Protocol 
29 October 2019
3.0
SCHEDULE OF STUDY PROCEDURES
Study Procedures a
S b
Study Days in Period 1 c
Days →
-1 (C-I d)
1
2
3
4
5
6-8 e
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations 
Full Physical Examination f
X
X g
Height
X
Weight
X
X g
12-Lead Safety ECGs
X
X h
X i
Vital Signs (heart rate and blood pressure)
X h
X j
Orthostatic Vital Signs (heart rate and blood pressure)
X
Vital Signs (respiratory rate and temperature)
X
Hematology, Serum Chemistry k, and UA
X
X
X
Urine Drug and Alcohol Screen
X
X
HIV/Hepatitis Screen
X
C-SSRS l
X
X
X
AE Monitoring
X
Concomitant Medication Monitoring
X
X
Study Drug Administration / PK
TK-831 Administration (oral)
X m
[14C]TAK-831 Administration (IV)
X n
Blood for TAK-831 Plasma PK o
X
X
X
X
X
Blood for [14C]TAK-831 Plasma PK o
X
X
X
X
X
Urine for [14C]TAK-831 PK and Total radioactivityp
X
X
Feces for [14C]TAK-831 PK and Total radioactivity p
X
X
Other Procedures
Confinement in the CRU e, q
X
X
Visit
X
d Subject to the Applicable Terms of Use
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Property of Takeda: :


TAK-831
Study ID TAK-831-1008
Page 14 of 79
Final Protocol 
29 October 2019
Study Procedures a
Study Days in Period 2 c
FU r
Days →
-1 
(C-I d)
1
2
3
4
5
6
7
8 9-11 12-14 21-22 y 28-29 y
Safety Evaluations 
Full Physical Examination f
X
X s
12-Lead Safety ECG
X h
X t
X s
Vital Signs (heart rate and blood pressure)
X h
X u
X s
Hematology, Serum Chemistry k, and UA
X
X
X s
Urine Drug and Alcohol Screen
X
C-SSRS l
X
X s
AE Monitoring
X
Concomitant Medication Monitoring
X
Study Drug Administration / PK
[14C]TAK-831 Administration (oral) 
X m
Blood for Total Radioactivityv
X
X X X X X X X
X
Blood for TAK-831 Whole Blood PK v
X
X X X X X X X
X
Blood for TAK-831 Plasma PK v
X
X X X X X X X
X
Urine for Total Radioactivity, 
, and 
TAK-831 PK w
X
X
X
Feces for Total Radioactivity 
 
X
X
X
Other Procedures
Confinement in the CRU x
X
X
X
X
Phone call
X
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 the last dose in Period 1 and the dose in Period 2.
d
Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU. If subjects are confined throughout the 
washout period, some safety events at check-in of Period 2 (eg, clinical laboratory tests, urine drug and alcohol screen, vital 
signs, and ECGs) may not be performed, following a decision by the Investigator.
e
Subjects who do not meet one of the discharge criteria (ie, 80% or greater of the total dose of radioactivity administered is 
recovered in urine and fecal samples or the excretion of radioactivity in the urine and feces combined has declined to ≤1% of
the total administered radioactivity for at least 2 consecutive intervals where both a urine and fecal sample are collected) by 
Day 5, will remain confined and undergo study procedures until one of the discharge criteria is met or up to Day 8. Since up to 
an approximate 24-hour time lag is anticipated for radioactivity counting of samples, actual subject release from the CRU may 
occur 1 day after discharge criteria are met.
f
Full physical examinations will be conducted at scheduled time points. Symptom-driven physical examination may be 
performed at additional times, at the Investigator’s or designee’s discretion. If confinement extends more than 10 days
postdose in Period 2, a full physical examination will be repeated at the discharge day. If the subject returns to the CRU to 
collect urine and fecal samples in two blocks of 24-hour confinement period on Days 21 and 22 and Day 28 and 29 at the 
discretion of the Sponsor, a full physical examination will be repeated on each discharge day.
g
If the screening assessment was conducted within 4-7 days prior to dosing (Day 1), assessment will be conducted at check-in 
only if, in the opinion of the Investigator, there is reason to believe they have substantially changed.
h
To be performed within 24 hours prior to oral dosing.
i
To be performed at 1 and 4 hours post oral drug administration.
j
To be performed at 1 hour post oral drug administration.
CCI
CCI
CCI
Subject to the Applicable Terms of Use
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Property of Takeda: For Non-Comm
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and


TAK-831
Study ID TAK-831-1008
Page 15 of 79
Final Protocol 
29 October 2019
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
At screening, the C-SSRS Baseline/Screening version will be administered; at all other time points, the Since Last Visit 
version will be administered.
m
Oral drug administration will be performed at Hour 0 of Day 1.
n
A 15-minute IV drug administration will begin at 1.25 hours (75 minutes) post oral dose on Day 1 of Period 1.
o
For a detailed blood sampling schedule refer to Table 3.a.
p
For a detailed urine and fecal sampling schedule refer to Table 3.b.
q
Subjects who meet discharge criteria prior to Day 8 may be confined throughout the washout period at the discretion of the 
CRU.
r
The clinic will contact all subjects (including subjects who terminate the study early) 30 ±2 days after the last study drug 
administration to determine if any AEs have occurred since the last study visit.
s
To be performed at the end of Period 2 (prior to discharge) or prior to early termination from the study.
t
To be performed at 4 hours post oral drug administration.
u
To be performed at 4 and 12 hours post oral administration.
v
For a detailed blood sampling schedule refer to Table 3.c.
w
For a detailed urine and fecal sampling schedule refer to Table 3.d.
x
Subjects will remain confined to the CRU for at least 5 days postdose (ie, Day 6) and until 90% or greater of the total dose of 
radioactivity administered is recovered in urine and fecal samples. If less than 90% of the total dose of radioactivity 
administered is recovered in urine and fecal samples within 10 days postdose (ie, Day 11), the subject will continue to stay at 
the CRU until 80% or greater of the total dose of radioactivity administered is recovered in urine and fecal samples or the 
excretion of radioactivity in the urine and feces combined has declined to ≤1% of the total administered radioactivity for at 
least 2 consecutive intervals where both a urine and fecal sample are collected, whichever occurs first, or until Day 14. If 
neither one of the 2 discharge criteria is met by Day 14, at the discretion of the Sponsor, the subject may be required to return 
to the CRU for urine and fecal samples collection in two 24-hour periods at approximately 7 and 14 days after discharge from 
the CRU (eg, Days 21 and 22 and Days 28 and 29). Subjects will be confined in the CRU for these 24-hour sample collection
periods. Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, actual subject release 
from the CRU may occur 1 day after discharge criteria are met.
y
Only for subjects who do not meet neither one of the 2 discharge criteria by Day 14 and at the discretion of the Sponsor.
Abbreviations: AE = Adverse event, C-I = Check-in, C-SSRS = Columbia-suicide severity rating scale, CRU = Clinical research 
unit, ECG = Electrocardiogram, FU = Follow-up, HIV = Human immunodeficiency virus, INR = International normalized ratio, 
IV = Intravenous, PK = Pharmacokinetics, PT = Prothrombin time, S = Screening, UA = Urinalysis.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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mples. If 
nly 
mples. If 
hin 10
Onl
hin 10 day
nly
day
oactivity a
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mbined ha
Use 
mbined ha
and fecal 
Us
and fecal 
y Day
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y Day 14,
U
14,
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28 and 29
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armacoki
No
armacoki


TAK-831
Study ID TAK-831-1008
Page 16 of 79
Final Protocol 
29 October 2019
Table 3.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-831
(Period 1 - ABA Study Period)
Study 
Day
Time 
(relative to oral dosing)
Time 
(relative to IV infusion)
Blood Sample 
Collection
(oral dose)
Blood Sample 
Collection
(IV dose)
Matrix
Plasma 
Sample 1 a
Plasma Sample 2
b
Day 1
0 (predose)
X c
X c
0.5 hour postdose (± 2 min)
X c
1 hour postdose (± 2 min)
X c
1.25 hours postdose (- 2 min)
0 (predose) 
X c
1.5 hours postdose (± 2 min)
End of infusion
X
X
5 min after the end of infusion (± 2 
min)
X
15 min after the end of infusion (± 
2 min)
X
2 hours postdose (± 2 min)
30 min after the end of infusion (± 
2 min)
X
X
1 hour after the end of infusion (± 2 
min)
X
4.5 hours postdose (± 2 min)
3 hours after the end of infusion (± 
5 min)
X
X
6.5 hours postdose (± 2 min)
5 hours after the end of infusion (± 
5 min)
X
X
8.5 hours postdose (± 2 min)
7 hours after the end of infusion (± 
5 min)
X
X
12.5 hours postdose (± 5 min)
11 hours after the end of infusion 
(± 5 min)
X
X
Day 2
24.5 hours postdose (± 5 min)
23 hours after the end of infusion 
(± 5 min)
X
X
36.5 hours postdose (± 10 min)
35 hours after the end of infusion 
(± 10 min)
X
X
Day 3
48.5 hours postdose (± 10 min)
47 hours after the end of infusion 
(± 10 min)
X
X
Day 4
72.5 hours postdose (± 10 min)
71 hours after the end of infusion 
(± 10 min)
X
X
Day 5
96.5 hours postdose (± 15 min)
95 hours after the end of infusion 
(± 15 min)
X
X
a For determination of TAK-831 in plasma following oral tablet dose.
b For determination of [14C]-total radioactivity, and [14C]TAK-831 in plasma following IV infusion.
c Pre-IV dose samples should be stored separately away from the postdose samples to avoid cross contamination.
mmercial Use Only and Subject to the Applicable Terms of Use
e e 
n
dose)
rm
dose)
f
a Sample
Term
a Sample
b
Te
b
rm
X
e T
ble
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Subj
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bjejejej
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d S
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ly a
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a
ter the end
On
ter the end
On
our
U
ours
Us
s after
se
after
a
5
l
5 min)
al U
min)
se
23
cia
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al 
hour
(± 
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(± 5
i
5
al
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n)
m
n)
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3
r
3
For Non-Com
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er
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o
10 min)
om
min)
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ose (±
n-C
ose (± 10
C
10
C
postdose 
r No
postdose 
No
Property of Takeda: Fo
n of
F
of TAK
Fo
TAK
ation
da:
ation of
a: 
of [1
se
ke
se sampl
ked
sampl
Fo


TAK-831
Study ID TAK-831-1008
Page 17 of 79
Final Protocol 
29 October 2019
Table 3.b
Urine and Fecal Sampling Schedule (Period 1 – ABA Study Period)
Study Day
Time Interval (hours)
(Relative to Oral Dosing)
Urine Sample Collection
Feces Sample 
Collection
Matrix
Urine a
Feces b
Days -2 to 1
-48 to 0 hours (predose)
X c, d
X d, e
Day 1
0-1.25 hours (prior to IV dosing)
X d
X d
Day 1
1.25-12 hours
X
X (1.25-24 hours)
Days 1 to 2
12-24 hours
X
Days 2 to 3
24-48 hours 
X
X
Days 3 to 4
48-72 hours
X
X
Days 4 to 5
72-96 hours
X f
X f
Days 5 to 6
(if required)
96-120 hours
X g
X g
Days 6 to 7
(if required)
120-144 hours 
X g
X g
Days 7 to 8
(if required)
144-168 hours 
X g
X g
a Urine sample for [14C]TAK-831 and [14C]-total radioactivity following IV infusion.
b Feces sample for [14C]TAK-831 and [14C]-total radioactivity following IV infusion.
c Predose urine sample is to be obtained within 24 hours prior to IV infusion and prior to oral dosing.
d Pre-IV dose samples should be stored separately away from the postdose samples to avoid cross contamination.
e Predose fecal sample is to be obtained within 48 hours prior to oral dosing. Subjects will be asked to bring a fecal 
sample at check-in (if produced within 48 hours prior to oral dosing). Feces produced between check-in and dosing 
will also be collected as a predose sample with the sample produced nearest to oral dosing to be retained as the only 
predose sample.
f Including the urine and fecal sample collected on the morning of Day 5 (when passed) prior to furlough. Subjects 
will be asked to provide a urine and a fecal sample prior to release from the clinic on Day 5.
g For subjects who do not meet a discharge criterion by Day 5, samples will continue to be collected in 24-hour 
intervals until radioactivity in urine and feces combined is ≤1% of the total administered radioactivity for at least 2 
consecutive intervals where both a urine and fecal sample are collected, the excretion of radioactivity is ≥80% of the 
administered radioactive dose, or up to Day 8.
ubject to the Applicable Terms of Use
o
ms
erm
25
bl
25-
ble
-24 ho
ble 
24 ho
Te
X
b
X
ab
lic
pp
Ap
e A
th
g
ct
Commercial Use Only and Sub
wing IV i
Sub
wing IV i
llowing I
nd S
llowing I
r to IV in
and
r to IV in
om the p
nly a
om the p
rs prior to
Only
rs prior to
ior to 
e O
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O
or
the samp
Use
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ected on 
cial
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fecal sam
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fecal sam
charge cr
me
charge cr
rine and f
omm
rine and f
Property of Takeda: For Non
oth
Co
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Com
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dose, or u
n-C
dose, or u
ubj


