Clinical trial NCT03228433
Conditions: Healthy Participants
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2017-07-21; Completion date: 2018-05-12
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of TAK-418 following single oral doses in healthy participants.

Detailed description:
The drug being tested in this study is called TAK-418. TAK-418 is being tested in healthy participants in order to evaluate the safety, tolerability, and pharmacokinetics (PK) of single oral doses.

The study will enroll approximately 40 healthy participants. The study consists of equally divided 5 sequential cohorts of 8 participants each. In each of the following cohorts, 6 participants will be randomized to receive TAK-418 and 2 participants will receive matching placebo-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Cohort 1: TAK-418 5 mg
* Cohort 2: TAK-418 15 mg
* Cohort 3: TAK-418 30 mg Fasted + TAK-418 30 mg Fed
* Cohort 4: TAK-418 40 mg
* Cohort 5: TAK-418 60 mg

All participants will be asked to take TAK-418 or placebo-matching capsule once on Day 1 in each cohort. A washout period of 28-days will be maintained between the doses in Cohort 3.

This single center trial will be conducted in the United States. Participants in this study will be assigned to one of 5 possible dose cohorts. Male participants will return for additional outpatient visits on Days 91 and 93 (+/- 7 days) and may return for outpatient visits on Days 182 and 184 (+/- 7 days) (depending on results from the Day 93 Visit).

Arms: arm 1: TAK-418 5 milligram (mg), capsule, orally, once on Day 1. arm 2: TAK-418 15 mg, capsule, orally, once on Day 1. Actual dose of TAK-418 may vary based on safety, tolerability and PK data from previous Cohorts. arm 3: TAK-418 30 mg, capsule, in fasted state, orally, once on Day 1, followed by a 28-day washout period, further followed by TAK-418 30 mg, capsule, in fed state, orally, once on Day 1. Actual dose of TAK-418 may vary based on safety, tolerability and PK data from previous Cohorts. arm 4: TAK-418 40 mg, capsule, orally, once on Day 1. Actual dose of TAK-418 may vary based on safety, tolerability and PK data from previous Cohorts. arm 5: TAK-418 60 mg, capsule, orally, once on Day 1. Actual dose of TAK-418 may vary based on safety, tolerability and PK data from previous Cohorts. arm 6: TAK-418 placebo-matching, capsule, orally, once on Day 1.
Interventions: intervention 1: TAK-418 intervention 2: TAK-418 Placebo
Intervention descriptions: intervention 1: TAK-418 Capsule. intervention 2: TAK-418 placebo-matching capsules.

Protocol documents:
Prot_000.pdf: 


•
Title: A Randomized, Double-Blind, Placebo-Controlled, Ascending Oral Single Dose Trial to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of TAK-418 in Healthy Subjects
NCT Number: NCT03228433
Protocol Approve Date: 07 July 2017
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.


CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Ascending Oral Single Dose Trial to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-418 in Healthy Subjects
Sponsor:
Takeda Development Center Americas, Inc. 
One Takeda Parkway
Deerfield, IL 60015
Trial Number:
TAK-418-1001
Compound:
TAK-418
Date:
07 July 2017
Version/Amendment 
Number:
01
Amendment History:
Date
Amendment Number
Amendment Type 
(Substantial/Nonsubstantial
Region
06 April 2017
Initial version
Not applicable
Global
07 July 2017
01
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
1.1
Protocol Amendment No. 01 Summary of Changes .................................................11
2.0
TRIAL SCHEMATIC ...................................................................................................12
3.0
SCHEDULE OF TRIAL PROCEDURES......................................................................13
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.2
Rationale for the Proposed Trial...............................................................................19
4.3
Benefit/Risk Profile .................................................................................................19
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective............................................................................................21
5.1.2
Secondary Objective........................................................................................21
5.1.3
Exploratory Objectives ....................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoint.............................................................................................21
5.2.2
Secondary Endpoints .......................................................................................22
5.2.3
Exploratory Endpoints .....................................................................................22
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................23
6.1
Trial Design.............................................................................................................23
6.2
Dose Escalation .......................................................................................................25
6.3
Justification for Trial Design, Dose, and Endpoints..................................................25
6.3.1
Justification of Trial Design and Regimen .......................................................25
6.3.2
Dose ................................................................................................................26
6.3.3
Justification for Endpoints ...............................................................................28
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures..............29
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.5
Trial Beginning and End/Completion.......................................................................30
6.5.1
Definition of Beginning of the Trial.................................................................30
6.5.2
Definition of End of the Trial...........................................................................30
6.5.3
Definition of Trial Completion.........................................................................31
6.5.4
Definition of Trial Discontinuation ..................................................................31
6.5.5
Criteria for Premature Termination or Suspension of the Trial .........................31
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............32


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7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................32
7.3
Excluded Medications, Supplements, Dietary Products............................................34
7.4
Diet, Fluid, Activity.................................................................................................35
7.4.1
Diet and Fluid..................................................................................................35
7.4.2
Activity ...........................................................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................35
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................36
7.7
Subject Replacement................................................................................................36
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................37
8.1
Clinical Trial Drug...................................................................................................37
8.1.1
Clinical Trial Drug Labeling............................................................................37
8.1.2
Clinical Trial Drug Inventory and Storage .......................................................37
8.1.3
Clinical Trial Drug Blinding ............................................................................37
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs.............................37
8.1.5
Ancillary Supplies ...........................................................................................37
8.1.6
Randomization Code Creation and Storage......................................................37
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure..................................37
9.0
STUDY PROCEDURES...............................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent Procedure............................................................................39
9.1.2
Assignment of Screening and Randomization Numbers ...................................39
9.1.3
Clinical Trial Drug Assignment .......................................................................39
9.1.4
Inclusion and Exclusion Criteria ......................................................................39
9.1.5
Medical History, Medication History, and Demographics ................................39
9.2
Clinical Procedures and Assessments.......................................................................40
9.2.1
Full Physical Examination ...............................................................................40
9.2.2
Neurological Examination ...............................................................................40
9.2.3
Height and Weight...........................................................................................40
9.2.4
BMI.................................................................................................................40
9.2.5
Vital Signs.......................................................................................................40
9.2.6
12-Lead ECG...................................................................................................40
9.2.7
Trial Drug Administration ...............................................................................41
9.2.8
BL-VAS ..........................................................................................................41
9.2.9
Cognitive Testing ............................................................................................42


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9.2.10
AE Monitoring ................................................................................................42
9.2.11
Laboratory Procedures and Assessments..........................................................42
9.2.12
C-SSRS ...........................................................................................................44
9.3
Biomarker, PK, PD, and PGx, Samples....................................................................44
9.3.1
PK Measurements............................................................................................45
9.3.2
Biomarker Measurements ................................................................................46
9.3.3
PGx Measurements..........................................................................................46
9.3.4
Actigraphy and Biometric Monitoring .............................................................48
9.3.5
Confinement....................................................................................................48
10.0
ADVERSE EVENTS ....................................................................................................49
10.1
Definitions and Elements of AEs .............................................................................49
10.1.1
SAEs ...............................................................................................................51
10.1.2
Special Interest AEs.........................................................................................52
10.2
AE Procedures.........................................................................................................52
10.2.1
Assigning Severity/Intensity of AEs ................................................................52
10.2.2
Assigning Causality of AEs .............................................................................52
10.2.3
Assigning Relationship to Trial Procedures......................................................52
10.2.4
Start Date.........................................................................................................53
10.2.5
Stop Date.........................................................................................................53
10.2.6
Frequency........................................................................................................53
10.2.7
Action Concerning Trial Drug .........................................................................53
10.2.8
Outcome..........................................................................................................53
10.2.9
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................54
10.2.10 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...56
11.0
STATISTICAL METHODS..........................................................................................57
11.1
Statistical and Analytical Plans ................................................................................57
11.1.1
Analysis Sets ...................................................................................................57
11.1.2
Analysis of Demographics and Other Baseline Characteristics.........................57
11.1.3
PK Analysis.....................................................................................................57
11.1.4
PD Analysis.....................................................................................................58
11.1.5
Biomarker Analysis .........................................................................................58
11.1.6
Safety Analysis................................................................................................58
11.2
Interim Analysis and Criteria for Early Termination ................................................59
11.3
Determination of Sample Size..................................................................................59
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................60


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12.1
Trial-Site Monitoring Visits.....................................................................................60
12.2
Protocol Deviations..................................................................................................60
12.2.1
Exploratory Biomarkers and Wearable Devices ...............................................60
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................60
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................62
13.1
IRB and/or IEC Approval ........................................................................................62
13.2
Subject Information, Informed Consent, and Subject Authorization .........................63
13.3
Subject Confidentiality ............................................................................................64
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................64
13.4.1
Publication and Disclosure...............................................................................64
13.4.2
Clinical Trial Registration................................................................................65
13.4.3
Clinical Trial Results Disclosure......................................................................65
13.5
Insurance and Compensation for Injury....................................................................65
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................66
14.1
Administrative Information......................................................................................66
14.1.1
Trial Contact Information ................................................................................66
14.1.2
INVESTIGATOR AGREEMENT ...................................................................67
14.1.3
Trial-Related Responsibilities ..........................................................................67
14.1.4
List of Abbreviations .......................................................................................68
14.1.5
Corporate Identification...................................................................................70
15.0
DATA HANDLING AND RECORDKEEPING............................................................71
15.1
CRFs (Electronic and Paper)....................................................................................71
15.2
Record Retention .....................................................................................................71
16.0
REFERENCES..............................................................................................................73
17.0
APPENDICES...............................................................................................................74
LIST OF IN-TEXT TABLES
Table 6.a
Schematic and Planned Doses of Trial DesignCohorts 1 to 5..........................23
Table 6.b
Trial Schedule....................................................................................................25
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................34
Table 9.a
Primary Specimen Collections ...........................................................................45
Table 10.a
Takeda Medically Significant AE List................................................................52


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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................74
Appendix B
Elements of the Subject Informed Consent.........................................................76
Appendix C
Investigator Consent to Use of Personal Information..........................................79
Appendix D
Pregnancy and Contraception.............................................................................80
Appendix E 
Detailed Description of Amendments to Text.....................................................82


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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. 
One Takeda Parkway
Deerfield, IL 60015
Compound:
TAK-418
Trial Number: 
TAK-418-1001
Phase: 1 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Ascending Oral Single Dose Trial to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TAK-418 in Healthy Subjects
Trial Design:
This first-in-human (FIH), randomized, double-blind, placebo-controlled trial is designed to evaluate the safety, 
tolerability, and pharmacokinetics (PK) of TAK-418 in healthy adult subjects.
TAK-418 and placebo will be administered orally in capsule formulation and will be prepared and dispensed in a 
blinded fashion by an unblinded pharmacist or qualified trial site personnel; the subject, the investigator, and the 
sponsor personnel or delegate(s) who are involved in the treatment or clinical evaluation of the subjects will be 
unaware of the treatment group assignments.
Since the PK, pharmacodynamic, and safety profiles of TAK-418 in humans are still being evaluated, modifications to 
the dose or dosing regimen may be required to achieve the scientific goals of the trial objectives and/or to ensure 
appropriate safety monitoring of the trial subjects. Dose escalation and subsequent dose levels will be based on a 
blinded review of available safety (including neurological assessment), tolerability, and PK data from the previous 
dose levels and will only occur following agreement between the investigator and the sponsor.
This study will involve 40 subjects, equally divided among 5 sequential cohorts of 8 subjects each, as shown in 
Table 1. In each cohort, 6 subjects will be randomized to receive TAK-418 and 2 will receive matching placebo. A 
minimum of 4 male subjects will be enrolled in each cohort. The schedule for dosing and procedures is provided in 
Table 2.
Table 1. Schematic and Planned Doses for Cohorts 1 Through 5
Dose 5 mg
Dose 15 mg
Dose 45 mg
Dose 90 mg
Dose 180 mg
Cohort 1
(n=8; 6 active: 2 placebo)
Cohort 2
(n=8; 6 active: 
2 placebo)
Cohort 3A and 3B
(n=8; 6 active: 
2 placebo)
Cohort 4
(n=8; 6 active: 
2 placebo)
Cohort 5
(n=8; 6 active: 
2 placebo)
Additional cohorts may be studied if deemed necessary to fully characterize the pharmacologically active exposure 
range.
Doses planned to be administered range from 5 to 180 mg, but the actual doses administered after the first dose will be 
based on emerging safety and tolerability data from the previous doses. If needed, a dose higher than 180 mg but less 
than 300 mg may be evaluated providing its predicted exposure does not exceed the following exposure levels: the 
highest dose administered will have a predicted mean area under the plasma concentration-time curve (AUC) that does 
not exceed the monkey AUC at the no effect level for 
 from 
the 13-week toxicology study or mean maximum observed concentration (Cmax) that does not exceed one-tenth 
(
) of the monkey Cmax at the NOAEL (
 from the 4-week toxicology study.
Because this is a FIH trial, a sentinel dosing regimen will be used for Cohort 1 (with the initial 2 subjects receiving 
either active drug or placebo [1:1]) to ensure adequate safety and tolerability. The remaining 6 subjects will be dosed 
in 2 groups of 3 subjects each after a review of 72 hours postdose safety and tolerability data of the previous group. A 
staggered dosing regimen will be used for Cohorts 2 to 5. Each cohort will be divided by 2 groups (3 active:1 placebo), 
and the second group will be dosed 48 hours after the first group, following assessment of safety and tolerability data. 
Subjects in Cohort 3 will receive 2 doses (under fasted state [Cohort 3A] and with food [Cohort 3B]), with at least 7 
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days of washout between dose administrations. Subjects enrolled in Cohort 3A will return to the site to complete 
Cohort 3B and will be administered TAK-418/placebo under fed condition with a high fat/high calorie breakfast, 
which must be consumed within 30 minutes and the dose given within 5 minutes after the end of the meal. All 
assessments from Day -1 to Day 4 in Cohort 3B will be same as in Cohort 3A and there will be no Day 14 follow-up 
for Cohort 3A. Post-trial assessments days will be adjusted (including follow-up on Day 14 for all subjects and 
Days 91, 93, and 182 and 184 postdose, if needed) with respect to Cohort 3B. 
Table 2. Trial Schedule
Screening Period (a)
Pretreatment 
(a)
Treatment
Post-trial (c)
Dose Administration (b)
Postdose Procedures (b)
Days -28 to -2
Day -1
Day 1
Days 1 to 4
Day 14 (±2)
Days 91, 93, 182, 
and 184 (±7)
(a)
(b) Subjects will remain in the phase 1 unit for a minimum of 48 hours following the dose of trial drug and may be 
released after 48 hours and complete the 72 hour and later procedures at an outpatient visit. Subject may be kept in 
clinic for the entire time at the PI's discretion.
(c) 
 
 
Primary Objective:
The primary objective of this trial is to evaluate the safety and tolerability of TAK-418 following single oral doses in 
healthy subjects.
Secondary Objective:
The secondary objective of this trial is to evaluate the PK of TAK-418 free base (F) following a single oral doses 
(under fasted and fed states) in healthy subjects. 
Subject Population: Healthy adults aged 18 to 55 years, inclusive.
Number of Subjects:
40 subjects (8 subjects in each of 5 cohorts)
Number of Sites:
1 site
Dose Levels:
5 mg (Cohort 1), 15 mg (Cohort 2), 45 mg (Cohort 3), 90 
mg (Cohort 4), and 180 mg (Cohort 5)
Route of Administration:
Oral
Duration of Treatment:
One single dose in Cohorts 1, 2, 4, and 5
Two single doses in Cohort 3 (under fasted and fed 
states)
Period of Evaluation:
Female subjects (Cohorts 1, 2, 4, and 5): approximately 42 
days.
Female subjects (Cohort 3): approximately 49 days.
Male subjects (Cohorts 1, 2, 4, and 5): approximately 121 
days (212 days if serum analysis is abnormal on Day 93).
Male subjects (Cohort 3): approximately 128 days (219 
days if serum analysis is abnormal on Day 93 post Cohort 
3B).
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Main Criteria for Inclusion:
To be eligible for trial participation, subjects must: 
∀
Be a male subject or female subject (with no childbearing potential) with a body mass index from ≥18.5 to 
≤30.0 (kg/m2) at the Screening Visit.
∀
Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine patch) for at least 
6 months before trial drug administration.
∀
Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, 
medical history, physical examination, 12-lead electrocardiogram (ECG), and vital sign measurements performed 
at the Screening Visit and before administration of the trial drug/invasive procedure. 
∀
Male subjects must have 
 that equal or exceed the World Health Organization reference values.
∀
Must meet stringent birth control requirements as specified in the protocol.
Main Criteria for Exclusion:
The subject must be excluded from participating in the trial if the subject: 
∀
Has a history of cancer (malignancy).
∀
Is positive for hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus.
∀
Male subjects have their serum 
 levels that are clinically abnormal.
∀
Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks before the Screening 
Visit. 
∀
Has a risk of suicide according to the investigator’s clinical judgment per the Columbia–Suicide Severity Rating 
Scale at Screening or has made a suicide attempt in the 6 months before Screening.
∀
Has a clinically significant history of head injury, trauma, or seizures.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the trial is a composite of safety variables and dose-limiting effects of TAK-418 that will be 
evaluated after dosing on Day 1 by the number and percentage of subjects who:
∀
Experience at least 1 treatment-emergent adverse event.
∀
Discontinue because of an adverse event.
∀
Meet the markedly abnormal criteria for safety laboratory tests at least once postdose.
∀
Meet the markedly abnormal criteria for vital sign measurements at least once postdose.
∀
Meet the markedly abnormal criteria for safety 12-lead ECG parameters at least once postdose.
The secondary endpoints will be as follows:
∀
Evaluation of the following PK parameters after dosing on Day 1: 
#
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast).
#
Area under the concentration-time curve from time 0 to infinity (AUC∞).
#
Maximum observed concentration (Cmax).
#
Time of first occurrence of Cmax (tmax).
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Statistical Considerations:
Safety Analysis
Safety parameters will be summarized by pooled placebo, each TAK-418 dose level, and TAK-418 overall (as 
appropriate). Safety data collected after administration of trial drug under fed conditions will be summarized 
separately.
PK Analysis
Plasma concentrations of TAK-418F will be summarized by dose over each scheduled sampling time using 
descriptive statistics.
The amount of TAK-418F excreted in urine will be summarized by dose using descriptive statistics.
Plasma and urine PK parameters of TAK-418F will be summarized by dose using descriptive statistics.
Individual plasma and urine concentration versus time data and PK parameters will be presented in a data listing. 
If sufficient data are available, dose proportionality of TAK-418F plasma exposures (Cmax and AUC) will be assessed 
statistically using a power model. For evaluation of potential food effect on TAK-418F PK, log-transformed Cmax and 
AUC values will be compared between the treatments (Reference=fasting administration; Test=fed administration) 
using an analysis of variance (ANOVA) with fixed effect for treatment and a random effect for subject. The geometric 
mean relative bioavailability and 90% confidence intervals (CIs) for Cmax, AUClast, and AUC∞will be calculated based 
upon the adjusted means (LS means) from the ANOVA.
Individual results of Bond-Lader Visual Analogue Scale, Columbia–Suicide Severity Rating Scale, and cognitive 
testing will be provided in the data listings. For cognitive testing, Baseline, postdose and change from Baseline to 
postdose data will be summarized by dose. 
A more detailed analysis will be presented in the statistical analysis plan. Additional analyses will be included, if 
appropriate.
Sample Size Justification: The sample size of 8 subjects per cohort (6 active: 2 placebo) chosen is based upon 
precedents from other FIH trials rather than a formal assessment of statistical power.
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed appropriate by the 
investigator and the sponsor. The trial site should contact the sponsor for the replacement subject’s treatment 
assignment and randomization number.