TAK-831
Study ID TAK-831-1008
Page 18 of 79
Final Protocol 
29 October 2019
Table 3.c
Blood Collection Schedule (Period 2 - ADME Study Period)
Study Day
Matrix
Sample collected 
for analysis in 
Whole Blood
Sample collected for analysis in Plasma
Time 
(Relative to Oral Suspension 
Dosing)
Blood Sample a
Plasma 
Sample 1 b
Plasma 
Sample 2 c
Plasma 
Sample 3 d
Day 1
0 (predose)
X e
X e
X e
X e
0.25 hour postdose (± 2 min)
X
X
X
0.5 hour postdose (± 2 min)
X
X
X
X
1 hour postdose (± 2 min)
X
X
X
X
2 hours postdose (± 2 min)
X
X
X
4 hours postdose (± 2 min)
X
X
X
X
6 hours postdose (± 2 min)
X
X
X
8 hours postdose (± 2 min)
X
X
X
X
12 hours postdose (± 5 min)
X
X
X
X
Day 2
24 hours postdose (± 5 min)
X
X
X
X
36 hours postdose (± 10 min)
X
X
X
Day 3
48 hours postdose (± 10 min)
X
X
X
X
Day 4
72 hours postdose (± 10 min)
X
X
X
X
Day 5
96 hours postdose (± 15 min)
X
X
X
Day 6
(if required)
120 hours postdose (± 30 min)
X
X
X
X
Day 7
(if required)
144 hours postdose (± 30 min)
X
X
X
Day 8
(if required)
168 hours postdose (± 30 min)
X
X
X
X
Day 9
(if required)
192 hours postdose (±1 hour)
X
X
X
Day 10
(if required)
216 hours postdose (±1 hour)
X
X
X
Day 11
(if required)
240 hours postdose (±1 hour)
X
X
X
a Blood sample 1 – Blood sample for total [14C] determination (total radioactivity) in whole blood.
b Plasma sample 1 – Blood sample for total [14C] determination in plasma.
c Plasma sample 2 – Blood sample for TAK-831 PK in plasma.
d Plasma sample 3 – Blood sample for 
e Predose blood and plasma samples should be stored separately away from the postdose samples to avoid cross 
contamination.
CCI
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ma
ms
ma
Plasma 
Ter
Plasma 
Sampl
le T
Sampl
ms
ble
ab
ab
ab
ca
X
plic
X
A
X
App
X
e 
X
e A
th
to
to
to
to
to
X
bj
X
ec
X
ubj
X
bj
X
Su
d
nd
a
X
O
X
nly
X
e O
X
O
se
ia
min)
erc
min)
iaiaia
cia
(±
om
(± 30 
mm
30 mi
m
mi
me
stdose (±
n-C
stdose (±
Co
urs
r
urs postd
r N
postd
No
240 hour
a: F
240 hour
Fo
Property of Take
ample
ked
ample 1
d
1
ma
Ta
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Tak
samp
lasma
f T
lasma sa
T
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Plasm
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Plasm
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rt
e Pre
ty
Pre
da


TAK-831
Study ID TAK-831-1008
Page 19 of 79
Final Protocol 
29 October 2019
Table 3.d
Urine and Fecal Sampling Schedule (Period 2 - ADME Study Period)
Study Day
Time Interval (hour)
(Relative to Oral Suspension Dosing)
Urine Sample Collection
Feces Sample Collection
Matrix
Urine a
Feces b
Day -1 to 1
-24 to 0 hour (predose)
X c
X d
Day 1
0-12 hour
X
X (0-24 hour)
Days 1 to 2
12-24 hour
X
Days 2 to 3
24-48 hour
X
X
Days 3 to 4
48-72 hour
X
X
Days 4 to 5
72-96 hour
X
X
Days 5 to 6
96-120 hour
X
X
Days 6 to 7
(if required)
120-144 hour
X
X
Days 7 to 8
(if required)
144-168 hour
X
X
Days 8 to 9
(if required)
168-192 hour
X
X
Days 9 to 10
(if required)
192-216 hour e
X
X
Days 10 to 11
(if required)
216-240 hour e
X
X
Days 11 to 12 e
(if required)
240-264 hour e
X
X
Days 12 to 13 e
(if required)
264-288 hour e
X
X
Days 13 to 14 e
(if required)
288-312 hour e
X
X
Days 21 to 22 e
(if required)
480-504 hour e
X
X
Days 28 to 29 e
(if required)
648-672 hour e
X
X
a Urine samples for total [14C] determination, for 
 and for assessment of TAK-831 PK.
b Feces samples for total [14C] determination (total radioactivity) and for 
c Predose urine sample is to be obtained within 24 hours prior to dosing. Predose urine samples should be stored separately away from 
the postdose samples to avoid cross contamination.
d Predose fecal sample is to be obtained within 48 hours prior to dosing. Subjects will be asked to bring a fecal sample at check-in (if 
produced within 48 hours prior to dosing). Feces produced between check-in and dosing will also be collected as a predose sample 
with the sample produced nearest to dosing to be retained as the only predose sample. Predose fecal samples should be stored 
separately away from the postdose samples to avoid cross contamination.
e Samples will continue to be collected in 24-hour intervals until radioactivity in urine and feces combined is ≥90% of the administered
radioactive dose or up to 10 days postdose (Day 11). If less than 90% of the total dose of radioactivity administered is recovered in 
urine and fecal samples within 10 days postdose (ie, Day 11), the subject will continue to stay at the CRU until 80% or greater of the 
total dose of radioactivity administered is recovered in urine and fecal samples or the excretion of radioactivity in the urine and feces 
combined has declined to ≤1% of the total administered radioactivity for at least 2 consecutive intervals where both a urine and fecal 
sample are collected, whichever occurs first, or until Day 14. If neither one of the 2 discharge criteria is met by Day 14, at the 
discretion of the Sponsor, the subject may be required to return to the CRU for urine and fecal samples collection in two 24-hour 
periods at approximately 7 and 14 days after discharge from the CRU (eg, Days 21 and 22 and Days 28 and 29). Subjects will be 
confined in the CRU for these 24-hour sample collection periods.
CCI
CCI
e Only and Subject to the Applicable Terms of Use
ction
of U
ction
Us
o
d
ms
X (0
le T
X (0-
e T
-24
T
24 h
er
bl
ic
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Ap
A
th
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ect
X
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S
an
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Only
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se
ur
c
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04 hour
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erc
648-
Com
648-672 h
om
672 h
mm
da: For Non-C
determin
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For 
es to avoi
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Property of Taked
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mples will 
Ta
mples will 
adioactiv
of T
adioactiv
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total
ty 
total
co
t
co
C


TAK-831
Study ID TAK-831-1008
Page 20 of 79
Final Protocol 
29 October 2019
4.0
INTRODUCTION
4.1
Background
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; van Os 2009). 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 (Krystal 2003). 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 (Calcia 2012, Ohnuma 2008, Hashimoto 2003,
Hashimoto 2005). 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 
(Kakegawa 2011). 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 (van Os 2009, Lane 2013).
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. It also 
demonstrated a positive effect on cognition and social interaction in rodent cognition and 
behavioral models. TAK-831 is under development for cognitive impairment associated with 
schizophrenia and negative symptoms of schizophrenia (IB 2019).
Pharmacokinetics
CCI
mercial Use Only and Subject to the Applicable Terms of Use
s, and
ms o
s, and
vation 
erm
vation 
impaire
e Te
impaire
cognit
ble 
cognitiviv
ptors is
icab
ptors is
which co
plic
which co
ges in th
App
ges in th
of pat
he A
of patie
A
ie
uma
the
uma 20
he
20
nist of N
t to 
nist of N
transmi
ect 
transmi
ndogeno
bje
ndogeno
and l
Sub
and lon
u
on
potentia
nd S
potentia
weak inh
and
weak inh
c
n
cogni
nly a
ogniti
y a
ti
iti
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iti v
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Lane
On
Lane 20
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20
inhibito
Use 
inhibito
acids a
l Us
acids a
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serine l
cognit
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mme
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sympto
Com
sympto
Property of Takeda: For Non


TAK-831
Study ID TAK-831-1008
Page 21 of 79
Final Protocol 
29 October 2019
Safety
To date, TAK-831 has been administered to a total of 199 healthy subjects in 5 completed phase 1 
studies (TAK-831-1001, TAK-831-1003, TAK-831-1004 TAK-831-1005, and TAK-831-1006) 
and to 40 subjects with Friedreich ataxia in a completed phase 2 study. Three studies are ongoing, 
including a phase 1 study in healthy adult Asian subjects (TAK-831-1002), and two phase 2 
studies in adult subjects with schizophrenia (TAK-831-2001 and TAK-831-2002).
The safety data from healthy subjects cannot be directly generalized for patients. However, no 
safety signal has manifested that would prevent additional studies in healthy subjects or in subjects 
with schizophrenia.
Refer to the Investigator’s Brochure (IB) for detailed background information on TAK-831
(IB 2019).
4.2
Rationale for the Proposed Study
The primary purposes of the present study are to characterize the ABA (Period 1) and the 
absorption, metabolism, excretion, and mass balance of TAK-831 after single oral administration 
(Period 2) in healthy adult male subjects, by collecting plasma, urine, and feces samples for drug 
concentration analysis, and plasma, whole blood, urine, and fecal samples for total radioactivity 
analysis 
. The study will provide data required to evaluate the mass balance 
CCI
CCI
CCI
CCI
to the Applicable Terms of Use
com
lica
comple
ca
ple
mp
m
ca
mp
m
n
Ap
nd TAK
Appl
d TAK
hree stu
e Ap
hree stu
002), an
the 
002), an
AK
to
AK-831
o th
-831
of Takeda: For Non-C
h
N
heal
Non
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on
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ltl
on
ltl
manifest
or N
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Fo
renia.
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Terms of U
-Commercial Use Only and Subject to
Propert
perty of
I
y
I


TAK-831
Study ID TAK-831-1008
Page 22 of 79
Final Protocol 
29 October 2019
 of TAK-831 in humans. Based on preliminary data in healthy subjects, 
the geometric mean plasma terminal t1/2z of TAK-831 is approximately 15 hours; thus, more than 
90% of the radioactivity should be eliminated within 60 hours postdose.
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 healthy subjects participating in this study. The dose of 500 mg TAK-831 in both T2 
tablets and suspension formulation is administered according to the dosing recommendations 
found in the IB (IB 2019), was previously found to be well tolerated, and is not anticipated to 
induce any potential health risk.
The estimated radiation dose from a single IV administration of [14C]TAK-831 (~1 µCi) and a 
single oral dose of [14C]TAK-831 (~100 μCi) is below the radiation dose limits set forth in 21 CFR 
361 for the whole body, active blood forming organs, lens of the eye, gonads, and other organs (see 
Section 6.3.2). Thus, the health risk resulting from exposure to radiation in the study drug is very 
low.
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (eg, 12-lead ECG, vital signs, C-SSRS, clinical laboratory tests, AE questioning, and 
physical examinations) are adequate to protect the subjects’ safety and should detect all expected 
TEAEs.
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.
CCI
nd Subject to the Applicable Terms of Use
ntial ris
e Te
ntial ris
in
ble
in both
le 
both
mmenda
cab
mmenda
ot antici
plic
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TAK
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Property of Takeda: For Non-Commercial Use Only a
nical lab
and
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Use 
tudy par
nro
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nrolled i
l Us
lled i


TAK-831
Study ID TAK-831-1008
Page 23 of 79
Final Protocol 
29 October 2019
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
NA
5.2
Study Objectives
5.2.1
Study Primary Objectives
Period 1 (ABA)

To determine ABA of TAK-831 following a single microdose IV administration of 
50 µg (~1 µCi) [14C]TAK-831 and a single oral administration of 500 mg TAK-831 tablets.
Period 2 (ADME)

To assess the mass balance (ie, cumulative excretion of total radioactivity in urine and feces) 
following a single oral administration of 500 mg (~100 µCi) [14C]TAK-831 suspension.

To characterize the PK of TAK-831 in plasma and urine, and total radioactivity concentration 
equivalents in plasma and whole blood following a single oral suspension dose of 
500 mg (~100 µCi) [14C]TAK-831.
5.2.2
Study Secondary Objectives
Period 1 (ABA)

To determine the PK of [14C]TAK-831 following a single IV administration of 50 µg 
[14C]TAK-831 and the PK of TAK-831 following a single oral administration of 500 mg 
TAK-831 tablets.
Periods 1 (ABA) and 2 (ADME)

To assess the safety of TAK-831 during the ABA and ADME study periods.
5.2.3
Study Exploratory Objectives
5.3
Endpoints
For full description of the PK parameters indicated below see Section 9.3.1.
CCI
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
ministra
e Ap
ministra
500
the
500 mg
he 
mg
tal radio
bjec
tal radio
S
µCi
Subj
µCi) [
bj
) [1
e
1
urine, a
nd S
urine, a
ng a sing
an
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AK
erci
AK-
rci
-831
cia
831
f TAK-
mer
f TAK-
ADME)
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C
et
N
ety 
No
y of
on
of T
n
T
f
n
f
Property of Takeda: F
Explora
For
Explora
roperty of Takeda: F


TAK-831
Study ID TAK-831-1008
Page 24 of 79
Final Protocol 
29 October 2019
5.3.1
Primary Endpoints
Period 1 (ABA):

Absolute bioavailability (F) as percent F (%F) for TAK-831.
Period 2 (ADME):

Percent of total radioactivity recovered in urine (Cum%Dose[UR]) and feces 
(Cum%Dose[FE]) relative to the administered radioactive dose (Combined Cum%Dose).