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1.1
Protocol Amendment No. 01 Summary of Changes
Rationale for Amendment No. 01
This document describes the changes in reference to the protocol incorporating Amendment
No. 01. The primary reason for this amendment is to change the study design from a combined 
single rising dose (SRD) and multiple rising dose (MRD) study to a SRD study, with assessment of 
 and exploratory biomarkers as additional safety parameters. In addition, several 
clarifications and administrative changes have been made.
Minor grammatical, editorial, and formatting changes are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment No. 01:
1. Modified study design to delete the MRD part of the study and associated assessments, and 
clarified the SRD part.
2. Added objectives relating to 
.
3. Added inclusion and exclusion criteria based on 
 levels in 
male subjects.
4. Added biomarkers.
5. Added preliminary data from 13-week toxicology study.
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2.0
TRIAL SCHEMATIC
Sentinel dosing for Cohort 1 and staggered dosing for the remaining cohorts. Groups 3A (fasted) and 3B (fed) have 7 
days of washout between them.


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3.0
SCHEDULE OF TRIAL PROCEDURES
Schedule of Activities
Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
S
-28 
to -2
-1
Hours
Days
Screen
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 
182, 184 
(±7)
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical history/ 
demographics
X
Prior and concomitant 
medication review
X--------------------------------------------------------Continuous Review--------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X (d)
X
Neurological examination
X
X (d)
X
X
X
Height
X
Weight
X
X
X
X
BMI
X
Semirecumbent vital signs 
(HR, SBP, and DBP)
X
X (e)
X
X
X
X
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Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
-28 
to -2
-1
Hours
Days
Screen
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 
182, 184 
(±7)
Vital signs (respiratory 
rate, oral [at the floor of 
the mouth]/tympanic 
temperature)
X
X (e)
X
X
X
X
12-lead ECG
X
X
X (e)
X
X
X
X
TAK-418/placebo 
administration
X
C-SSRS
X
X
X
X
X
X
BL-VAS
X
X
X
AE monitoring
X-------------------------------------------------------------Continuous Monitoring----------------------------------------------------X
Laboratory Procedures/Assessments
Hematology
X
X
X
X
Urinalysis
X
X
X
X
Serum chemistry
X
X
X
X
hCG (females) 
X
X
X
X
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Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
-28 
to -2
-1
Hours
Days
Screen
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 
182, 184 
(±7)
Urine drug screen
X
X
Urine/breath alcohol test 
(j)
X
X
Hepatitis screen
X
HIV
X
PK Evaluations
Blood for plasma PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for PK (k)
X----------------------------------------------------------------------------------------------X
Biomarker Evaluations
Company Confidential Information
Company Confidential Information
Company Confidential Information
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Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
S
-28 
to -2
-1
Hours
Days
Screen
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 
182, 184 
(±7)
PGx Evaluations
Blood sample for DNA 
PGx (n)
X
Blood sample for RNA 
PGx (o)
X
X
Other
Confinement
X-----------------------------------------------------------------------------------------------X
Footnotes are on the last table page.
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AE=adverse event, BL-VAS=Bond-Lader Visual Analogue Scale, BMI=body mass index, C-SSRS=Columbia–Suicide Severity Rating Scale, DBP=diastolic 
blood pressure, ECG=electrocardiogram, ET=early termination, F-FAD=formyl-flavin adenine dinucleotide, 
, hCG=human 
chorionic gonadotropin, HIV=human immunodeficiency virus, HR=heart rate, 
, PBMC=peripheral blood mononuclear cell, 
PGx=pharmacogenomics, PK=pharmacokinetic, SBP=systolic blood pressure.
(a) For Cohort 3, there will be a 7 day washout between Cohorts 3A and 3B, starting from TAK-418 administration on Day 1 for Cohort 3A. For Cohort 3B, all 
assessments on Days -1 through Day 4 will be same as Cohort 3A. 
(b) For all cohorts, except Cohort 3, all subjects will report back to the trial clinic to return wearable device(s) on Day 14 (±2) and will be re-evaluated per 
investigator’s discretion. Cohort 3A subjects will return wearable devices at on Day 7 (predose Cohort 3B). 
(c) 
(d) Predose physical and neurological examinations may be done within approximately 24 hours predose.
(e) Vital signs and a 12-lead ECG will be performed within approximately 1 hour predose on Day 1.
(f) 
 
(g) 
(h) 
(i) 
(j) A urine alcohol test may be performed at the discretion of the investigator.
(k) Urine sample for TAK-418F concentrations may be collected at a dose level projected to produce therapeutic exposure at the following time intervals: Predose 
(spot collection), 0 to 12 hours, 12 to 24 hours, 24 to 48 hours.
(l) 
 
 
(n) Blood for DNA PGx will be collected within 60 minutes predose.
(o) Blood for RNA PGx will be collected within 60 minutes predose and 24 hours postdose.
(p) For Cohorts 1, 2, 4, and 5, 
 at the 
mandatory follow-up visit on Day 14. For Cohort 3, 
and returned to the site at predose Cohort 3B.
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4.0
INTRODUCTION
4.1
Background
Lysine-specific demethylase 1A (LSD1) is involved in a wide variety of cellular processes and 
pathologies, including signal transduction, transcriptional regulation, viral pathogenesis, cancer 
proliferation and metastasis, development, differentiation, and chromatin remodeling [1]. As such, 
LSD1 has emerged as a potential therapeutic target for cancer as well as development disorders 
involving chromatin remodeling defects, such as autism spectrum disorder (ASD). 
An area of focus in ASD research has been on the genetic causes of ASD, since there is a strong 
heritable component [2]. ASDs are a heterogeneous group of neurodevelopmental disorders that 
manifest in early childhood, are defined by behavioral observations, and are characterized by 
impairments in communication and social interaction along with restrictive and repetitive 
behaviors [3-5]. These dysfunctions hinder the individual’s ability to function socially, at 
school/work, or other areas of life, and require full-time engagement of a one-on-one therapist 
over many years, often resulting in suboptimal outcomes [4]. There is a clear role for epigenetics, 
since genes involved in chromatin biology have been identified as risk factors [6]. This is in 
addition to trials in which chromatin modifications via either gene methylation or histone 
modification affect gene expression (silencing or activation) and subsequent development of the 
disorder [7].
One of the modifications that has been extensively studied is methylation of lysine in position 4 of 
type 3 histone (H3K4) [8], and an important regulator of H3K4 methylation is the LSD1, a 
member of the lysine-specific demethylase family 1 (KDM1). LSD1 uses a flavin adenine 
dinucleotide cofactor to oxidize carbon-nitrogen bonds with subsequent production of a 
demethylated lysine residue and formaldehyde by-product. The first reported specific substrate of 
LSD1 was histone H3K4me1/2 (LBR1), and subsequently further specific substrates have been 
identified.
LSD1 operates as a catalytic subunit within specific stable complexes formed with additional 
biomolecules and enzymes that perform coregulatory or scaffolding functions. Such interactions 
link the catalytic activity of LSD1 to distinctive biological occupations and have been shown to 
influence the degree of catalytic activity, substrate specificity, and/or localization of this enzyme 
within the chromatin [1]. Examples of complexes that contain LSD1 include CoREST, REST, 
TLX orphan nuclear receptor complex, TAL1 complex, CtBP complex, NuRD complex, androgen 
receptor nuclear hormone complex, and the Snail/Gfi-1 (SNAG family) of proteins. 
Modulation of neuronal histone methylation has been shown to have an impact on both learning 
and memory processes [5]. This has been further substantiated by the demonstration that LSD1 
activity plays an important role in the development of pyramidal cortical neurons and neural stem 
cell proliferation [5]. Consequently, the development of brain-penetrant LSD1 inhibitors as 
treatment agents for mood and psychosis disorders has been proposed [7,9].
TAK-418 is a novel small molecule that possesses inhibitory activity against human LSD1, also 
known as KDM1A. X-ray crystallography and mass spectrometric analysis have demonstrated that 
TAK-418 reacts on the catalytic flavin adenine dinucleotide (FAD) to form the formylated FAD 


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(F-FAD) in LSD1. F-FAD can therefore be used as a biomarker of target engagement for 
TAK-418. Nonclinical data with TAK-418 have demonstrated: (a) effects on social interaction in 
valproic acid and synthetic double-stranded RNA (polyinosinic:polycytidylic acid) autism rodent 
models, suggesting utility for treatment of social interaction and cognitive deficits in ASD, and (b) 
effects on declarative and emotional short-term memory task in rodents.
Please refer to the current TAK-418 Investigator’s Brochure for additional background 
information. Preliminary information from 13-week nonclinical toxicity in monkeys is in 
Section 6.3.2. 
4.2
Rationale for the Proposed Trial
Nonclinical pharmacology, pharmacokinetic (PK), and toxicology trials support the proposed trial 
in humans to further develop TAK-418 for the treatment of ASD. TAK-418 has shown effects on 
declarative and emotional short-term memory tasks in rodents and social interaction in autism 
rodent models that suggest utility for treatment of cognitive deficits in ASD. The nonclinical safety 
profile of TAK-418 supports clinical development of this compound. 
The proposed dose range of TAK-418 to be explored in this first-in-human (FIH) trial is 
anticipated to achieve a sufficient range of plasma exposures with a margin above the predicted 
pharmacologically active exposures. The preliminary safety and tolerability data information will 
facilitate the design and dose selection of a multiple rising dose (MRD) trial.
4.3
Benefit/Risk Profile
This proposed phase 1, randomized, double-blind, placebo-controlled, single-center trial will 
evaluate the safety, tolerability, and PK of TAK-418 following single oral doses in healthy 
volunteers aged 18 to 55 years, inclusive. As this is a healthy volunteer trial, there is no expected 
clinical benefit to the trial participants. 
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this trial is to evaluate the safety and tolerability of TAK-418 following 
single oral doses in healthy subjects.
5.1.2
Secondary Objective
The secondary objectives of this trial is to evaluate the PK of TAK-418 free base (F) following a 
single oral dose (under fasted and fed states) in healthy subjects. 
5.1.3
Exploratory Objectives
Exploratory objectives of the trial include:
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint of the trial is a composite of safety variables and dose-limiting effects of 
TAK-418 that will be evaluated after dosing on Day 1 by the number and percentage of subjects 
who:
∀
Experience at least 1 treatment-emergent adverse event (TEAE).
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∀
Discontinue because of an adverse event (AE).
∀
Meet the markedly abnormal criteria for neurological assessment measurements at least once 
postdose.
∀
Meet the markedly abnormal criteria for safety laboratory tests at least once postdose.
∀
Meet the markedly abnormal criteria for vital sign measurements at least once postdose.
∀
Meet the markedly abnormal criteria for safety 12-lead ECG parameters at least once postdose.
5.2.2
Secondary Endpoints
The secondary endpoints will be as follows:
Evaluation of the following PK parameters in healthy subjects after dosing on Day 1: 
∀
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).
∀
Area under the concentration-time curve from time 0 to infinity (AUC∞).
∀
Maximum observed concentration (Cmax).
∀
Time of first occurrence of Cmax (tmax).
5.2.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters in healthy subjects after 
dosing on Day 1: 
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is an FIH, randomized, double-blind, placebo-controlled trial to evaluate the safety, 
tolerability, and PK of TAK-418 in healthy adult subjects. The trial will also explore the PD of 
TAK-418 and its effects on selected biomarkers following single oral doses in healthy adult 
subjects. 
TAK-418 will be administered orally as a capsule formulation. TAK-418 and placebo will be 
prepared and dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site 
personnel. The subject, the investigator, and sponsor personnel or delegate(s) who are involved in 
the treatment or clinical evaluation of the subjects will be unaware of the treatment group 
assignments.
Because this is a phase 1 assessment of TAK-418 in humans, and the PK, PD, and safety profiles 
of the compound are still being evaluated, modifications to the dose or dosing regimen may be 
required to achieve the scientific goals of the trial objectives and/or to ensure appropriate safety 
monitoring of the trial subjects. Details of allowed modifications are provided in Section 6.4.
This study consists of 5 cohorts of subjects, sequentially paneled, with a double-blind design. Each 
cohort will consist of 8 subjects, where 6 subjects will be randomized to receive TAK-418 and 
2 subjects will be assigned to receive matching placebo. A minimum of 4 male subjects will be 
enrolled in each cohort. The trial population will be approximately 40 healthy subjects. Additional 
cohorts may be studied if deemed necessary to fully characterize the pharmacologically active 
exposure range. For Cohort 3, there will be at least 7 days of washout between dose administration 
in the fasted and fed states.
The planned dose levels of TAK-418 to be evaluated in Cohorts 1 to 5 are outlined in Table 6.a. 
Table 6.a
Schematic and Planned Doses of Trial DesignCohorts 1 to 5
Dose 5 mg
Dose 15 mg
Dose 45 mg
Dose 90 mg
Dose 180 mg
Cohort 1
(n=8; 6 active: 
2 placebo)
Cohort 2
(n=8; 6 active: 
2 placebo)
Cohort 3A and 3B
(n=8; 6 active: 
2 placebo)
Cohort 4
(n=8; 6 active: 
2 placebo)
Cohort 5
(n=8; 6 active: 
2 placebo)
Additional cohorts may be studied if deemed necessary to fully characterize the pharmacologically 
active exposure range.
Doses planned to be administered range from 5 to 180 mg, but the actual doses administered after 
the first dose will be based on emerging safety and tolerability data from the previous doses. If 
needed, a dose higher than 180 mg but less than 300 mg may be evaluated providing its predicted 
exposure does not exceed the following exposure levels. The highest dose administered will have a 
predicted mean area under the plasma concentration-time curve (AUC) that does not exceed the 
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toxicology study or mean maximum observed concentration (Cmax) that does not exceed one-tenth 
of the monkey Cmax from the 4-week toxicology study.
Subjects in Cohort 3 will receive 2 doses (under fasted state [Cohort 3A] and with food [Cohort 
3B]), with at least 7 days of washout between dose administrations. Subjects enrolled in Cohort 3A 
will return to the site to complete Cohort 3B and will be administered TAK-418/placebo under fed 
condition with a high fat/high calorie breakfast, which must start 30 minutes before the dose is 
administered. All assessments from Day -1 to Day 4 in Cohort 3B will be same as in Cohort 3A; 
however, there will be no follow-up for 
 after Cohort 3A and the Day 14 follow-up 
assessment for Cohort 3B. For male subjects, 
 days will be adjusted based on 
dosing in Cohort 3B.
A sentinel dosing regimen will be used for Cohort 1 (with the initial 2 subjects [1a] receiving 
either active drug or placebo in a 1:1 ratio) to ensure adequate safety and tolerability. After a 
minimum of 72 hours after the dosing of Cohort 1a, 3 subjects (Cohort 1b) will be dosed after 
review of the postdose safety and tolerability of the initial 2 subjects (Cohort 1a). After a minimum 
of 72 hours after dosing Cohort1b, the last 3 subjects of Cohort 1(1c), will be dosed after review of 
the postdose safety and tolerability.
A staggered dosing regimen will be used for Cohorts 2 to 5. Each cohort will be divided by 
2 groups (3 active: 1 placebo), and the second group will be dosed after a minimum of 48 hours 
after the first group, following assessment of safety and tolerability data. Subjects in Cohort 3 
receive 2 doses (fasted and fed state). There will be at least 7 days of washout between dose 
administrations.
The trial schedule is detailed in Table 6.b.
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Table 6.b
Trial Schedule
Screening 
Period
Pretreatment 
(a)
Treatment
Posttrial (c)
Dose Administration (b)
Postdose Procedures (b)
Days -28 to -2
Day -1
Day 1
Days 1 to 4
Day 14 (±2) (c)
Days 91, 93, 182, 
and 184 (±7)
(a) 
(b) Subjects will remain in the phase 1 unit for a minimum of 48 hours following the dose of trial drug and may be released after 48 
hours and complete the 72 hour and later procedures at an outpatient visit. Subjects may be kept in the clinic for longer time at PI's 
discretion.
(c) 
 
 
6.2
Dose Escalation
Dose escalation and subsequent dose levels will be based on a blinded review of available safety 
(including neurological assessment) and tolerability data from the previous dose levels and will 
only occur following agreement between the investigator and the sponsor. PK data will be used to 
guide dose selection after each cohort.
Following Cohort 1, subsequent dose levels may be higher, may be lower, or may remain the same 
as the preceding dose level. After Cohort 2, dose escalations will be limited to an escalated dose 
that is predicted to give no greater than a 3-fold increase in either Cmax or AUC of the immediate 
prior dose level. Dosing will continue as long as the mean AUC of the highest dose level is 
predicted not to exceed the mean area under the serum concentration-time curve from time 0 to 
24 hours (AUC24) at the no effect level for 
 findings in male monkeys (the more sensitive 
species) from the 13-week toxicology study (
) or the mean Cmax of the 
highest dose is predicted not to exceed one-tenth of the mean Cmax of the NOAEL from the 
4 weeks toxicology study in monkeys (
). If 
needed, a higher dose than the planned dose of 180 mg but less than 300 mg will be evaluated 
providing that the predicted exposure of this dose does not exceed the exposure levels mentioned 
above. If the majority of plasma concentrations of TAK-418F are below the limit of detection, the 
dose will be escalated to the next planned dose level provided safety and tolerability at the 
preceding dose level are considered acceptable.
6.3
Justification for Trial Design, Dose, and Endpoints
6.3.1
Justification of Trial Design and Regimen
Because this is an FIH trial, a sentinel dosing regimen will be used for Cohort 1 (with the initial 
2 subjects receiving either active drug or placebo [1:1]) to ensure adequate safety and tolerability. 
The remaining 6 subjects will be dosed in 2 groups of 3 subjects each after a review of 72 hours 
postdose safety and tolerability data of the previous group. A staggered dosing regimen will be 
used for Cohorts 2 to 5. Each cohort will be divided by 2 groups (3 active: 1 placebo), and the 
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second group will be dosed 48 hours after the first group, following assessment of safety and 
tolerability data. Subjects in Cohort 3 receive 2 doses (fasted and fed state) with food, with at least 
7 days of washout between dose administrations.
The planned initial dose of TAK-418 for Cohort 1 is 5 mg. Doses for subsequent periods/cohorts 
will be determined based on the available safety, tolerability, and PK data from the preceding 
period/cohort. The doses will be administered to the subjects by the investigator or the 
investigator’s designee. TAK-418 will be administered orally in a capsule formulation. 
6.3.2
Dose
The proposed starting dose for this study was determined by calculating the human equivalent 
dose (HED) (Food and Drug Administration [FDA] Guidance for Industry Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers, July 2005) from nonclinical toxicity studies and by taking into consideration the 
estimated pharmacologically active dose (PAD)/exposures in human subjects. Converting the 
NOAEL of 
 for male monkeys from the 13-week toxicity study, which is the more 
sensitive species, results in a HED value of 
 based on body surface area. Multiplying 
this HED of 
, a conservative estimate of human body weight, achieves a 
total daily dose of 77 mg/day. By adding a 10-fold safety factor as per FDA guidance, the 
maximum recommended starting dose is 
. The pharmacologically active exposure 
based on the nonclinical pharmacology models was 
. Using the most conservative 
exposure for allometry and physiologically based PK modeling, this exposure would be achieved 
at a dose of approximately 13 to 35 mg in humans. Therefore, the proposed starting dose is 5 mg, 
which is below the maximum safe starting dose and projected PAD. In the event that the majority
of individual plasma concentrations of TAK-418F in human volunteers are below the limit of 
detection, the dose will be escalated to the next planned dose level, provided that safety and 
tolerability at the preceding dose level are considered acceptable.
Convulsions were observed in 3 monkeys at dose levels ≥75 mg/kg/day in the 13-week toxicology 
study currently in the reporting phase, but were not observed when the dose was lowered to 
 