Total radioactive recovery in urine (Ae[UR]) and feces (Ae[FE]) and the percent of the 
radioactive dose excreted in the urine (%Dose[UR]) and feces (%Dose[FE]).

PK parameters Cmax, tmax, t1/2z, AUC∞, and AUClast for TAK-831 in plasma. 

PK parameters Cmax, tmax, t1/2z, AUC∞, and AUClast for total radioactivity concentration 
equivalents in plasma and whole blood.

PK parameters for renal clearance (CLR) for TAK-831 in urine.
5.3.2
Secondary Endpoints 
Period 1 (ABA):

PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUClast, and t1/2z for 
TAK-831, and [14C]TAK-831 in plasma.
Periods 1 (ABA) and 2 (ADME):

Tabulated TEAEs and summary statistics for clinically relevant 12-lead ECGs, vital signs, and 
clinical laboratory tests results.
5.3.3
Exploratory Endpoints
CCI
Commercial Use Only and Subject to the Applicable Terms of Use
um%Do
able
um%Do
percent 
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TAK-831
Study ID TAK-831-1008
Page 25 of 79
Final Protocol 
29 October 2019
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is an open-label, 2-period, single-dose study in 6 male healthy subjects. 
On Day 1 of Period 1 (ABA Study Period), subjects will receive a single unlabeled oral 500 mg 
dose of TAK-831 as tablets. At 1.25 hours (75 minutes) post oral dosing (ie, 15 minutes prior to 
the median tmax for the oral unlabeled dose [~1.5 hours]), subjects will receive a 15-minute IV 
infusion of a microdose of 50 µg (~1 µCi) [14C]TAK-831. Serial blood sampling will be 
performed up to Day 5 to determine the PK of TAK-831 in the plasma for the oral dose and 
[14C]-total radioactivity and PK of [14C]TAK-831 in the plasma for the IV dose. Urine and fecal 
output will also be collected up to the morning of Day 5 postdose to determine [14C]TAK-831 
concentrations. Subjects will remain in the CRU and continue with urine and feces collection until 
one of the discharge criteria is met (ie, 80% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples or the excretion of radioactivity in the urine 
and feces combined has declined to ≤1% of the total administered radioactivity for at least 
2 consecutive intervals where both a urine and fecal sample are collected) or up to Day 8 but no 
less than Day 5 for [14C]-total radioactivity excretion in urine and feces. 
In Period 1, subjects will be confined in the CRU for at least 5 days (until after the last PK sample 
and morning urine and fecal sample [when passed] are collected) and until one of the discharge 
criteria is met or up to Day 8. Subjects will return to the CRU on Day -1 of Period 2 for Period 2 
procedures.
There will be a washout period of at least 7 days between the last dose in Period 1 and the dose in 
Period 2.
On Day 1 of Period 2 (ADME Study Period), subjects will receive a single dose of 500 mg 
(~100 μCi) [14C]TAK-831 as an oral suspension. Serial blood sampling will be performed and 
urine and feces will be collected to determine the PK of TAK-831 in plasma and urine, and total 
radioactivity in plasma, whole blood, urine, and feces, 
 
 Complete urinary and fecal output will be collected 
during the confinement period until discharge criteria are met (anticipated to be 10 days postdose 
or less).
In Period 2, subjects will be confined in the CRU for at least 5 days postdose (ie, Day 6) and until 
90% or greater of the total dose of radioactivity administered is recovered in urine and fecal 
samples. If less than 90% of the total dose of radioactivity administered is recovered in urine and 
fecal samples within 10 days postdose (ie, Day 11), the subject will continue to stay at the CRU 
until 80% or greater of the total dose of radioactivity administered is recovered in urine and fecal 
samples or the excretion of radioactivity in the urine and feces combined has declined to ≤1% of 
the total administered radioactivity for at least 2 consecutive intervals where both a urine and fecal 
sample are collected, whichever occurs first, or until Day 14. If neither one of the 2 discharge 
criteria is met by Day 14, at the discretion of the Sponsor, the subject may be required to return to 
the CRU for urine and fecal sample collection in two 24-hour periods at approximately 7 and 
CCI
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 26 of 79
Final Protocol 
29 October 2019
14 days after discharge from the CRU (eg, Days 21 and 22 and Days 28 and 29). Subjects will be 
confined in the CRU for these 24-hour sample collection periods.
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, 
actual subject release from the CRU may occur 1 day after discharge criteria are met.
In both Periods 1 and 2, any subject who experiences emesis within 3 hours post oral dosing will 
be excluded in the final data analysis and may be replaced with a new subject. For a subject who 
drops out in Period 2, the replacement subject will be required to complete Period 2 only. If a 
subject experiences emesis after dosing in Period 2, vomitus will be collected throughout the study 
and assayed for total radioactivity.
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days 
after the last study drug administration to determine if any AEs have occurred since the last study 
visit.
The planned dose levels of TAK-831 to be evaluated are outlined in Table 6.a. 
Table 6.a
Planned Dose Levels of TAK-831 and [14C]TAK-831
Dose
Route of Administration
Period 1 (Treatment A)
TAK-831
500 mg
Oral tablet
[14C]TAK-831
50 µg (1 µCi)
IV
Period 2 (Treatment B)
[14C]TAK-831
500 mg (~100 µCi)
Oral suspension
6.2
Dose Escalation
NA
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
In Period 1 of the study, the ABA of TAK-831 will be estimated using a labeled IV microdose 
administered 1.25 hours (75 minutes) after an unlabeled oral dose in order to characterize the 
disposition properties of TAK-831. In order to determine ABA accurately and reliably, a healthy 
adult population is chosen.
Characterization of the disposition of a drug following IV administration facilitates the 
understanding of fundamental aspects of TAK-831’s PK that cannot be determined from oral 
dosing alone, including bioavailability, intrinsic clearance, and volume of distribution. The results 
of this study will contribute to a robust understanding of the PK characteristics of TAK-831.
In Period 2 of the study, characterization of the absorption, metabolism, excretion, and mass 
balance of TAK-831 after oral administration of a single 500 mg (~100 μCi) [14C]TAK-831 will 
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 27 of 79
Final Protocol 
29 October 2019
be achieved by collecting plasma samples for drug concentration analysis, and plasma, urine, and 
fecal samples for total radioactivity analysis 
. The study will provide data 
required to evaluate the mass balance 
 of TAK-831 in humans. 
6.3.2
Rationale for Dose
A single dose of 500 mg has been selected for this study as it is within the therapeutic dose range 
currently tested in Phase 2 studies of TAK-831. The highest dose of TAK-831 tested in healthy 
subjects was 
 in oral suspension and was found to be safe and well tolerated.
A radioactive IV dose of ~1 µCi in Period 1 (ABA) followed by an oral dose of ~100 µCi in 
Period 2 (ADME) were selected based on organ exposure data derived from a rat quantitative 
whole-body autoradiography/autoradioluminography study (see below) and the need to have 
sufficient specific radioactivity, for detection and analysis of parent drug and/or 
in 
plasma, urine, and fecal samples.
The calculated radiation absorbed doses were relatively low (<2.500 mrem and <0.025 mSv) for 
26 of 27 tissues for male human subjects following a single oral dose of [14C]TAK-831 of 100 μCi.
The highest estimated absorbed dose was in the kidneys, which represented 0.30% of the 
allowable 5000 mrem Food and Drug Administration (FDA) exposure limit for a single tissue.
The overall human male whole-body exposure was predicted to be 0.7633 mrem (0.0076 mSv), 
which represented approximately 0.025% of the allowable 3000 mrem FDA exposure limit and 
0.76% of the allowable International Commission on Radiological Protection (ICRP) limit of
1 mSv and is considered to be safe.
A single oral dose of up to 100 μCi (3.70 MBq) of [14C]TAK-831 is not expected to represent a 
major whole-body radiation exposure risk to human male subjects as defined in the FDA and ICRP 
guidelines.
6.3.3
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the blood, urine, and feces collections for radioactivity, plasma concentrations, and 
for TAK-831 are the critical procedures and are required to be collected, as 
appropriate, as close to the scheduled times defined in this protocol as possible.
CCI
CCI
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TAK-831
Study ID TAK-831-1008
Page 28 of 79
Final Protocol 
29 October 2019
6.4
Study 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. Discontinued subjects 
may be replaced at the discretion of the Sponsor and the Investigator. In both Periods 1 and 2, any 
subject who experiences emesis within 3 hours post the oral dose may be discontinued, excluded 
from the final data analysis, and may be replaced with a new subject. For a subject who drops out 
in Period 2, the replacement subject will be required to complete Period 2 only.
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first subject.
6.5.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0).
6.5.3
Definition of Study 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.
6.5.4
Definition of Study 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 Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
n-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 29 of 79
Final Protocol 
29 October 2019
6.5.6
Criteria for Premature Termination or Suspension of a Site
There is no predetermined criteria for termination of suspension of a site. 
Termination or suspension of a site may occur at any time at the discretion of the Sponsor.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-831
Study ID TAK-831-1008
Page 30 of 79
Final Protocol 
29 October 2019
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subjects must fulfill all the following inclusion criteria to be eligible for participation in the study:
1. Healthy, adult, male, 19-55 years of age, inclusive, at screening.
2. Weighs at least 45 kg and body mass index (BMI) ≥18.0 and ˂32.0 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. Subjects who are sexually active with a female partner of childbearing potential must use a 
highly effective method of contraception as indicated in Appendix D or true sexual abstinence, 
only if this is in line with the preferred and usual lifestyle of the subject. True abstinence is 
defined for male subjects as refraining from heterosexual intercourse during the entire period 
of the study, from 1 month prior to the first dose until 95 days after the last dosing.
5. Must agree not to donate sperm from the first dosing until 95 days after the last dosing.
6. Is able to swallow multiple tablets.
7. Understands the study procedures and agrees to participate by providing written informed 
consent, and be willing and able to comply with all study procedures and restrictions.
7.2
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, gastric bypass surgery, 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 alcohol 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.
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 31 of 79
Final Protocol 
29 October 2019
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. Positive urine drug or alcohol results at screening or first check-in.
10. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg), or hepatitis C virus (HCV).
11. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
12. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
13. Orthostatic vital sign results with a decrease in systolic >20 mmHg or decrease in diastolic 
>10 mmHg, and increase in pulse of >20 bpm at screening.
14. QTcF interval is >460 msec or ECG findings are deemed abnormal with clinical significance 
by the Investigator or designee at screening.
15. Estimated creatinine clearance <80 mL/min at screening.
16. Has tattoo(s) or scarring at or near the site of IV infusion or any other condition which may 
interfere with infusion site examination, in the opinion of the Investigator.
17. Has infrequent bowel movements (less than approximately once per day) within 30 days prior 
to first dosing.
18. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, 
within 2 weeks prior to first dosing.
19. Has received radiolabeled substances or has been exposed to radiation sources within 
12 months of first dosing or is likely to receive radiation exposure or radioisotopes within 
12 months of first dosing such that participation in this study would increase their total 
exposure beyond the recommended levels considered safe (ie, weighted annual limit 
recommended by the ICRP of 3000 mrem).
20. 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. Milk of 
Magnesia (ie, magnesium hydroxide) (≤60 mL per day) may be administered 
approximately on Day 4 (Period 1) or Day 8 (Period 2) to ensure defecation, with 
agreement between the study Investigator and Sponsor Physician. Additional 
administration of milk of Magnesia may be needed on other days at discretion of the 
Investigator and Sponsor Physician.

Any drugs known to be significant inducers of uridine diphosphate 
glucuronosyltransferase or sulfotransferase, including St. John’s Wort, within 28 days 
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
face
rm
face
t screen
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t screen
decrease
App
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TAK-831
Study ID TAK-831-1008
Page 32 of 79
Final Protocol 
29 October 2019
prior to the first dosing and throughout the study, including the follow-up period. 
Appropriate sources (eg, Flockhart Table™) will be consulted to confirm lack of 
PK/pharmacodynamic interaction with study drug(s).

Alcohol, as defined in Table 7.a.
21. 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.
22. Donation of blood or significant blood loss within 56 days prior to the first dosing.
23. Plasma donation within 7 days prior to the first dosing.
24. 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 Period 1 of the current study.
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. 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.
Milk of Magnesia (ie, magnesium hydroxide) (≤60 mL per day) may be administered 
approximately on Day 4 (Period 1) or Day 8 (Period 2) to ensure defecation, with agreement 
between the study Investigator and Sponsor Physician. Additional administration of milk of 
Magnesia may be needed on other days at discretion of the Investigator and Sponsor Physician.
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.
ercial Use Only and Subject to the Applicable Terms of Use
gator or
Ter
gator or
dosing.
icab
dosing.
st dosing
he Ap
st dosing
or dosin
the
r dosin
ducts
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24
nd
24 hou
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Use
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N
(


TAK-831
Study ID TAK-831-1008
Page 33 of 79
Final Protocol 
29 October 2019
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Randomization 
(Days -28 to predose [Day 1])
Post-Randomization (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from 48 hours prior to 
first dosing in each period and 
throughout the period of PK 
sample collection.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing (a)
Prohibited from 24 hours prior to 
first dosing in each period and 
throughout the period of PK 
sample collection (a).
Medications
See Sections 7.2 and 7.3
See Sections 7.2 and 7.3
Nicotine
Prohibited from check-in
Prohibited throughout 
confinement
Food substance
Poppy seeds
Prohibited from 96 days prior to first dosing
Prohibited until end of PK 
collection in Period 2
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited until end of PK
collection in Period 2
(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.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Water (except water provided with each oral dosing) will be restricted 1 hour prior to and 1 hour 
after each oral 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.
Subjects will fast overnight for at least 10 hours prior to each oral study drug administration and 
will continue to fast for at least 4 hours post oral dosing.
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all food 
and drink except water between meals and snacks
7.4.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours post oral dosing, except 
when they are supine or semi-reclined for study procedures (eg, IV dosing on Day 1 of Period 1).
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.
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
io
m
ior to 
ms
r to 
oro
m
oro
d and
erm
d and
of PK 
Ter
of PK 
s o
24
ab
24 hours
able
hours
n each pe
lica
n each pe
t the peri
pplic
t the peri
collectio
App
collectio
Sections
he A
Sections
Prohibite
o the
Prohibite
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rst 
d
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e
Su


TAK-831
Study ID TAK-831-1008
Page 34 of 79
Final Protocol 
29 October 2019
7.5
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.

Positive urine drug or alcohol results.

Difficulties in blood collection.
Any subject who experiences emesis within 3 hours post the oral dose may be discontinued, 
excluded from the final data analysis, and may be replaced with a new subject. In Period 2, if a 
subject experiences emesis after oral dosing, vomitus will be collected throughout the study and 
assayed for total radioactivity.
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.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the Investigator. In addition, efforts should be made to perform all procedures scheduled for the 
end-of-study or early termination as described in Section 3.0.
7.7
Subject Replacement
Discontinued subjects may be replaced at the discretion of the Sponsor and the Investigator. For a 
subject who drops out in Period 2, the replacement subject will be required to complete Period 2 
only.
al Use Only and Subject to the Applicable Terms of Use
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t in Peri
Non
t in Peri


TAK-831
Study ID TAK-831-1008
Page 35 of 79
Final Protocol 
29 October 2019
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
8.1.1
TAK-831 Tablet
A single unlabeled 500 mg dose of TAK-831 (5 x 100 mg T2 tablets) will be administered in 
Period 1 of the study. 
Oral dose of TAK-831 drug product is a nonsterile, oral, tablet dosage form, containing 100 mg (as 
freebase) of TAK-831.
8.1.2
[14C]TAK-831 IV Sterile Solution
An IV dose of 50 μg [14C]TAK-831 (~1 µCi) will be administered as a 15-minute infusion at 
1.25 hours (75 minutes) after the TAK-831 oral dose (Section 6.1) in Period 1 of the study. 
The drug product is prepared in the CRU pharmacy as an IV solution. The solution will be 
prepared and labeled by licensed pharmacy staff according to the procedures outlined in the 
pharmacy manual.
8.1.3
[14C]TAK-831 Oral Suspension
A dose of 500 mg [14C]TAK-831 (~100 µCi) as oral suspension will be administered in Period 2 of 
the study.
The drug product is prepared in the CRU pharmacy as an oral suspension. The suspension will be 
prepared and labeled by licensed pharmacy staff according to the procedures outlined in the 
pharmacy manual.
8.1.4
Clinical Study Drug Labeling
TAK-831 tablet, [14C]TAK-831 IV solution, and [14C]TAK-831 oral suspension containers will be 
affixed with clinical labels in accordance with local regulatory requirements.
8.1.5
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-831 products to allow completion of this 
study. 
Celerion will provide sufficient quantities of preparation and/or dilution solutions to allow 
completion of the study. The same lot number will be used throughout the 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.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
red in
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erty
The
r


TAK-831
Study ID TAK-831-1008
Page 36 of 79
Final Protocol 
29 October 2019
8.1.6
Clinical Study Drug Blinding
This is an open-label study.
8.1.7
Randomization Code Creation and Storage 
NA
8.1.8
Clinical Study Blind Maintenance/Unblinding Procedure
NA
8.1.9
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.
ct to the Applicable Terms of Use
be retai
o the
be retai
instruct
t to 
instruct
Property of Takeda: For Non-Commercial Use Only and Subjec
accounta
ect 
accounta


TAK-831
Study ID TAK-831-1008
Page 37 of 79
Final Protocol 
29 October 2019
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 identification number at the time of the first dosing, different from the screening number.
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).
9.1.1.2
Study Drug Assignment
This is a fixed-sequence study. All subjects will receive the same treatments as detailed in 
Section 6.1.
9.1.2
Inclusion and Exclusion
Subjects must satisfy all of the inclusion criteria and meet none of the exclusion criteria as outlined 
in Sections 7.1 and 7.2.
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 recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Sections 7.2 and 7.3. 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.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
ll be
Te
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9.2
erty
9.2


TAK-831
Study ID TAK-831-1008
Page 38 of 79
Final Protocol 
29 October 2019
For this study, the collections for blood, urine, and feces for total radioactivity, plasma and urine 
concentrations, and 
 for TAK-831 are the critical parameters and need 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.
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 
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.
CCI
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
as 
o
as 
preceden
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e o
A
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A
f Stud
Ap
Stud
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the A
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predose
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15
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procedur
9.2
ert
9.2


TAK-831
Study ID TAK-831-1008
Page 39 of 79
Final Protocol 
29 October 2019
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 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-Suicide Severity 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 
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 oral tablet and [14C]TAK-831 oral suspension and IV solution will be provided as 
described in Section 8.1.
Subjects will be instructed not to crush, split, or chew the TAK-831 tablets.
Treatments A and B are described as follows: 
Treatment A: 500 mg TAK-831 in tablets (5 x 100 mg T2 tablets) administered orally at Hour 0 
on Day 1 followed by 50 µg (~1 μCi) [14C]TAK-831 IV solution administered at 
Hour 1.25 (75 minutes post oral dosing) for 15 minutes.
Treatment B: 500 mg (~100 μCi) [14C]TAK-831 oral suspension administered at Hour 0 on 
Day 1.
The oral doses of TAK-831 and [14C]TAK-831 will be administered following an overnight fast 
with approximately 240 mL of water, then will be instructed to fast for an additional 4 hours. All 
subjects may then consume water ad libitum with the exception of 1 hour before and 1 hour after 
oral administration. The exact clock time of oral dosing will be recorded. 
The IV dose will be administered over approximately 15 minutes. The start and end time of the IV 
infusion will be recorded.
The pharmacy at the CRU will provide the IV dose ready for the 15-minute infusion, the oral 
tablets dose in individual unit dose containers, and the oral suspension dose in a glass bottle for 
each subject.
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
me
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er
Th


TAK-831
Study ID TAK-831-1008
Page 40 of 79
Final Protocol 
29 October 2019
9.2.8
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study formulations 
and/or procedures as described in Section 10.0.
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.
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 being
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 only if subjects have 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)
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
res 
e T
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uppe
C


TAK-831
Study ID TAK-831-1008
Page 41 of 79
Final Protocol 
29 October 2019
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
9.3
PK Samples
Primary specimen collection parameters are provided in Table 9.a.
Instructions for plasma, urine, fecal samples processing and handling will be provided separately.
to the Applicable Terms of Use
of
ms
er
e T
b
lic
examinat
pplic
examinat
al Use Only and Subject to
includes
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includes
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drocode
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nd S
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yd
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
nly
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
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
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C
on param
Com
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a, urine
on-C
a, urine


TAK-831
Study ID TAK-831-1008
Page 42 of 79
Final Protocol 
29 October 2019
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Period 1
Plasma for TAK-831 PK
Plasma
PK analysis
Mandatory
Plasma for total radioactivity 
and [14C]TAK-831 PK
Plasma
Total radioactivity and PK 
analysis
Mandatory
Urine for [14C]TAK-831 PK
Urine
Total radioactivity recovery 
and PK analysis
Mandatory
Feces for [14C]TAK-831 PK
Feces
Total radioactivity recovery 
and PK analysis
Mandatory
Period 2
Blood for total radioactivity 
Blood
Total radioactivity
Mandatory
Plasma for total radioactivity 
Plasma
Total radioactivity
Mandatory
Plasma for TAK-831 PK
Plasma
PK analysis
Mandatory
Urine for total radioactivity 
Urine
Total radioactivity
Mandatory
Urine for TAK-831 PK
Urine
PK analysis
Mandatory
Feces for total radioactivity
Feces
Total radioactivity
Mandatory
9.3.1
PK Measurements 
9.3.1.1
Whole Blood and Plasma for PK Measurements
The following PK parameters for whole blood and plasma radioactivity concentration equivalents 
(plasma in both Periods 1 and 2, whole blood in Period 2 only) and for plasma TAK-831
concentrations (Periods 1 and 2) will be calculated, unless otherwise specified:
AUClast:
Area under the concentration-time curve from time 0 to time of the last
quantifiable concentration.
AUCt:
Area under the concentration-time curve from time 0 to time of the last 
common time point “t” at which total radioactivity and TAK-831 are 
quantifiable for all subjects.
AUC∞:
Area under the concentration-time curve from time 0 to infinity, calculated 
using the observed value of the last quantifiable concentration.
CCI
CCI
CCI
d Subject to the Applicable Terms of Use
ion
s
ion
ms
Mandato
Te
Mandato
Ter
Man
ble 
Man
e T
ry 
pl
y 
ica
recover
e Ap
recover
Ap
t
dioactivit
ect t
dioactivit
t t
l radioac
bje
l radioac
jec
PK analy
Su
PK analy
ub
d S
e Only a
On
Property of Takeda: For Non-Commercial 
mm
ents
on-C
ents
lood an
or N
lood an
g PK pa
a: F
g PK pa
both
eda
both P
trations
aked
trations
AUC
f T
AUClast
T
last
a
A
ty
A
mmercial Use O y and S


TAK-831
Study ID TAK-831-1008
Page 43 of 79
Final Protocol 
29 October 2019
AUCextrap%:
Area under the curve from the last quantifiable concentration to infinity 
calculated using the observed value of the last quantifiable concentration, 
expressed as a percentage of AUC∞.
Cmax:
Maximum observed concentration.
λz:
Terminal disposition phase rate constant.
tmax:
Time of first occurrence of Cmax.
t1/2z:
Terminal disposition phase half-life.
The following PK parameters for plasma concentrations of [14C]TAK-831 following IV infusion 
(Period 1) will be calculated, unless otherwise specified:
AUClast:
Area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration.
AUCt:
Area under the concentration-time curve from time 0 to time of the last 
common time point “t” at which plasma total radioactivity and plasma
TAK-831 are quantifiable for all subjects (plasma only).
AUC∞:
Area under the concentration-time curve from time 0 to infinity, calculated 
using the observed value of the last quantifiable concentration.
AUCextrap%:
Area under the curve from the last quantifiable concentration to infinity 
calculated using the observed value of the last quantifiable concentration, 
expressed as a percentage of AUC∞.
Ceoi:
Concentration at the end of infusion.
λz:
Terminal disposition phase rate constant.
t1/2z:
Terminal disposition phase half-life.
No value for λz, AUC∞, AUCextrap%, or t1/2z 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 or radioactivity 
concentration equivalents at 2 or fewer consecutive time points. 
Individual and mean plasma concentration- or radioactivity concentration equivalent-time curves 
(both linear and log-linear) will be included in the final report.
The ABA parameters for TAK-831 (Period 1) will be calculated as follows:
F:
Absolute bioavailability, calculated for plasma TAK-831.
%F:
Percent absolute bioavailability, calculated for plasma TAK-831 as 
[Dose (IV) x AUC∞(oral)] / [Dose (oral) x AUC∞(IV)] x 100.
ommercial Use Only and Subject to the Applicable Terms of Use
31 
he
31 fo
e A
follo
A
llo
m t
ct t
m time
t to
ime
urve fro
Sub
urve fro
plasma t
nd S
plasma t
all subje
and
all subje
on
On
on-
nl
-time
nly
time
e of the 
e On
e of the 
ve from 
Use
ve from 
the obse
ial U
the obse
a percen
rcia
a percen
tion at 
me
tion at 
ty of Takeda: For Non-Co
inal disp
Com
inal disp
erminal
on-C
erminal
z, AUC
Fo
, AUC
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da: F
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paramet
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paramet
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Tak
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Individu
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Individu
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(both
T
e
T