 
 Based on allometric scaling from rat and monkey 
PK, the projected human TAK-418F Cmax and AUC following a single dose of TAK-418 
 
range from 
 and 
, respectively. The projected human 
TAK-418F Cmax and AUC following a single dose of TAK-418 180 mg range from 
 
L and 
, respectively. 
TAK-418 demonstrated good absorption with bioavailability of 
 
 after oral administration. The terminal disposition phase half-life (t1/2z) value after 
intravenous (IV) administration was
 
in mice, rats, 
monkeys, and humans 
 
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 The in vitro metabolism of [ C]TAK-418 was evaluated using 
hepatic microsomes and hepatic cytosol from mice, rats, dogs, monkeys, and humans. TAK-418 
was mainly metabolized to unidentified metabolites via cytochrome P450 (CYP) 2D6 and to a 
lesser extent via CYP1A2, CYP2C8, CYP2C19, and CYP3A4. In addition, TAK-418 was 
eliminated via non-CYP pathways (including degradation). TAK-418 has no substantial inhibition 
of any CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4/5) at concentrations up to100 μmol/L. An in vitro induction study indicated that 
TAK-418 has no substantial induction potential for CYP1A2, CYP2B6, or CYP3A4 at 
concentrations up to 100 μmol/L. 
A comprehensive series of nonclinical safety studies (Good Laboratory Practice [GLP] compliant) 
have been conducted with TAK-418 to support early human studies. No safety concerns were 
identified in standard safety pharmacology assessment of the central nervous system in rats up to 
oral doses of 300 mg/kg. An effect on human ether-à-go-go-related gene potassium currents was 
observed at ≥5 μg/mL free concentration of TAK-418 
 total plasma concentration of 
TAK-418 in humans); however, no effect on ECG parameters in telemetrized monkeys was
observed through 100 mg/kg although an increase in mean systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) and an increase in HR were observed at 100 mg/kg; all parameters 
were normal at 20 mg/kg. A decrease in respiration rate and minute volume at 300 mg/kg but not 
100 mg/kg was observed in a rat respiration study using plethysmography. 
In GLP-compliant toxicity studies, no safety concerns for genotoxicity were identified in an Ames 
test or in vivo assessment of DNA damage or micronucleus formation in rats through a 
300 mg/kg/day dose. Ultraviolet-visible absorption of light by TAK-418 did not indicate a 
potential for phototoxicity. In 4-week repeated-dosing toxicity studies in rats, changes that were 
seen included excessive salivation, decreases in red blood cell parameters, plasma potassium and 
chloride, increases in urea nitrogen and urine volume, and gastric erosion at 300 mg/kg/day; the 
NOAEL was 
 for both sexes. The mean Cmax and AUC24 values at 
 
after the 30th dose were 
 and 
 (females), respectively. In a 4-week monkey toxicity study, decreased food 
intake, weight loss, and emesis at 100 mg/kg/day were the basis for a NOAEL of 
. 
The mean Cmax and AUC24 values at 
 after the 28th dose were 
 and 
 (females), respectively. Recovery 
groups were not included in the 4-week repeat-dose studies. In the 13-week study, currently in the 
reporting phase, clinical observations associated with administration of TAK-418 included 
convulsions, emesis, decreased activity, hunched posture, lying on side in cage, and reduced 
appetite predominantly at 100/75/60 mg/kg/day. 
 degeneration in 
mature male monkeys was observed in 1 monkey at 20 mg/kg/day and 2 monkeys at 
100 mg/kg/day, one of which was recovery. Though severity of finding was less in the one 
recovery animal, the recovery period was of insufficient duration to assess reversibility. The 
NOAEL for 
 finding in male monkeys was 
. Convulsions were observed at 
 and were observed within 1-hour postdose, lasted less than 2 minutes, and reversed 
without therapeutic intervention. No convulsions occurred at 
. Liquid feces occurred 
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at 
 but did not increase in frequency with dose. Minimal decrease in red blood cell 
(RBC) mass was observed at 100/75/60 mg/kg/day. Minimal increase in fibrinogen, decrease in 
albumin, and increase alkaline phosphatase of uncertain relationship to TAK-418 was observed in 
individual animals across dose groups. At 
, the mean Cmax and AUC24 values after 
the 91st dose were 
 (males) and 
 and 
 (females). At 
, the mean Cmax and AUC24 values after the 91st dose 
were 
 for male monkeys.
6.3.3
Justification for Endpoints
6.3.3.1
Safety and PK
The primary endpoint for this trial is the composite of safety variables to determine the safety and 
tolerability of single oral doses of TAK-418, and dose-limiting effects of TAK-418. The secondary 
endpoints consist of standard PK variables to determine drug exposure at each dose to facilitate 
dose escalation.
6.3.3.2
Exploratory Endpoints
6.3.3.3
Biomarkers
6.3.3.4
Pharmacogenomics (PGx) 
DNA and RNA from blood samples will be used to evaluate drug metabolizing enzymes and 
transporter polymorphisms that may contribute to the variability in the PK of TAK-418. 
6.3.3.5
Wearable Devices 
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6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this trial, the collecting blood samples for TAK-418F (PK) is the critical procedure. 
∀
At any postdose time point, the blood sample for TAK-418F (PK) needs to be collected as 
close to the exact time point as possible.
∀
All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
∀
The order of priority can be changed during the trial with joint agreement of the investigator 
and the sponsor. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 1 assessment of TAK-418 in humans, and the PK, PD, and safety profiles of the 
compound are still being elucidated. This protocol is written with some flexibility to accommodate 
the inherent dynamic nature of phase 1 clinical trials. Modifications to the dose, dosing regimen, 
and/or clinical or laboratory procedures currently outlined below may be required to achieve the 
scientific goals of the trial objectives and/or to ensure appropriate safety monitoring of the trial 
subjects. 
Some alterations from the currently outlined dose and/or dosing regimen may be permitted based 
on newly available data, but the maximum daily dose/exposure detailed in Section 6.3.2, may not 
exceed those currently outlined.
∀
Additional cohorts may be added.
∀
Repeat of or decrease in the dose of the trial drug administered.
∀
Entire cohorts may be omitted.
∀
Lengthening of the washout period between doses if supported by safety and PK evidence.
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
Decrease of the washout period between doses if supported by safety and PK evidence.

A planned PK data review may be eliminated if agreed to by the sponsor and investigator and if 
no further increases in total daily dose occur. 

Addition of a PK data review.

Instructions to take trial drug with or without food or drink may also be modified based on 
newly available data, that is, food effect is known.

Modification of the fed cohort to another cohort.
The PK/PD sampling scheme currently outlined in the protocol may be modified during the trial 
based on newly available PK or PD data (eg, to obtain data closer to the time of peak plasma 
concentrations). If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or additional PD markers.
Up to an additional 50 mL of blood may be drawn over the course of the study for PK and/or 
biomarker analyses. This may include repeat samples or modified PK/biomarker time points based 
on emerging data. The total blood volume withdrawn from any single subject will not exceed the 
maximum allowable volume during his/her participation in the entire trial. 
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests) currently outlined in the protocol may be modified during the trial based on newly 
available safety, tolerability, PK, or PD/biomarker data (eg, to obtain data closer to the time of 
peak plasma concentrations). These changes will not increase the number of trial procedures for a 
given subject during his/her participation in the entire trial. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatine kinase to serum chemistry panel that was 
already drawn). 
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the sponsor in 
a letter to the Trial File and forwarded to the investigator for retention. The letter may be 
forwarded to the institutional review board (IRB)/independent ethics committee (IEC) at the 
discretion of the investigator.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.5.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or Follow-up 
Visit/interaction associated with a planned visit (this can be a phone contact), discontinues from 
the trial, or is lost to follow-up (ie, the investigator is unable to contact the subject).


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6.5.3
Definition of Trial Completion
The primary objective of this early phase 1 trial is to evaluate safety and tolerability of TAK-418 
when administered as single oral doses in healthy subjects. It is possible that trial subjects may not 
receive all doses specified in the protocol if this objective is achieved at lower dose levels in this 
trial. This is not considered an early termination of the trial, but rather an earlier than anticipated 
achievement of the trial objective(s) or trial completion. Therefore, the definition of trial 
completion follows the same rules as definition of end of trial (Section 6.5.2) for the dosing group 
achieving the primary objective. 
6.5.4
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a non–safety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a nonsafety-related reason. 

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons: 

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from nonclinical or clinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.5.5
Criteria for Premature Termination or Suspension of the Trial
6.5.5.1
Criteria for Premature Termination or Suspension of Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
is unable to ensure adequate performance of the trial, or as otherwise permitted by the contractual 
agreement.
6.5.5.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Site(s)
If the sponsor, an IRB, or regulatory authority elects to terminate or suspend the trial or the 
participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or trial suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
To be eligible for participation in this trial, the subject must:
1. Understand the trial procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all trial procedures and restrictions.
3. Be male subject or a female subject (with no childbearing potential) aged 18 to 55 years, 
inclusive, at the Screening Visit.
4. Have a body mass index (BMI) ≥18.5 and ≤30.0 (kg/m2) at the Screening Visit.
5. Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months before administration of the initial dose of trial drug or invasive 
procedure.
6. Be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign 
measurements performed at the Screening Visit and before administration of the initial dose of 
trial drug or invasive procedure as per principal investigator's judgment.
7. Female subjects with no childbearing potential, defined by at least 1 of the following criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in women aged 
>45 years, 6 months of spontaneous amenorrhea in women aged >45 years with 
 
evels >40 mIU/mL). Appropriate documentation of 
 levels is required.
b) Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
c) Had a tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
8. Male subjects must have 
 
9. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening, throughout the duration of the trial, and for 5 half-lives plus 90 days after last dose 
of trial medication and follow necessary precautions listed in Appendix D
7.2
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject: 
1. Has participated in another investigational trial within 4 weeks before the pretrial (Screening) 
visit. The 4-week window will be derived from the date of the last trial procedure and/or AE 
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related to the trial procedure in the previous trial to the pretrial/Screening Visit of the current 
trial.
2. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of clinical 
research unit (CRU) or of the sponsor.
3. Has a history of cancer (malignancy).
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
5. Has a positive alcohol or drug screen.
6. Has a positive pregnancy test.
7. Is breastfeeding.
8. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies, or human 
immunodeficiency virus (HIV), confirmatory testing is allowed; most sensitive test should 
take precedence.
9. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks 
before the pretrial Screening Visit.
10. Male subjects who have serum 
 that are clinically abnormal.
11. Is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies beginning approximately 7 days before 
administration of the initial dose of trial drug, throughout the trial (including washout intervals 
between treatment periods), until the posttrial visit. There may be certain medications that are 
permitted, see Section 7.3.
12. Has a history of alcohol consumption exceeding 3 standard drinks per day on average (1 glass 
is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce] per day).
13. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated 
beverages per day.
14. Is currently a regular user (including “recreational use”) of any illicit drugs or has a history of 
drug (including alcohol) abuse within approximately 6 months.
15. Has a risk of suicide according to the investigator’s clinical judgment per C-SSRS at Screening 
or has made a suicide attempt in the 6 months before Screening.
16. Has a clinically significant history of head injury, trauma, or seizures.
17. Has a lifetime history of major psychiatric disorder, such as major depressive disorder, bipolar 
disorder, or schizophrenia.
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18. Is of any concern to the investigator regarding the safe participation of the subject in the trial or 
for any other reason the investigator considers the subject inappropriate for participation in the 
trial.
19. Screening ECG reveals a QT interval with Fridericia correction method (QTcF) >450 ms 
(men) or >470 ms (women). 
20. Has a resting HR outside of the range of 50 to 100 beats per minute, confirmed on repeat 
testing within a maximum of 30 minutes, at Screening Visit or Check-in (Day -1).
21. Has a history of serious skin reactions (hypersensitivity) to adhesives, metals, or plastic; this 
criterion applies only to subjects participating in the trial of the 2 wearable digital devices.
7.3
Excluded Medications, Supplements, Dietary Products
Use of excluded agents (prescription or nonprescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and 
Randomization (Days -28 to Predose 
[Day 1])
Postrandomization (Day 1) to 
Follow-up 
Tobacco- and 
nicotine-containing products
Completely restricted
Completely restricted
Cannabis products
Completely restricted
Completely restricted 
Alcohol
Completely restricted 7 days before 
dosing
Completely restricted 7 days before 
dosing 
At all other times no more than 3 
drinks/day
Xanthine and/or caffeine
Completely restricted 24 hours before 
dosing
Completely restricted 24 hours before 
dosing 
At all other times no more than 6 
units/day
Medications
Completely restricted 7 days before 
dosing
Completely restricted (a)
Food substance
Grapefruit/grapefruit juice
Completely restricted 7 days before 
dosing
Completely restricted
Fruit juice
No restriction
Dosing will occur without 
consumption of fruit juice. Fruit juice 
is restricted up to 4 hours postdose.
Mustard green (b)
Completely restricted 7 days before 
dosing
Completely restricted
Charbroiled meat
Completely restricted 7 days before 
dosing
Completely restricted
(a) If medications are required to treat an AE, certain medications may be allowed after discussion and agreement 
between the sponsor and principal investigator.
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7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
During confinement, subjects will be given 3 meals (with the exception of breakfast on Day 1 of 
the fasting regimens [all cohorts except Cohort 3B]) and an evening snack. Each meal will contain 
approximately 30% fat (relative to the total calories) except for the high fat meal on Day 1 during 
the fed regimen (Cohort 3B). 
On Day 1 of the fasting regimens, subjects will be administered TAK-418 by mouth with 240 mL 
of water after an overnight fast of at least 10 hours. Subjects will continue to fast for an additional 
4 hours after dosing. Lunch will be served following the 4-hour postdose PK blood collection. 
Subjects may consume water ad libitum with the exception of 1 hour before and 1 hour after trial 
drug administration. 
On Day 1 of the fed regimen (Cohort 3B), after an overnight fast of at least 10 hours, subjects will 
receive a high-fat (approximately 50% of total caloric content of the meal) and high-calorie 
(approximately 800 to 1000 calories) meal (eg, 2 eggs fried in butter, 2 strips of bacon, 2 slices of 
toast with butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk). This test meal 
should derive approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, 
respectively. The caloric breakdown of the test meal should be provided in the trial report. The 
meal must be consumed within 30 minutes. Within 5 minutes after the end of the meal, subjects 
will be administered TAK-418 by mouth with 240 mL of water. Lunch will be served following 
the 4-hour postdose PK blood collection. Subjects may consume water ad libitum with the 
exception of 1 hour before and 1 hour after trial drug administration. 
Subjects will remain semirecumbent for 4 hours following trial drug administration, except as 
necessitated by the occurrence of an AE/or trial procedures (eg, obtaining 12-lead ECG).
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the Screening Visit until the posttrial visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. The subject experiences an AE that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the AE.
2. Liver Function Test (LFT) Abnormalities
In multidose trials, trial drug should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 10.2.9.5), if the following circumstances occur at any time 
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–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 times the upper 
limit of normal (ULN), or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
3. Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
4. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the trial. The reason for withdrawal, if provided, should be recorded in the 
electronic case report form (eCRF). 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
6. Trial termination. The sponsor, IRB, or regulatory agency terminates the trial.
Note: Skin reactions (cutaneous hypersensitivity) to one of the wearable digital devices will lead to 
removal of that device for the remainder of the trial. The subject would not be required to 
discontinue the other device or the trial as a whole. 
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial when 
the subject meets the trial 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 trial. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
7.7
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The trial site should contact the sponsor for the 
replacement subject’s treatment assignment and randomization number.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
8.1
Clinical Trial Drug 
Details regarding the composition and extemporaneous preparation of the active and placebo are 
found in the Pharmacy Manual, Compounding Instructions, and/or similar documents. Clinical 
trial drug will be packaged to support enrollment and replacement of subjects as required. When a 
replacement subject is required, the sponsor needs to be contacted before dosing.
8.1.1
Clinical Trial Drug Labeling
Clinical trial drug will be affixed with a clinical label in accordance with regulatory requirements.
8.1.2
Clinical Trial Drug Inventory and Storage
Clinical trial drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of trial drug must be recorded by an 
authorized unblinded person at the trial site. 
8.1.3
Clinical Trial Drug Blinding
This trial is blinded but provided open-label; therefore, an unblinded pharmacist or qualified trial 
site personnel will be used to blind supplies. Treatment identity (name, strength, or potency) is 
included in the label text; randomization code/disclosure envelopes or lists are provided.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical trial drug received from 
the sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the conclusion of the trial. For all trial sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for clinical trial drug 
accountability, return, and destruction (or sponsor or designee-approved site equivalent forms).
8.1.5
Ancillary Supplies
All ancillary supplies will be provided by either the site or Takeda, based upon availability. If 
provided by Takeda, unused ancillary supplies will be accounted for and disposed of as directed by 
Takeda or a Takeda designee.
8.1.6
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee of the sponsor will generate the 
randomization schedule. All randomization information will be stored in a secured area, accessible 
only by authorized personnel.
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure
Clinical trial drug blind is maintained through a randomization schedule held by the site unblinded 
pharmacist. The clinical trial drug blind shall not be broken by the investigator unless information 


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concerning the clinical trial drug is necessary for the medical treatment of the subject. If possible, 
the medical monitor should be contacted before the trial drug blind is broken. Unblinding is 
performed per the standard operating procedures of the sponsor or contract research organization 
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9.0
STUDY PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Trial Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator. 
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject entering into the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2. A separate optional informed consent is required for the digital device component 
of the trial. Subject participation in the wearable device component of the trial is optional.
9.1.2
Assignment of Screening and Randomization Numbers 
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only 1 screening number. Screening numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event.
All eligible subjects will be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another 
subject. A single subject cannot be assigned more than 1 randomization number. 
9.1.3
Clinical Trial Drug Assignment
On Day 1, subjects will be assigned a randomization number in ascending numerical order at each 
trial site. The randomization number encodes the subject assignment to either the TAK-418 or the 
placebo arm of the trial, according to the randomization schedule generated before the trial by the 
sponsor’s Statistics Department. Each participant will be dispensed blinded trial treatment, labeled 
with his/her unique randomization number, throughout the trial.
9.1.4
Inclusion and Exclusion Criteria 
Each subject is assessed through randomization, according to the eligibility criteria provided in 
Section 7.0.
9.1.5
Medical History, Medication History, and Demographics
Qualified site personnel are to collect subject significant medical history (past and concurrent) per 
the site’s standard of care and appropriate clinical judgment and subject demographics. 