TAK-831
Study ID TAK-831-1008
Page 44 of 79
Final Protocol 
29 October 2019
9.3.1.2
Urine for PK Measurements
The following PK parameters for urine [14C]TAK-831 concentrations (Period 1; IV dose), and for 
TAK-831 concentrations and urine total radioactivity (both Periods 1 and 2) will be calculated, 
unless otherwise specified:
Aet1-t2:
Amount of drug excreted in urine from time 1 to time 2.
Ae(UR):
Cumulative amount excreted in urine.
%Dose(UR):
Percent of administered radioactive dose excreted in urine within a given 
collection interval.
Cum%Dose(UR):
Cumulative percent of administered dose excreted in urine.
CLR:
Renal clearance. 
Total radioactivity excreted in urine will be presented in mass equivalent units.
9.3.1.3
Feces for PK Measurements
The following PK parameters for fecal [14C]TAK-831 concentrations (Period 1; IV dose), and for 
fecal total radioactivity (both Periods 1 and 2) will be calculated, unless otherwise specified:
Ae(FE):
Cumulative amount of total radioactivity excreted in feces.
%Dose(FE):
Percent of administered radioactive dose excreted in feces within a given 
collection interval.
Cum%Dose(FE):
Cumulative percent of administered dose excreted in feces.
Total radioactivity excreted in feces will be presented in mass equivalent units.
9.3.1.4
Additional PK Measurements
The following PK parameters for combined urine and fecal total radioactivity (Period 1, IV dose 
and Period 2) will be calculated, unless otherwise specified:
Combined 
Cum%Dose:
Cumulative combined percent of administered dose excreted in urine and 
feces.
9.3.2
Biomarker Measurements
NA
9.3.3
PGx Measurements 
NA
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 45 of 79
Final Protocol 
29 October 2019
9.3.4
Confinement
In Period 1, subjects will be housed on Day -1, at the time indicated by the CRU until at least after 
the Day 5 blood draw and/or study procedures and until one of the discharge criteria is met or up to 
Day 8. Subjects will be eligible for discharge in Period 1, if they meet either one of the following 
discharge criteria:

≥80% of the total dose of radioactivity administered has been recovered in the urine and feces; 
or 

There is ≤1% of the total administered radioactivity in each of two consecutive 24-hour 
intervals where both a urine and fecal sample is provided.
Subjects who meet discharge criteria prior to Day 8 may be confined throughout the washout 
period at the discretion of the CRU.
In Period 2, subjects will be housed on Day -1, at the time indicated by the CRU, for at least 5 days 
postdose (ie, Day 6) and until ≥90% of the total dose of radioactivity administered has been 
recovered in the urine and feces.
If less than 90% of the total dose of radioactivity administered is recovered in urine and fecal 
samples within 10 days postdose (ie, Day 11), subjects will be eligible for discharge if they meet 
either of the following discharge criteria or until Day 14:

≥80% of the total dose of radioactivity administered has been recovered in the urine and feces; 
or 

There is ≤1% of the total administered radioactivity in each of two consecutive 24-hour 
intervals where both a urine and fecal sample is provided.
If neither one of the 2 discharge criteria is met by Day 14, at the discretion of the Sponsor, the 
subject may be required to return to the CRU for urine and fecal sample collection in two 24-hour 
periods at approximately 7 and 14 days after discharge from the CRU (eg, Days 21 and 22 and 
Days 28 and 29). Subjects will be confined in the CRU for these 24-hour sample collection
periods.
All urine and fecal collections will be analyzed for radioactivity levels to determine if the 
discharge criteria are met. 
It is expected that the majority (≥90%) of the administered radioactivity will be recovered within 
60 hours post TAK-831 dose.
Release of subjects who do not meet a discharge criterion by Day 8 (Period 1) and/or Day 14
(Period 2) will be reviewed on a case-by-case basis.
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, 
actual subject release from the CRU may occur 1 day after discharge criteria are met.
ommercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 46 of 79
Final Protocol 
29 October 2019
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) 30 ± 2 days 
after the last study drug administration to determine if any AEs have occurred since the last study 
visit.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ays
s o
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study
ms 
study


TAK-831
Study ID TAK-831-1008
Page 47 of 79
Final Protocol 
29 October 2019
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the Investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the Investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 48 of 79
Final Protocol 
29 October 2019
of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled 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 CRF, in order to capture this important safety information consistently in the 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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ert



TAK-831
Study ID TAK-831-1008
Page 49 of 79
Final Protocol 
29 October 2019
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
ercial Use Only and Subject to the Applicable Terms of Use
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Property of Takeda: For Non-Comm
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TAK-831
Study ID TAK-831-1008
Page 50 of 79
Final Protocol 
29 October 2019
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
There are no AEs of Special Interest for TAK-831.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
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 
ommercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 51 of 79
Final Protocol 
29 October 2019
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
Investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of Adverse Event (Frequency)
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
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 
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
nistratio
Term
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uch as 
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TAK-831
Study ID TAK-831-1008
Page 52 of 79
Final Protocol 
29 October 2019
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up phone call on Day 31 (± 2 days), approximately 30 days after the last dose of 
investigational product. For subjects who discontinue prior to the administration of study 
medication, AEs will be followed until the subject discontinues study participation. 
10.2.8.2 Reporting AEs
At each study visit, the Investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
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:

Event term.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
erved
ms
erved
ma
Te
maly; th
Term
ly; th
vered/no
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vered/no
AE but w
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TAK-831
Study ID TAK-831-1008
Page 53 of 79
Final Protocol 
29 October 2019

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 study 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.
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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
d be rep
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Study ID TAK-831-1008
Page 54 of 79
Final Protocol 
29 October 2019
10.2.8.4 Reporting Special Interest AEs 
NA
10.2.8.5 Reporting of Abnormal LFTs
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, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 55 of 79
Final Protocol 
29 October 2019
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 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 total radioactivity (whole blood, plasma, urine, feces, 
and if applicable, emesis), TAK-831 concentrations and PK parameters (plasma and urine), and 
[14C]TAK-831 plasma and urine radioactivity concentrations equivalent, using appropriate 
summary statistics to be fully specified in the SAP.
PK parameters for whole blood and plasma concentrations (as appropriate) and total radioactivity 
will be calculated as described in Section 9.3.1.1 and for urine and feces, as described in 
Sections 9.3.1.2 and 9.3.1.3, respectively.
ABA of TAK-831 (Period 1) will be estimated using a 90% CI constructed for the difference in LS 
mean on the log scale for dose normalized AUC∞between a single oral dose and the IV microdose. 
Exponentiating the log-scale 90% CI will provide a 90% CI for the dose normalized AUC∞
geometric mean ratio (TAK-831 administered as oral dose / [14C]TAK-831 administered as IV 
microdose). AUClast and Cmax will be analyzed in a similar fashion.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 56 of 79
Final Protocol 
29 October 2019
11.1.4 Analysis of Mass Balance
In Period 2, mass balance will be calculated as a sum of the percent of the total radioactivity 
recovered in urine and feces plus any radioactivity dose lost due to emesis (if any occurred)
relative to the administered radioactivity dose.
11.1.7 PD Analysis 
NA
11.1.8 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.
11.1.8.1 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 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.
11.1.8.2 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.
11.1.8.3 Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
CCI
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TAK-831
Study ID TAK-831-1008
Page 57 of 79
Final Protocol 
29 October 2019
11.1.8.4 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.
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization drug and will be listed by subject.
C-SSRS findings will be presented in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
NA
11.3
Determination of Sample Size
The sample size of 6 male healthy subjects was selected without statistical considerations and is 
deemed adequate to meet the study objectives. In addition, this sample size is limited based on 
clinical considerations for this type of study and in order to limit exposure to radioactivity.
ject to the Applicable Terms of Use
mit
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Property of Takeda: For Non-Commercial Use Only and Subj
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to limit 
Sub
to limit 


TAK-831
Study ID TAK-831-1008
Page 58 of 79
Final Protocol 
29 October 2019
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 (Clinical Research Organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study 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 study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator should consult with the Sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
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.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
ll
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of data 
records
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TAK-831
Study ID TAK-831-1008
Page 59 of 79
Final Protocol 
29 October 2019
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 GCP. Each Investigator will conduct the study according to applicable local or regional 
regulatory requirements and align his or her conduct in accordance with the “Responsibilities of 
the Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through 
the protocol and through appendices containing requirements for informed consent and 
Investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form (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 study. Until the site receives drug/notification 
no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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.
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 60 of 79
Final Protocol 
29 October 2019
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) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the Investigator to explain the detailed elements of the 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 
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 61 of 79
Final Protocol 
29 October 2019
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 
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 Study Registration Policy
13.4.1 Publication and Disclosure
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the Investigator) without the consent of the Investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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.
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 62 of 79
Final Protocol 
29 October 2019
13.4.2 Clinical Study Registration 
In order to ensure that information on clinical studies reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical studies it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting study
information. Once subjects receive Investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the Investigator has questions regarding this policy, he or she should contact the Sponsor
or Sponsor’s designee.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 63 of 79
Final Protocol 
29 October 2019
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
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Ter
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plplicable T


TAK-831
Study ID TAK-831-1008
Page 64 of 79
Final Protocol 
29 October 2019
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)
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
ge
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f
ked


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Page 65 of 79
Final Protocol 
29 October 2019
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
~
Approximately
%
Percent
%Dose(FE)
Percent of administered radioactive dose excreted in feces within a given collection 
interval
%Dose(UR)
Percent of administered radioactive dose excreted in urine within a given collection 
interval
%F
Percent absolute oral bioavailability
[14C]
Carbon-14; radiocarbon
ABA
Absolute bioavailability
ADME
Absorption, distribution, metabolism, and elimination
AE
Adverse event
Aet1-t2
Amount of drug excreted in the urine from time 1 to time 2
Ae(FE)
Amount of total radioactivity excreted in feces within a given collection interval
Ae(UR)
Amount of total radioactivity excreted in urine within a given collection interval
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUCextrap%
Area under the curve from the last quantifiable concentration to infinity calcufate dusing 
the observed value of the last quantifiable concentration, expressed as a percentage of 
AUC∞
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUCt
Area under the concentration-time curve from time 0 to time t
AUC∞
Area under the concentration-time curve from time 0 to infinity
BMI
Body mass index
bpm
Beats per minute
C-SSRS
Columbia-suicide severity rating scale
Ceoi
Concentration at end of infusion
CFR
Code of Federal Regulations
CI
Confidence interval
CLR
Renal clearance
cm
Centimeter
Cmax
Maximum observed concentration 
CRF
Case report form
CRU
Clinical research unit
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
hin a giv
App
hin a giv
ine within
the
ine within
and elim
d S
and elim
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ly a
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ty excret
On y
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Us
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transfera
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Area und
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Area und
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Non
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A
N
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CFR
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CFR
CI
erty
CI
C
e
C


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Final Protocol 
29 October 2019
CYP
Cytochrome P450
DAO
D-amino acid oxidase
ECG
Electrocardiogram
F
Bioavailability
FDA
Food and Drug Administration
g
Gram
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous
kg
Kilogram
λz
Terminal disposition phase rate constant
LS
Least-squares
μCi
Microcurie
μg
Microgram
m2
Meters squared
MBq
Megabecquerel
MedDRA®
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
mrem
Millirem
msec
Millisecond
mSv
Millisievert
NA
Not applicable
nCi
Nanocurie
NMDA
N-methyl-D-aspartate
oz
Ounce
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
QD
Once daily
SAE
Serious adverse event
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
tection
ject
tection
se rate co
e O
se rate co
uared
mer
uared
ecquerel
mm
ecquerel
dical Dic
Com
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Milligra
n-C
Milligra
Minu
Non
Minu
M
N
M
A
nC
ty
nCi
y
i
NM
erty
NM


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Study ID TAK-831-1008
Page 67 of 79
Final Protocol 
29 October 2019
SAP
Statistical analysis plan
SUSARs
Suspected unexpected serious adverse reactions
t1/2z
Terminal disposition phase half-life
TEAE
Treatment-emergent adverse event
tmax
Time of first occurrence of Cmax
TRA
Total radioactivity
ULN
Upper limit of normal
US
United States
USA
United States of America
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-831
Study ID TAK-831-1008
Page 68 of 79
Final Protocol 
29 October 2019
15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan.
15.1
CRFs
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. The 
final signed CRFs are provided to the Sponsor in the format as decided upon between Celerion and 
the Sponsor (eg, CD, flashdrive, SFTP). This will be documented in the Data Management Plan (if 
applicable).
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.
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.
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the 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), 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 
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
are 
Te
are 
y the PI
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lon


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Page 69 of 79
Final Protocol 
29 October 2019
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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
s
from
ms
from


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Study ID TAK-831-1008
Page 70 of 79
Final Protocol 
29 October 2019
16.0
REFERENCES
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.
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department of 
Health and Human Services National Cancer Institute. 27Nov2017.
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.
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.
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.
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.
Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of 
benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid 
oxidase inhibitor. JAMA Psychiatry 2013;70(12):1267-75.
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.
TAK-831. Takeda Pharmaceuticals, Inc. Global Investigator’s Brochure. Edition 4.0, 02Jul2018.
van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
Use Only and Subject to the Applicable Terms of Use
ent of 
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Property of Takeda: F
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ur S. Sc


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Study ID TAK-831-1008
Page 71 of 79
Final Protocol 
29 October 2019
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 
study-related duties and functions, the Investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
Investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
cable 
ms o
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auth
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auth
in
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in


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Final Protocol 
29 October 2019
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.
pplicable Terms of Use
essent
Term
essentia
m
ia
nsor
abl
nsor-
b
-
Property of Takeda: For Non-Commercial Use Only and Subject to the Ap
sup
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sup
AE, noti
App
AE, noti


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Page 73 of 79
Final Protocol 
29 October 2019
Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(Investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
Non-Commercial Use Only and Subject to the Applicable Terms of Use
es.
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es.
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Final Protocol 
29 October 2019
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
r
s
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inform
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subject’
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subject’
dual, un
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Final Protocol 
29 October 2019
25. 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 95 days after 
the last dose of study drug. If the partner of the subject is found to be pregnant during the study, 
the Investigator will offer the subject the choice to receive additional treatment information.
26. A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
y, 
o
y, 
on.
s
on.
in a 
Term
in a 


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Page 76 of 79
Final Protocol 
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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 study registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
on-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 77 of 79
Final Protocol 
29 October 2019
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, 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 throughout the duration of the study, and for 
95 days after last dose of study drug. Females of childbearing potential who are partners of male 
subjects are also advised to use additional contraception as shown in the list containing highly 
effective contraception below. Total abstinence (no sexual intercourse) may be considered an 
acceptable method of birth control if it agrees with the subject’s preferred and usual lifestyle.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). Acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomised subject (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 95 days after the
last dose.