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Qualified site personnel are to review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vitamin supplements, nutraceuticals, and 
oral herbal preparations.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
Qualified site personnel will conduct full physical examinations. 
9.2.2
Neurological Examination
Qualified site personnel will conduct full neurological examinations.
9.2.3
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.
9.2.4
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed. 
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 round down and 0.5 to 0.9 round up.
9.2.5
Vital Signs
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes before having vital sign 
measurements obtained. Vital signs will include HR, SBP, and DBP. The same method (eg, same 
size cuff, manual or automated) must be used for all measurements for each individual subject and 
should be the same for all subjects. 
Subjects will continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose except to stand for the measurement of standing vital signs (if needed) or other 
trial-related procedure.
9.2.6
12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bra. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
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QT intervals with QTcF will be used to calculate QT intervals in this trial.
Before each treatment period/cohort, a predose ECG will be obtained within approximately 1 hour 
before dosing of TAK-418. This measurement will be used as the baseline. The principal 
investigator should arrange to have a trial cardiologist available as needed to review ECG tracings 
with abnormalities.
During each treatment period, if a subject demonstrates an increase in QTcF interval ≥40 msec 
compared with a predose baseline measurement, the ECG will be repeated within 5 minutes. The 
average value of the QTcF interval from the 2 ECGs will represent the value at that time point. If 
the average QTcF interval increase from Baseline for any postdose time point is ≥40 msec, the 
subject will continue to be monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours 
or until the QTcF is within 40 msec of the baseline value. If prolongation of the QTcF interval 
≥40 msec persists, a consultation with a trial cardiologist may be appropriate and the sponsor 
should be notified.
If the QTcF interval is ≥500 msec, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be telemetry-monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted on 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy. 
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: HR, PR-interval, QRS-duration, QT-interval, 
QTcF-interval, and the interpretation of the ECG profile by the principal investigator.
9.2.7
Trial Drug Administration
For the trial, trial drug (or placebo) will be administered in the manner described in Section 7.4.1. 
9.2.8
BL-VAS
The Bond-Lader Visual Analogue Scale (BL-VAS) of Mood and Alertness consists of a 
questionnaire of 16 analogue scales that derive 3 factors that assess change in Self-Rated 
Alertness, Self-Rated Calmness, and Self-Rated Contentment. It has proven sensitivity to a wide 
range of compounds. In the original versions, ratings were performed by the subject by marking a 
point on a 10 cm line that is meant to represent the full range of the particular dimension (for 
example, alert—drowsy). Nine items assess alertness, 5 items assess contentedness, and 2 items 
assess calmness. A mark on the far left side or far right side of the scale represents extremes with 
regard to the adjectives on each side of the line (eg, a higher or more rightward score on a scale 
marked awake—drowsy indicates that the subject feels drowsier).


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9.2.9
 
9.2.10 AE Monitoring
AE monitoring begins following signing of informed consent. Changes in subject health status 
from baseline assessment to trial drug administration should be captured in the subject’s medical 
history. A complete description of AE collections and procedures is provided in Section 10.0.
9.2.11 Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken following a minimum 8-hour overnight fast on the days stipulated in the 
Schedule of Trial Procedures (Section 3.0).
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9.2.11.1 Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (RBCs)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute differential
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts.
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN total bilirubin will be fractionated
Protein (total)
9.2.11.2 Diagnostic Screening
Serum
Serum diagnostic evaluations will include the following tests:
HIV 
Hepatitis Screen (HBsAg, hepatitis C virus antibody)
β–human chorionic gonadotropin (females only)
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Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Urine
A urine drug screen will include the following tests: 
Amphetamines
Cotinine
Barbiturates
3,4-methylenedioxy-methamphetamine (MDMA)
Benzodiazepines
Methadone/metabolite
Buprenorphine/metabolite
Opiates
Cannabinoids
Oxycodone/oxymorphone
Cocaine/metabolites
Phencyclidine
9.2.12 C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures (Section 3.0). 
Two versions of the C-SSRS will be used in this trial: the Screening/Baseline C-SSRS Lifetime 
and the Since-Last-Visit C-SSRS. 
9.3
Biomarker, PK, PD, and PGx, Samples
Samples for PK, PD, and or other biomarker analysis will be collected as specified in the Schedule 
of Trial Procedures (Section 3.0). Please refer to the Laboratory Manual for information on the 
collection, processing, and shipment of samples to the Central Laboratory. 
 
 
 
 
 
 
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It is anticipated that the total blood volume drawn will be approximately 250 mL for all cohorts 
except cohort 3 (fasted and fed), where it will be approximately 415 mL.
Primary specimen collection parameters are provided in Table 9.a. 
Table 9.a
Primary Specimen Collections
9.3.1
PK Measurements 
The PK parameters of TAK-418F will be derived using noncompartmental analysis methods and 
will be determined from the concentration-time data for all evaluable subjects. Actual sampling 
times, rather than scheduled sampling times, will be used in all PK computations involving 
sampling times for plasma PK parameters. Nominal time intervals will be used for computations of 
urine PK parameters.
The following PK parameters will be calculated as appropriate:
∀
tmax.
∀
Cmax.
∀
AUClast.
∀
AUC∞.
∀
∀
∀
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∀
∀
∀
 
∀
Additional PK parameters may be calculated as appropriate. A detailed PK analysis plan will be 
prepared before PK parameter computation.
9.3.1.1
Plasma for PK Measurements
PK blood samples for plasma TAK-418F concentrations will be collected as specified in the 
Schedule of Trial Procedures (See Section 3.0). 
Plasma TAK-418F concentration will be measured by liquid chromatography with tandem mass 
spectrometry method.
9.3.1.2
Urine for PK Measurements
PK urine samples for urine TAK-418F concentrations will be collected as specified in the 
Schedule of Trial Procedures (See Section 3.0). 
Urine TAK-418F concentration will be measured by liquid chromatography with tandem mass 
spectrometry method.
9.3.2
Biomarker Measurements
9.3.2.1
 
 
9.3.2.2
 
9.3.2.3
9.3.3
PGx Measurements 
9.3.3.1
Blood Sample for DNA and RNA PGx Measurements
Blood samples for DNA and RNA PGx measurement will be taken. 
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When sampling of whole blood for PGx analysis occurs, every subject must sign an informed 
consent/be consented to participate in the trial. PGx is a component of the trial, and participation is 
mandatory. 
PGx is the study of variations of DNA and RNA characteristics as related to drug response. There 
is increasing evidence that an individual’s genetic background may affect the PK (absorption, 
distribution, metabolism, and excretion), PD (pharmacologic effects) and/or the clinical outcome 
(efficacy and/or safety).
PGx research in this trial may be conducted to understand how individual genetic variation in 
subjects affects their trial drug treatment response. This information may also be used, for 
example, to develop a better understanding of the safety and efficacy of TAK-418 and other trial 
drugs, to interpret changes in biomarkers, to increase understanding of the disease/condition being 
studied and other related conditions, to gain a better understanding of the drug pharmacology and 
for generating information needed for research, development, and regulatory approval of tests to 
predict response to TAK-418 or to monitor the response to TAK-418. 
Whole blood samples for DNA and RNA isolation will be collected from each consented subject in 
the trial. If necessary and feasible, a second aliquot of blood may be taken at a later time point if 
isolation of DNA from the first sample was not successful or possible. 
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.3.3.2
Biological Sample Retention and Destruction
In this study, blood, 
 and urine samples for biomarker measurement will be collected as 
described in Section 9.3.3.1. Any leftover biomarker samples if not used will be preserved and 
retained at sponsor selected for long term storage facility for up to 15 years from the end of study. 
After that time the samples will be destroyed.
The PGx samples will be initially stored at a vendor/comparable laboratory, under contract to 
Takeda, with validated procedures in place, and then preserved and retained at a sponsor selected 
long-term storage facility, for up to but not longer than 15 years from the end of the study when the 
study report is signed, or if less, the maximum period permitted under applicable law or until 
consent is withdrawn. 
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the trial will be stored securely with limited access 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main trial but using a code that 
is different from the code attached to the health information and other clinical test results collected 
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in the trial. The sample and data are linked to personal health information with code numbers; the 
samples are stripped of all personal identifying information but a key linking the samples to 
clinical analysis data exists. This link means that the subject may be identified but only indirectly. 
The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent at any time and request disposal of a stored sample. Any remaining sample that can 
be identified as coming from the subject will be destroyed. The trial doctor and sponsor may 
continue to use and distribute any information and test results gathered before the request to 
withdraw. 
9.3.4
9.3.5
Confinement
Subjects will report to the clinical site on the evening before (Day -1) the scheduled day of 
administration of the trial drug. Subjects will remain in the unit until 48 hours postdose. At the 
discretion of the investigator, subjects may be requested to remain in house longer.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a trial; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of trial 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 may be considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
a trial procedure. However, if the subject experiences a worsening or complication of such a 


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concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
trial medication or after any change in trial 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 trial medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) because of a worsening of the pre-existing condition, the worsening of the 
condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a trial subject, at a dose above that which is assigned to that individual subject 
according to the trial protocol. It is up to the investigator or the reporting physician to decide 
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, to capture this important safety information consistently in the database. 
AEs associated with an overdose will be documented on AE CRF(s) according to Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9.

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 
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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.2.9.3).
10.1.2 Special Interest AEs
No AEs of special interest have been identified for this compound.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.2.2 Assigning Causality of AEs
The relationship of each AE to trial 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 possible involvement of the drug can be 
argued, 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 drugs and concurrent treatments.
10.2.3 Assigning Relationship to Trial Procedures
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The relationship should be assessed as “Related” if the investigator considers that there is 
reasonable possibility that an event is due to a trial procedure. Otherwise, the relationship should 
be assessed as “Not Related”.
10.2.4 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.5 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.6 Frequency 
Episodic AEs (eg, headache) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.7 Action Concerning Trial Drug 

Drug withdrawn: a trial medication is stopped because of the particular AE.

Dose not changed: the particular AE did not require stopping a trial medication.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a trial medication was stopped for a reason other than the particular AE, for 
example, the trial has been terminated, the subject died, dosing with trial medication was 
already stopped before the onset of the AE.
10.2.8 Outcome 

Recovered/resolved: subject returned to first assessment status with respect to the AE.

Recovering/resolving: the intensity is lowered by one or more stages; the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved: there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the observed 
trial 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.”

Resolved with sequelae: the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
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
Fatal: an AE that is considered as the cause of death.