Hormonal Methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral †.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Term
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


TAK-831
Study ID TAK-831-1008
Page 78 of 79
Final Protocol 
29 October 2019

Intravaginal † (eg, ring).

transdermal †.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation1 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has been 
on contraceptive for 3 months;

oral †.

Injectable.

Implantable.
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.
3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy and sperm donation during 
the course of the study.
4. During the course of the study, all subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm donation as part of the study procedures. Such guidance 
should include a reminder of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in subjects with pregnant partners
c) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
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 subjects with pregnant partners.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831
Study ID TAK-831-1008
Page 79 of 79
Final Protocol 
29 October 2019

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? 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Women will not be included in this study.
If a female partner of a subject becomes pregnant during the subject’s participation in this study, 
the Sponsor must be contacted immediately by faxing a completed pregnancy form to the Takeda 
Global Pharmacovigilance department or designee (see Section 14.1.1). 
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.
If the female partner of a subject agrees to the primary care physician being informed, the 
Investigator should notify the primary care physician that the female partner of the subject was
participating in a clinical study at the time she became pregnant and provide details of the study 
drug the subject received (blinded or unblinded, as applicable).
All pregnancies of female partners of 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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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680c504a6
A Phase 1 Study to Assess Absolute Bioavailability of TAK-831 and to Characterize Mass Balance,
Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-831 in Male Healthy Subjects
Clinical Pharmacology Approval
30-Oct-2019 19:49 UTC
Biostatistics Approval
31-Oct-2019 13:19 UTC
Clinical VP Approval
01-Nov-2019 10:56 UTC
PPD
ble Terms of Use
e Te
ate 
T
ate 
ble T
HH:mm ‘U
ble 
HH:mm ‘U
Ter
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable
ble
49 UTC
able
49 UTC
19 13:19
pli
19 13:19
Nov-201
e A
Nov-201

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 Study to Assess Absolute Bioavailability of TAK-831 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-831 in Male Healthy 
Subjects
NCT Number: NCT04234672
SAP Approve Date: 16 April 2020
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-831-1008
CELERION STUDY NUMBER: CA28631
A Phase 1 Study to Assess Absolute Bioavailability of TAK-831 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]TAK-831 in Male Healthy 
Subjects
Version: Final
Date: 16 April 2020
Prepared by:
Based on:
Protocol Dated: 29 October 2019
Protocol Clarification Letter Dated: 17 February 2020
PPD
Only and Subject to the Applicable Terms of Use
31 and 
to 
31 and 
[
e
[14
c
14C]TA
ect t
C]TA
ilil 2020
and
2020
Prope
Cl
: Fo
Clar
Fo
ar
perty of Takeda:
a: For Non
Dated:
For N
Dated:
ol
: F
ol
on-Commercial Use O


TAK-831-1008
Celerion Study Number CA28631
Page 2 of 24
Statistical Analysis Plan Final
16 April 2020
1.1
Approval Signatures
Study Title:
A Phase 1 Study to Assess Absolute Bioavailability of TAK-831 and to 
Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion 
of [14C]TAK-831 in Male Healthy Subjects
Date
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
etion 
ms
etion 
Date
ppl
Date
plic
ect to the


TAK-831-1008
Celerion Study Number CA28631
Page 3 of 24
Statistical Analysis Plan Final
16 April 2020
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Hypothesis.................................................................................................................7
4.2
Primary Objectives ....................................................................................................7
4.3
Secondary Objective..................................................................................................7
4.4
Exploratory Objectives ..............................................................................................7
4.5
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................13
7.1.2
Definition of Study Days....................................................................................13
7.2
Study Treatments.....................................................................................................13
7.3
Analysis Sets ...........................................................................................................13
7.4
Disposition of Subjects ............................................................................................13
7.5
Demographic and Other Baseline Characteristics.....................................................14
7.6
Medical History and Concurrent Medical Conditions...............................................14
7.7
Medication History and Concomitant Medications...................................................14
7.8
Study Drug Exposure and Compliance.....................................................................14
7.9
Efficacy Analysis.....................................................................................................14
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................15
7.10.1 Pharmacokinetic Analysis ..................................................................................15
7.10.2 Pharmacodynamic Analysis ...............................................................................20
7.11
Other Outcomes.......................................................................................................20
7.12
Safety Analysis........................................................................................................20
7.12.1 Adverse Events..................................................................................................21
7.12.2 Clinical Laboratory Evaluations .........................................................................21
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 4 of 24
Statistical Analysis Plan Final
16 April 2020
7.12.3 Vital Signs .........................................................................................................22
7.12.4 12-Lead ECGs ...................................................................................................23
7.12.5 Physical Exams..................................................................................................23
7.12.6 Columbia Suicide Severity Rating Scale (C-SSRS)............................................23
7.12.7 Overdose............................................................................................................23
7.13
Interim Analysis ......................................................................................................24
7.14
Preliminary Analysis................................................................................................24
7.15
Changes in the Statistical Analysis Plan...................................................................24
8.0
REFERENCES..............................................................................................................24
Applicable Terms of Use
3
o
3
....
ms
....23
ms o
23
.........
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TAK-831-1008
Celerion Study Number CA28631
Page 5 of 24
Statistical Analysis Plan Final
16 April 2020
3.0
LIST OF ABBREVIATIONS
ABA
absolute bioavailability; F (often expressed as a percent, ie, %F)
ADME
absorption, distribution, metabolism, and elimination
Ae
amount of drug eliminated
AE
AUC
adverse event
area under the curve
AUC∞
area under the concentration-time curve from time 0 extrapolated to 
infinity
AUClast
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
AUCt
area under the concentration-time curve from time 0 to time at which the 
both the analyte of interest and total radioactivity are quantifiable, ie, 
time-matched AUC.
BLQ
BMI
below the limit of quantitation
body mass index
Ceoi
concentration at the end of infusion
CLR
renal clearance
Cmax
maximum observed concentration
CPAP
CRF
Clinical Pharmacology Analysis Plan
case report form
CRU
clinical research unit
CS
CSR
CV
DMP
ECG
clinically significant
clinical study report
coefficient of variation
Data Management Plan
electrocardiogram
eCRF
Geom CV
Geom Mean
electronic case report form
geometric coefficient of variation
geometric mean
ICF
ICH
informed consent form
International Conference on Harmonisation
IV
intravenous
ln
LSM
natural log
least-square means
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
xtrapola
plic
xtrapola
me 0 to 
he A
me 0 to 
om t
ct to
om tim
to
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TAK-831-1008
Celerion Study Number CA28631
Page 6 of 24
Statistical Analysis Plan Final
16 April 2020
Mean
MedDRA
arithmetic mean
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PI
PK
Principal Investigator
pharmacokinetics
SAE
serious adverse event
SD
SEM
SOC
t1/2z
standard deviation
standard error of the mean
system organ class
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tmax
tables, figures and listings
time of maximum observed concentration
WHO
World Health Organisation
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ntration
Sub
ntration


TAK-831-1008
Celerion Study Number CA28631
Page 7 of 24
Statistical Analysis Plan Final
16 April 2020
4.0
OBJECTIVES
4.1
Hypothesis
Not applicable.
4.2
Primary Objectives
Period 1 (Absolute Bioavailability [ABA])

To determine ABA of TAK-831 following a single microdose intravenous (IV)
administration of 50 µg (~1 µCi) [14C]TAK-831 and a single oral administration of 500 mg 
TAK-831 tablets.
Period 2 (Absorption, Distribution, Metabolism, and Elimination [ADME])

To assess the mass balance (ie, cumulative excretion of total radioactivity in urine and feces) 
following a single oral administration of 500 mg (~100 µCi) [14C]TAK-831 suspension.

To characterize the pharmacokinetics (PK) of TAK-831 in plasma and urine, and total 
radioactivity concentration equivalents in plasma and whole blood following a single oral 
suspension dose of 500 mg (~100 µCi) [14C]TAK-831.
4.3
Secondary Objective
Period 1 (ABA)

To determine the PK of [14C]TAK-831 following a single IV administration of 50 µg 
[14C]TAK-831 and the PK of TAK-831 following a single oral administration of 500 mg 
TAK-831 tablets.
Periods 1 (ABA) and 2 (ADME)

To assess the safety of TAK-831 during the ABA and ADME study periods.
4.4
Exploratory Objectives
CCI
Commercial Use Only and Subject to the Applicable Terms of Use
nous (
App
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IV
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TAK-831-1008
Celerion Study Number CA28631
Page 8 of 24
Statistical Analysis Plan Final
16 April 2020
4.5
Study Design
This is an open-label, 2-period, single dose study in 6 healthy male subjects. 
On Day 1 of Period 1 (ABA Study Period), subjects will receive a single unlabeled oral 500 mg 
dose of TAK-831 as tablets. At 1.25 hours (75 minutes) post oral dosing (ie, 15 minutes prior to 
the median tmax for the oral unlabeled dose of ~1.5 hours), subjects will receive a 15-minute IV 
infusion of a microdose of 50 µg (~1 µCi) [14C]TAK-831. Serial blood sampling will be 
performed up to Day 5 to determine the PK of TAK-831 in the plasma for the oral dose and total 
radioactivity and PK of [14C]TAK-831 in the plasma for the IV dose. Urine and fecal output will 
also be collected up to the morning of Day 5 postdose to determine [14C]TAK-831 
concentrations. Subjects will remain in the CRU and continue with urine and feces collection 
until one of the discharge criteria is met (ie, 80% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples or the excretion of radioactivity in the urine 
and feces combined has declined to 1% of the total administered radioactivity for at least 2 
consecutive intervals where both a urine and fecal sample are collected) or up to Day 8 but no 
less than Day 5 for total radioactivity excretion in urine and feces. In Period 1, subjects will be 
confined in the clinical research unit (CRU) for at least 5 days (until after the last PK sample and 
morning urine and fecal samples [when passed] are collected) and until one of the discharge 
criteria is met or up to Day 8. Subjects will return to the CRU on Day -1 of Period 2 for Period 2 
procedures. There will be a washout period of at least 7 days between the last dose in Period 1 
and the dose in Period 2.
On Day 1 of Period 2 (ADME Study Period), subjects will receive a single dose of 500 mg 
(~100 μCi) [14C]TAK-831 as an oral suspension. Serial blood sampling will be performed and
urine and feces will be collected to determine the PK of TAK-831 in plasma and urine, and total 
radioactivity in plasma, whole blood, urine, and feces, 
 
. Complete urinary and fecal output will be collected 
during the confinement period until discharge criteria are met (anticipated to be 10 days postdose 
or less). In Period 2, subjects will be confined in the CRU for at least 5 days postdose (ie, Day 6) 
and until 90% or greater of the total dose of radioactivity administered is recovered in urine and 
fecal samples. If less than 90% of the total dose of radioactivity administered is recovered in 
urine and fecal samples within 10 days postdose (ie, Day 11), the subject will continue to stay at 
the CRU until 80% or greater of the total dose of radioactivity administered is recovered in urine 
and fecal samples or the excretion of radioactivity in the urine and feces combined has declined 
to 1% of the total administered radioactivity for at least 2 consecutive intervals where both a 
urine and fecal sample are collected, whichever occurs first, or until Day 14. If neither one of the 
2 discharge criteria is met by Day 14, at the discretion of the Sponsor, the subject may be 
required to return to the CRU for urine and fecal sample collection in two 24-hour periods at 
approximately 7 and 14 days after discharge from the CRU (eg, Days 21 and 22 and Days 28 and 
29). Subjects will be confined in the CRU for these 24-hour sample collection periods.
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, 
actual subject release from the CRU may occur 1 day after discharge criteria are met.
CCI
mmercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 9 of 24
Statistical Analysis Plan Final
16 April 2020
In both Periods 1 and 2, any subject who experiences emesis within 3 hours post oral dosing will 
be excluded in the final data analysis and may be replaced with a new subject. For a subject who 
drops out in Period 2, the replacement subject will be required to complete Period 2 only. If a 
subject experiences emesis after dosing in Period 2, vomitus will be collected throughout the 
study and assayed for total radioactivity.
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days 
after the last study drug administration to determine if any adverse events (AEs) have occurred 
since the last study visit.
The study schematic is presented in Table 4.a.
Table 4.a
Study Schematic
Screening
Period 1 a
Within 28 days of 
first dosing in 
Period 1 
Day -1
Day 1
Days 2 - 8
Check-in
Oral Dosing at 
Hour 0
IV Dosing at Hour 1.25 (75 minutes post 
oral dosing)
Plasma, urine, and fecal sampling for ABA and safety monitoring for at least 96 hours post oral dose b
<- - - - - - - - - - - - confinement b - - - - - - - - - - - - >
a
There will be a washout period of at least 7 days between the last dose in Period 1 and the dose in Period 2.
b
Subjects will be confined in the CRU for at least 5 days (until after the last PK sample and morning urine and fecal sample [when passed] are 
collected) and until one of the discharge criteria is met (ie, 80% or greater of the total dose of radioactivity administered is recovered in urine 
and fecal samples or the excretion of radioactivity in the urine and feces combined has declined to ≤1% of the total administered radioactivity 
for at least 2 consecutive intervals where both a urine and fecal sample is collected) or up to Day 8.
Period 2 a
Follow-up
Day -1 b
Day 1
Days 2 - 6
Days 7 - 14
Days 21 - 22
Days 28 - 29
30 ± 2 days 
after last 
dosing
Check-in
Oral 
Dosing 
at Hour 0
Whole blood, plasma, urine, and fecal sampling for 
TAK-831 (plasma and urine), total radioactivity (plasma, 
whole blood, urine, and feces), 
 
 and safety monitoring (as 
applicable) up to approximately 240 hours postdose 
24-hour urine and fecal sampling for 
TAK-831 (urine only), total radioactivity, 
and 
<- - - - - - confinement c - - - - - >
<confinement c >
<confinement c>
<confinement c>
a
There will be a washout period of at least 7 days between the last dose in Period 1 and the dose in Period 2.
b
Day -1 of Period 2 will be the same day as Day 8 of Period 1 if the washout is exactly 7 days between doses in Periods 1 and 2.
c
Subjects will be confined in the CRU for at least 5 days postdose (ie, Day 6) and until 90% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples. If less than 90% of the total dose of radioactivity administered is recovered in urine and 
fecal samples within 10 days postdose (ie, Day 11), the subject will continue to stay at the CRU until 80% or greater of the total dose of 
radioactivity administered is recovered in urine and fecal samples or the excretion of radioactivity in the urine and feces combined has 
declined to ≤1% of the total administered radioactivity for at least 2 consecutive intervals where both a urine and fecal sample are collected, 
whichever occurs first, or until Day 14. If neither one of the 2 discharge criteria is met by Day 14, at the discretion of the Sponsor, the subject 
may be required to return to the CRU for urine and fecal samples collection in two 24-hour periods at approximately 7 and 14 days after 
discharge from the CRU (eg, Days 21 and 22 and Days 28 and 29). Subjects will be confined in the CRU for these 24-hour sample collection 
periods. Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, actual subject release from the CRU 
may occur 1 day after discharge criteria are met.
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Non


TAK-831-1008
Celerion Study Number CA28631
Page 10 of 24
Statistical Analysis Plan Final
16 April 2020
The planned dose levels of TAK-831 that were evaluated are outlined in Table4.b.
Table 4.b
Planned TAK-831 and [14C]TAK-831 Doses
Dose
Route of Administration
Period 1 (Treatment A)
TAK-831
500 mg
Oral tablet
[14C]TAK-831
50 µg (~1 µCi)
IVa
Period 2 (Treatment B)
[14C]TAK-831
500 mg (~100 µCi)
Oral suspension
aAdministered over 15 minutes from 1.25 to 1.5 hours after the oral dose of TAK-831.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoints of the study are:
Period 1 (ABA):

Absolute bioavailability (F) as percent F (%F) for TAK-831.
Period 2 (ADME):

Percent of total radioactivity recovered in urine and feces relative to the administered 
radioactive dose.

Total radioactive recovery in urine and feces and the percent of the radioactive dose excreted 
in the urine and feces.

PK parameters Cmax, tmax, t1/2z, AUC∞, AUClast, and AUCt for TAK-831 in plasma.

PK parameters Cmax, tmax, t1/2z, AUC∞, AUClast, and AUCt for total radioactivity concentration 
equivalents in plasma and whole blood.

Renal clearance (CLR) of TAK-831 in urine.
5.2
Secondary Endpoints
The secondary endpoints will be assessed through evaluation of the following parameters:
Period 1 (ABA):

PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUClast, AUCt, and t1/2z for 
TAK-831 and [14C]TAK-831 in plasma.
Periods 1 (ABA) and 2 (ADME):

Tabulated treatment-emergent AEs (TEAEs) and summary statistics for clinically relevant 
12-lead ECGs, vital signs, and clinical laboratory tests results.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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


TAK-831-1008
Celerion Study Number CA28631
Page 11 of 24
Statistical Analysis Plan Final
16 April 2020
5.3
Exploratory Endpoints
6.0
DETERMINATION OF SAMPLE SIZE
The sample size of 6 healthy male subjects was selected without statistical considerations and is 
deemed adequate to meet the study objectives. In addition, this sample size is limited based on 
clinical considerations for this type of study and in order to limit exposure to radioactivity.
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 9.4, or higher. All data recorded on the 
CRF will be listed by subject. All tables, figures and listings (TFLs) shells and numbering list 
specified in the Clinical Pharmacology Analysis Plan (CPAP) will be included.
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 mean ratios (GMRs) and 90% confidence intervals (CIs) around the 
ratio will be reported using 2 decimal places. 
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 (eg, BLQ value between measurable values), in 
which case they will be treated as missing.
CCI
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 12 of 24
Statistical Analysis Plan Final
16 April 2020
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that subject’s maximum concentration
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)
The details on PK parameter calculations will be outlined in the CPAP including specifics on the 
following:

Insufficient data to determine a reliable t1/2z value and other terminal disposition phase rate 
constant (z)-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 TFLs

Data presented in in-text and end-of-text figures

Figures for individual subjects presented in Appendix 16.2.6
For demographic data where appropriate, variables will be summarized descriptively over all
subjects. For the categorical variables, the count and proportions of each possible value will be 
tabulated over all subjects, 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.
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 13 of 24
Statistical Analysis Plan Final
16 April 2020
7.1.1
Study Definitions
7.1.2
Definition of Study Days
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 (Day 1); study day on or after 
the date of first dose will be calculated as: date of assessment/event - date of treatment
(Day 1) + 1.
7.2
Study Treatments
On Day 1 of Period 1 (ABA Study Period), subjects received a single unlabeled oral 500 mg 
dose of TAK-831 as tablets. At 1.25 hours (75 minutes) post oral dosing (ie, 15 minutes prior to 
the median tmax for the oral unlabeled dose [~1.5 hours]), subjects received a 15-minute IV 
infusion of a microdose of 50 µg (~1 µCi) [14C]TAK-831. 
There was a washout period of at least 7 days between the last dose in Period 1 and the dose in 
Period 2.
On Day 1 of Period 2 (ADME Study Period), subjects received a single dose of 500 mg 
(~100 μCi) [14C]TAK-831 as an oral suspension. 
7.3
Analysis Sets
Safety Set:
All subjects who received at least one dose of the study drug(s) will be included in the safety set. 
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 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. In terms of criteria for evaluable subjects, please see 
CPAP.
7.4
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 overall. Individual subject’s dosing
status by treatment, study completion status, including reason for discontinuation, will also be 
listed by subject in a table. 
Only and Subject to the Applicable Terms of Use
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7.4


TAK-831-1008
Celerion Study Number CA28631
Page 14 of 24
Statistical Analysis Plan Final
16 April 2020
7.5
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized over all subjects. 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). Height, weight, and BMI collected at screening will be used in the baseline 
summaries. Demographics data will also be listed as recorded on the CRF, including the date of 
informed consent.
7.6
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include 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. All medical 
and surgical history recorded during the study will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®), Version 22.1, and listed. The medical history listing will 
include whether the event was medical or surgical, the body system or organ class involved, the 
MedDRA system organ class (SOC) and preferred term (PT), the 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.
7.7
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-2019 b3, and listed. The listing will include 
the medication name, coded term, 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. 
7.8
Study Drug Exposure and Compliance
Not applicable.
7.9
Efficacy Analysis
Not applicable.
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TAK-831-1008
Celerion Study Number CA28631
Page 15 of 24
Statistical Analysis Plan Final
16 April 2020
7.10
Pharmacokinetic/Pharmacodynamic Analysis
7.10.1 Pharmacokinetic Analysis
Blood, urine, and feces were collected as specified in Tables 7.a to 7.d.
Table 7.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-831 
(Period 1 - ABA Study Period)
Study 
Day
Time 
(relative to oral dosing)
Time 
(relative to IV infusion)
Blood Sample 
Collection
(oral dose)
Blood Sample 
Collection
(IV dose)
Matrix
Plasma Sample 1 a
Plasma Sample 2 b
Day 1
0 (predose)
X c
X c
0.5 hour postdose 
(± 2 min)
X c
1 hour postdose (± 2 min)
X c
1.25 hours postdose (- 2 
min)
0 (predose) 
X c
1.5 hours postdose 
(± 2 min)
End of infusion
X
X
5 min after the end of infusion (± 2 
min)
X
15 min after the end of infusion (± 2 
min)
X
2 hours postdose 
(± 2 min)
30 min after the end of infusion (± 2 
min)
X
X
1 hour after the end of infusion (± 2 
min)
X
4.5 hours postdose 
(± 2 min)
3 hours after the end of infusion (± 
5 min)
X
X
6.5 hours postdose 
(± 2 min)
5 hours after the end of infusion (± 
5 min)
X
X
8.5 hours postdose 
(± 2 min)
7 hours after the end of infusion (± 
5 min)
X
X
12.5 hours postdose (± 5 
min)
11 hours after the end of infusion (± 
5 min)
X
X
Day 2
24.5 hours postdose (± 5 
min)
23 hours after the end of infusion (± 
5 min)
X
X
36.5 hours postdose 
(± 10 min)
35 hours after the end of infusion 
(± 10 min)
X
X
Day 3
48.5 hours postdose 
(± 10 min)
47 hours after the end of infusion 
(± 10 min)
X
X
Day 4
72.5 hours postdose 
(± 10 min)
71 hours after the end of infusion 
(± 10 min)
X
X
Day 5
96.5 hours postdose 
(± 15 min)
95 hours after the end of infusion 
(± 15 min)
X
X
a For determination of TAK-831 in plasma following oral tablet dose.
b For determination of total radioactivity, and [14C]TAK-831 in plasma following IV infusion.
c Pre-IV dose samples should be stored separately away from the postdose samples to avoid cross contamination.
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
of TAK
ble T
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TAK-831-1008
Celerion Study Number CA28631
Page 16 of 24
Statistical Analysis Plan Final
16 April 2020
Table 7.b
Urine and Fecal Sampling Schedule (Period 1 – ABA Study Period)
Study Day
Time Interval (hours)
(Relative to Oral Dosing)
Urine Sample Collection
Feces Sample Collection
Matrix
Urine a
Feces b
Days -2 to 1
-48 to 0 hours (predose)
X c, d
X d, e
Day 1
0-1.25 hours (prior to IV dosing)
X d
X d
Day 1
1.25-12 hours
X
X (1.25-24 hours)
Days 1 to 2
12-24 hours
X
Days 2 to 3
24-48 hours 
X
X
Days 3 to 4
48-72 hours
X
X
Days 4 to 5
72-96 hours
X f
X f
Days 5 to 6
(if required)
96-120 hours
X g
X g
Days 6 to 7
(if required)
120-144 hours 
X g
X g
Days 7 to 8
(if required)
144-168 hours 
X g
X g
a Urine sample for [14C]TAK-831 and total radioactivity following IV infusion.
b Feces sample for [14C]TAK-831 and total radioactivity following IV infusion.
c Predose urine sample is to be obtained within 24 hours prior to IV infusion and prior to oral dosing.
d Pre-IV dose samples should be stored separately away from the postdose samples to avoid cross contamination.
e Predose fecal sample is to be obtained within 48 hours prior to oral dosing. Subjects will be asked to bring a fecal sample at 
check-in (if produced within 48 hours prior to oral dosing). Feces produced between check-in and dosing will also be collected 
as a predose sample with the sample produced nearest to oral dosing to be retained as the only predose sample.
f Including the urine and fecal sample collected on the morning of Day 5 (when passed) prior to furlough. Subjects will be asked 
to provide a urine and a fecal sample prior to release from the clinic on Day 5.
g For subjects who do not meet a discharge criterion by Day 5, samples will continue to be collected in 24-hour intervals until 
radioactivity in urine and feces combined is ≤1% of the total administered radioactivity for at least 2 consecutive intervals 
where both a urine and fecal sample are collected, the excretion of radioactivity is ≥80% of the administered radioactive dose, 
or up to Day 8.
t to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 17 of 24
Statistical Analysis Plan Final
16 April 2020
Table 7.c
Blood Collection Schedule (Period 2 - ADME Study Period)
Study Day
Matrix
Sample collected for analysis 
in Whole Blood
Sample collected for analysis in Plasma
Time 
(Relative to Oral 
Suspension Dosing)
Blood Sample a
Plasma 
Sample 1 b
Plasma 
Sample 2 c
Plasma 
Sample 3 d
Day 1
0 (predose)
X e
X e
X e
X e
0.25 hour postdose 
(± 2 min)
X
X
X
0.5 hour postdose (± 2 
min)
X
X
X
X
1 hour postdose (± 2 min)
X
X
X
X
2 hours postdose (± 2 min)
X
X
X
4 hours postdose (± 2 min)
X
X
X
X
6 hours postdose (± 2 min)
X
X
X
8 hours postdose (± 2 min)
X
X
X
X
12 hours postdose 
(± 5 min)
X
X
X
X
Day 2
24 hours postdose 
(± 5 min)
X
X
X
X
36 hours postdose 
(± 10 min)
X
X
X
Day 3
48 hours postdose 
(± 10 min)
X
X
X
X
Day 4
72 hours postdose 
(± 10 min)
X
X
X
X
Day 5
96 hours postdose 
(± 15 min)
X
X
X
Day 6
(if required)
120 hours postdose 
(± 30 min)
X
X
X
X
Day 7
(if required)
144 hours postdose 
(± 30 min)
X
X
X
Day 8
(if required)
168 hours postdose 
(± 30 min)
X
X
X
X
Day 9
(if required)
192 hours postdose 
(±1 hour)
X
X
X
Day 10
(if required)
216 hours postdose 
(±1 hour)
X
X
X
Day 11
(if required)
240 hours postdose 
(±1 hour)
X
X
X
a Blood sample 1 – Blood sample for determination of total radioactivity in whole blood.
b Plasma sample 1 – Blood sample for determination of total radioactivity in plasma.
c Plasma sample 2 – Blood sample for TAK-831 PK in plasma.
d Plasma sample 3 – Blood sample for 
e Predose blood and plasma samples should be stored separately away from the postdose samples to avoid cross contamination.
CCI
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 18 of 24
Statistical Analysis Plan Final
16 April 2020
Table 7.d
Urine and Fecal Sampling Schedule (Period 2 - ADME Study Period)
Study Day
Time Interval (hour)
(Relative to Oral Suspension Dosing)
Urine Sample Collection
Feces Sample Collection
Matrix
Urine a
Feces b
Day -1 to 1
-24 to 0 hour (predose)
X c
X d
Day 1
0-12 hour
X
X (0-24 hour)
Days 1 to 2
12-24 hour
X
Days 2 to 3
24-48 hour
X
X
Days 3 to 4
48-72 hour
X
X
Days 4 to 5
72-96 hour
X
X
Days 5 to 6
96-120 hour
X
X
Days 6 to 7
(if required)
120-144 hour
X
X
Days 7 to 8
(if required)
144-168 hour
X
X
Days 8 to 9
(if required)
168-192 hour
X
X
Days 9 to 10
(if required)
192-216 hour e
X
X
Days 10 to 11
(if required)
216-240 hour e
X
X
Days 11 to 12 e
(if required)
240-264 hour e
X
X
Days 12 to 13 e
(if required)
264-288 hour e
X
X
Days 13 to 14 e
(if required)
288-312 hour e
X
X
Days 21 to 22 e
(if required)
480-504 hour e
X
X
Days 28 to 29 e
(if required)
648-672 hour e
X
X
a Urine samples for determination of total radioactivity, for
, and for assessment of TAK-831 PK.
b Feces samples for determination of total radioactivity and for 
c Predose urine sample is to be obtained within 24 hours prior to dosing. Predose urine samples should be stored separately away 
from the postdose samples to avoid cross contamination.
d Predose fecal sample is to be obtained within 48 hours prior to dosing. Subjects will be asked to bring a fecal sample at 
check-in (if produced within 48 hours prior to dosing). Feces produced between check-in and dosing will also be collected as a 
predose sample with the sample produced nearest to dosing to be retained as the only predose sample. Predose fecal samples 
should be stored separately away from the postdose samples to avoid cross contamination.
e Samples will continue to be collected in 24-hour intervals until radioactivity in urine and feces combined is ≥90% of the 
administered radioactive dose or up to 10 days postdose (Day 11). If less than 90% of the total dose of radioactivity 
administered is recovered in urine and fecal samples within 10 days postdose (ie, Day 11), the subject will continue to stay at 
the CRU until 80% or greater of the total dose of radioactivity administered is recovered in urine and fecal samples or the 
excretion of radioactivity in the urine and feces combined has declined to ≤1% of the total administered radioactivity for at 
least 2 consecutive intervals where both a urine and fecal sample are collected, whichever occurs first, or until Day 14. If 
neither one of the 2 discharge criteria is met by Day 14, at the discretion of the Sponsor, the subject may be required to return 
to the CRU for urine and fecal samples collection in two 24-hour periods at approximately 7 and 14 days after discharge from 
the CRU (eg, Days 21 and 22 and Days 28 and 29). Subjects will be confined in the CRU for these 24-hour sample collection
periods.
CCI
CCI
Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 19 of 24
Statistical Analysis Plan Final
16 April 2020
The actual date and time of sample collection will be recorded on the source document and 
electronic case report form (eCRF).
7.10.1.1 Pharmacokinetic Analysis
Descriptive statistics will be provided for the total radioactivity (whole blood, plasma, urine, 
feces, and if applicable, emesis), TAK-831 (plasma and urine), and [14C]TAK-831 (plasma, 
urine, and feces) concentrations (or concentration equivalents) and PK parameters.
All PK parameters for all analytes are listed in the CPAP for this study and will be determined 
using noncompartmental analysis methods. 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.
Individual urine sample weight, fecal homogenate weight, analyte concentrations, analyte 
amounts, and percentage of dose will be listed by time interval. Amounts and percentage of dose 
recovered will also be summarized descriptively for each collection interval, and the overall 
collection period. Summary will be done by treatment using the summary statistics listed in the 
CPAP. Excluded data will be presented and footnoted as such in the table listings, and those 
values will be excluded from the descriptive summary statistics. 
Individual subject and arithmetic mean profiles of the cumulative percent of dose recovered-time 
data will be plotted on linear (with and without SD) scale. For summary statistics and arithmetic 
mean concentration-time 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 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. 
A comparison of ln-transformed dose-normalized AUC∞will be made to evaluate the absolute 
bioavailability (Period 1) of TAK-831 administered as oral dose versus [14C]TAK-831
administered as IV microdose. The comparison will be done by performing an ANOVA model 
using PROC MIXED of SAS®. The ANOVA model will include route of administration (oral 
and IV) as a fixed effect and subject as a random effect. The inferential results (least-squares 
[LS] means, difference between LS means, and 90% confidence intervals [CIs] of the difference) 
will be exponentiated to the original scale. Geometric LS means, geometric LS mean ratios 
(GMRs) and 90% CIs will be presented. The GMRs and CIs will be expressed as a percentage 
relative to the reference route of administration (i.e., [14C]TAK-831 administered as IV 
microdose). AUClast and Cmax will be analyzed in a similar fashion.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 20 of 24
Statistical Analysis Plan Final
16 April 2020
The ANOVA analysis will be performed using the following SAS® code:
PROC MIXED;
CLASS ROUTE;
MODEL LN(PK_PARAMETER) = ROUTE/ DDFM = KR;
RANDOM SUBJECT;
ESTIMATE “Oral vs Intravenous” ROUTE 1 -1 / cl alpha=0.1 e;
RUN;
Programmer Note: The coefficient estimates will be adjusted according to the route of 
administration decodes.
7.10.1.2 Analysis of Mass Balance
In Period 2, mass balance will be calculated as a sum of the percent of the total radioactivity
recovered in urine and feces plus any radioactivity dose lost due to emesis (if any occurred)
relative to the administered radioactivity dose.
7.10.2 Pharmacodynamic Analysis
Not applicable. 
7.11
Other Outcomes
Not applicable.
7.12
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and relationship to study drug of 
TEAEs, changes from baseline in the subjects’ clinical laboratory results, vital signs, and ECG’s 
using the safety set. All clinical safety data will be listed by subject and assessment time points, 
including rechecks, unscheduled assessments, and early termination, chronologically. 
CCI
Subject to the Applicable Terms of Use
he route
Appli
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cent of t
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due to e
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due to e
Property of Takeda: For No
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For N
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Other 
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7.12
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7.12
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Non-Commercial Use Only and Su


TAK-831-1008
Celerion Study Number CA28631
Page 21 of 24
Statistical Analysis Plan Final
16 April 2020
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.
7.12.1 Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (Mild, Moderate, and Severe), relationship to study drug (related or 
not related), action relative to the study drug, outcome, and procedures. All AEs occurring during 
this study will be coded using MedDRA®, Version 22.1. However, only TEAEs occurring after 
administration of the first dose of study drug and through the follow-up phone call (31 +/- 2 days 
after the last study drug 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. TEAEs occurring at or 
after Period 1 Day 1 oral dosing and prior to Period 2 Day 1 dosing will be considered treatment-
emergent to Treatment A (i.e., single oral dose of 500 mg TAK-831 followed by a single 
intravenous dose of 50 µg [14C]-TAK-831 [Period 1]) and those occurring at or after Period 2 
Day 1 dosing will be considered treatment-emergent to Treatment B (i.e., single oral dose of 500 
mg [14C]-TAK-831 [Period 2]).   
For each treatment, TEAEs will be coded using MedDRA® 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, excluding SAEs) will also be summarized
separately. For the list of all AE summary tables 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. Similarly, a table of the events per subject will be included where 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 only. 
Should any SAEs (including all-cause mortalities) occur, they will be listed and 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. 
7.12.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1) 
of Period 1, Day 3 in each period, and prior to discharge in Period 2 or early termination. In 
addition, laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the Principal Investigator (PI). Coagulation tests (PT/INR) will be performed if 
subjects has on-study aspartate aminotransferase or alanine aminotransferase elevated ≥3x the 
upper limit of normal.
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 22 of 24
Statistical Analysis Plan Final
16 April 2020
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 in a similar way. Baseline is defined as the last 
assessment including rechecks taken prior to oral dosing on Day 1 of Period 1 (Day -1 Check-in 
of Period 1). 
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 point for each treatment. For urinalysis tests, the categories are normal (N) and abnormal 
(A). Out-of-range values and corresponding recheck results will be listed. 
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 
laboratory tests, as indicated by the PI, and the corresponding values will be listed by subject. All 
clinical laboratory data will be presented in by-subject data listings.
7.12.3 Vital Signs
Single measurements of vital signs will be collected as outlined in Table 7.e. 
Table 7.e
Collection of Vital Signs 
Measurement Type
Period
Day
Time Point
Vital Signs (Heart Rate and Blood 
Pressure)
Screen
1
-1
1
1 hour post oral dose
2
1
4 and 12 hours post oral dose
Discharge or 
ET*
Vital Signs (Respiratory Rate and 
Temperature)
Screen
* ET = Early termination
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 by treatment and time point of collection. Change from baseline will be summarized 
in a similar way. Baseline is defined as the last assessment including rechecks taken prior to 
Use Only and Subject to the Applicable Terms of Use
last 
s o
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TAK-831-1008
Celerion Study Number CA28631
Page 23 of 24
Statistical Analysis Plan Final
16 April 2020
Day 1 oral dosing in Period 1 (Day -1 Check-in of Period 1). Vital signs will also be displayed in 
a data listing by subject. Orthostatic vital signs (heart rate and blood pressure) will be collected 
at screening (3-minute standing minus 1-minute sitting) and will also be presented in this data 
listing.
7.12.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded as outlined in Table 7.f. 
Table 7.f
Collection of Electrocardiograms
Measurement Type
Period
Day
Time Point
12-Lead ECG
Screen
1
-1
1
1 and 4 hours post oral dose
2
1
4 hours post oral dose
Discharge or 
ET*
* ET = 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 Day 1 oral dosing in Period 1 (Day -1 
Check-in of Period 1). ECG data will also be displayed in a data listing by subject with 
QTcF > 450 ms and QTcF change from baseline > 30 ms flagged.
7.12.5 Physical Exams
A full physical exam will be performed at screening and at Check-in of each period and prior to 
Period 2 discharge or early termination. Symptom driven physical exams may be performed at 
other times at the discretion of the PI. Physical exam findings, as recorded on the CRF, will be 
presented in a data listing by subject. 
7.12.6 Columbia Suicide Severity Rating Scale (C-SSRS)
Assessments of C-SSRS questionnaires will be performed using Baseline/Screening Version at 
screening and Since Last Visit Version at Check-in of each period, Day 5 of Period 1, and prior 
to Period 2 discharge or early termination. The C-SSRS results will be listed by subject. 
7.12.7 Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs. 
d Subject to the Applicable Terms of Use
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TAK-831-1008
Celerion Study Number CA28631
Page 24 of 24
Statistical Analysis Plan Final
16 April 2020
7.13
Interim Analysis
No interim analysis will be performed. 
7.14
Preliminary Analysis
If requested, QCed whole blood and plasma concentration data will be plotted using nominal 
times to aid in the determination of samples for repeat bioanalysis. If requested, a preliminary 
PK 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 (not actual sampling 
times) will be used for the calculation of PK parameters in whole blood and plasma; 3) tables 
and figures will be created using Phoenix® WinNonlin® Version 7.0 or higher for whole blood 
and plasma data, and using SAS® Version 9.4, or higher for urine and feces data.
7.15
Changes in the Statistical Analysis Plan 
There analyses in the statistical analysis plan are the same as those specified in the protocol.
8.0
REFERENCES
Not applicable.
the Applicable Terms of Use
no
e
nominal
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Property of Takeda: For Non-Commercial Use Only and Su
as those
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680d595b1
TAK-831-1008_(CA28631)_SAP_Final_16Apr2020
Biostatistics Approval
17-Apr-2020 01:03 UTC
PPD
ble Terms of Use
e Te
ate 
T
ate 
ble T
HH:mm ‘U
ble 
HH:mm ‘U
Ter
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable
ble
:03 UTC
able
:03 UTC