Unknown: the course of the AE cannot be followed up because of hospital change or residence 
change at the end of the subject’s participation in the trial.
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.9.1 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. For female subjects, routine collection of AEs will 
continue until the follow-up on Day 14 (±2 days). In addition, for male subjects, routine collection 
of AEs will continue until Days 93 and/or 184 (±7 days). For subjects who discontinue before the 
administration of trial medication, AEs will be followed until the subject discontinues trial 
participation. 
10.2.9.2 Reporting AEs
At each trial 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 trial. Subjects experiencing an SAE before the 
first exposure to investigational product must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to Baseline or there is a satisfactory 
explanation for the change. Nonserious AEs that begin before the first exposure to investigational 
product, related or unrelated to the trial procedure, need not be followed-up for the purposes of the 
protocol.
All subjects experiencing AEs, whether considered associated with the use of the trial medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of trial 
medication(s) (related or not related).

Investigator’s opinion of the causal relationship to trial procedure(s), including the details of 
the suspected procedure.

Action concerning trial medication.

Outcome of event.


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
Seriousness.
10.2.9.3 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 trial 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 trial participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.9.4 Reporting Special Interest AEs 
No AEs of special interest have been identified for TAK-418.
10.2.9.5 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.


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If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
per Section 10.2.9.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.11 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (per Section 10.2.10). 
10.2.9.6 Exploratory Biomarkers and Data From Wearable Devices

Changes from Baseline in exploratory biomarkers will not be considered as adverse events and 
will not be used to guide the subject’s medical care during the study.

The vital sign and cardiac rhythm data derived from the Body Guardian device will be 
analyzed at the end of the trial. These data are exploratory in nature. Abnormalities detected 
solely by the digital devices will not be considered AEs and will not be used to guide a 
subject’s medical care during this trial. 
10.2.10 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 trial is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all trial objectives.
A targeted data review will be conducted before unblinding of subject’s treatment assignment.
This review will assess the accuracy and completeness of the trial database, subject evaluability, or 
appropriateness of the planned statistical methods.
11.1.1 Analysis Sets
Safety Set
The safety set will consist of all subjects who receive at least 1 dose of trial drug. Subjects in this 
analysis set will be used for demographic, baseline characteristics, and safety summaries.
PK Set
The PK set will consist of all subjects who receive at least 1 dose of trial drug and have at least 1 
measurable plasma concentration or amount of drug in the urine for TAK-418. All subjects with 
valid PK parameter estimates will be included in the summaries and analyses for that parameter.
PD/Biomarker Set
The PD/biomarker set will consist of all subjects who receive at least 1 dose of trial drug and have 
at least 1 postdose value for PD/biomarker parameter.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in the 
PK and PD analyses; however, data for all subjects will be presented in the data listings.
11.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for the pooled placebo group, each 
TAK-418 dose level, TAK-418 overall, and overall including placebo group. Summary statistics 
(number of subjects, mean, SD, median, minimum, and maximum) will be presented for 
continuous variables (eg, age, weight, and BMI), and the number and percentage of subjects within 
each category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristic data will be provided in the data listings.
11.1.3 PK Analysis
Plasma concentrations of TAK-418F will be summarized by dose over each scheduled sampling 
time using descriptive statistics.
The amount of TAK-418F excreted in urine will be summarized by dose using descriptive 
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Individual plasma and urine concentration versus time and PK parameter data will be presented in 
a data listing. 
Plasma and urine PK parameters of TAK-418F will be summarized by dose using descriptive 
statistics. 
If sufficient data are available, dose proportionality of TAK-418F plasma exposures (Cmax and 
AUC) will be assessed statistically using a power model. For evaluation of potential food effect on 
TAK-418F PK, log-transformed Cmax and AUC values will be compared between the treatments 
(Reference=fasting administration; Test=fed administration) using an analysis of variance 
(ANOVA) with fixed effect for treatment and a random effect for subject. The geometric mean 
relative bioavailability and 90% CIs for Cmax, AUClast, and AUC% will be calculated based upon 
the adjusted means (LS means) from the ANOVA.
A more detailed analysis will be presented in the SAP. Additional analyses will be included, if 
appropriate.
11.1.4
 
11.1.5
11.1.6 Safety Analysis
The safety set will be used for all summaries of safety parameters. These summaries will be 
presented by pooled placebo, each TAK-418 dose level, and TAK-418 overall (as appropriate). 
Safety data collected after administration of trial drug under fed conditions will be summarized 
separately.
11.1.6.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). TEAEs with onset occurring within 30 days 
(onset date – last date of dose +1≤30) after trial drug administration will be included in the 
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summary tables. All AEs will be in the listings. TEAEs will be summarized by SOC and PT. The 
following summary tables will be included in the report: summary of TEAEs and drug-related 
AEs, relationship of AEs to trial drug (related vs not related), severity of AEs, and related AEs. 
Data listings will be provided for all AEs including TEAEs, AEs leading to trial drug 
discontinuation, and SAEs.
11.1.6.2 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal criteria will be summarized and provided in the data listings. 
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized. All
clinical laboratory data will be provided in the data listings.
11.1.6.3 Vital Signs
Individual results of vital signs that meet Takeda’s markedly abnormal criteria will be summarized 
and provided in the data listings. Baseline, postdose, and changes from Baseline in vital sign 
measurements will be summarized. All vital sign data will be provided in the data listings.
11.1.6.4 ECGs
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria will be summarized and provided in the data listings. 
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized. Shift tables will be generated to show the investigator’s ECG interpretations at each 
postdose collection by the interpretation at Baseline.
All ECG data will be provided in the data listings.
11.1.6.5 Other Safety Parameters
Physical examination findings will be presented in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
No formal interim analyses will be conducted. Safety and PK data (at least up to 24 hours 
postdose) will be reviewed after each dose before escalation to the next dose.
11.3
Determination of Sample Size
The sample size of 8 subjects per cohort (6 active: 2 placebo) chosen is based upon precedents 
from other FIH trials rather than a formal assessment of statistical power.
Subjects who drop out for nonsafety reasons may be replaced on a case-by-case basis at the 
discretion of the sponsor in consultation with the investigator. Subjects who replace dropouts will 
be allocated to the same dose as the subject they replace. Subjects who drop out for safety reasons 
will not be replaced.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Trial-Site Monitoring Visits
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and trial site guarantee access to source documents by the sponsor or its designee 
(CRO) and by the IRB or IEC.
All aspects of the trial and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, trial drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
trial personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). 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 trial 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. 
12.2.1
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The trial 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 trial. In 
addition, there is the possibility that this trial 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 
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trial 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 trial 
documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE STUDY
This trial 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 trial 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 trial, written notification regarding his or her abstinence from voting 
must also be obtained. Those Americas sites unwilling to provide names and titles of all members 
because of privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the trial (ie, before shipment of the sponsor-supplied drug or trial specific 
screening activity). The IRB or IEC approval must refer to the trial by exact protocol title, number, 
and version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug/notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives drug/notification no 
protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the trial at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the trial. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the trial, its objectives, and potential risks and benefits, in addition to 
the date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the trial, and (2) decide whether or not to participate in the trial. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the trial, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the trial. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent and before subject entering into the trial; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a blood and/or 
 samples for DNA and/or RNA 
analysis can withdraw their consent and request disposal of a stored sample at any time before 
analysis. Notify sponsor of consent withdrawal.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to the 
sponsor’s clinical trial 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 trial participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the trial. During and after the trial, only the sponsor may make trial 
information available to other trial investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical trial site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or trial results, other 
than trial recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the trial (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of trial, 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 trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the trial 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 trial insurance against the risk of injury to trial subjects. Refer to the 
trial 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 
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Trial Contact Information 
Contact Type/Role
Contact
SAE and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052


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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this trial in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of trial subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.10 of this protocol.

Terms outlined in the trial site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
14.1.3 Trial-Related Responsibilities 
The sponsor will perform all trial-related activities with the exception of those identified in the 
Trial-Related Responsibilities template. The vendors identified for specific trial-related activities 
will perform these activities in full or in partnership with the sponsor.


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14.1.4 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
ASD
autism spectrum disorder
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the serum concentration-time curve from time 0 to 24 hours
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration 
BDNF
brain-derived neurotrophic factor
BL-VAS
Bond-Lader Visual Analogue Scale
BMI
body mass index
CFR
Code of Federal Regulations
Clu
clusterin 
Cmax
maximum observed concentration
CoREST
REST corepressor 1
CRO
contract research organization
CRU
clinical research unit
C-SSRS
Columbia Suicide Severity Rating Scale
CtBP
C-terminal-binding protein
CYP
cytochrome P-450
DBP
diastolic blood pressure
DSST
Digital Symbol Substitution Test
ECG
Electrocardiogram
eCRF
electronic case report form
F
free base
FAD
flavin adenine dinucleotide
FDA
Food and Drug Administration
F-FAD
formyl-flavin adenine dinucleotide
FIH
first-in-human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GTPase
guanosine triphosphatase
H3K4
position 4 of type 3 histone
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HED
human equivalent dose
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HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
KDM1
lysine-specific demethylase family 1
KDM1A
LSD1
LFT
liver function test
LSD1
lysine-specific demethylase 1A
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple rising dose
mRNA
messenger RNA
miRNA
micro RNA
NOAEL
no-observed-adverse-effect level
NuRD
nucleosome Remodeling Deacetylase
PAD
pharmacologically active dose
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamic(s)
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
Ptgds
prostaglandin D2 synthase
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
REST
repressor element-1 silencing transcription factor
RNA-Seq
RNA-sequencing
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SNAG
SNAIL (Zinc finger protein SNAI1)/Gfi-1 (Zinc finger protein encoded by the GFI1 gene)
SOC
system organ class
SRD
single rising dose
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TAL1
T-cell acute lymphocytic leukemia protein 1
TEAE
treatment-emergent adverse event
TLX
Nuclear receptor encoded by the NR2E1 gene
tmax
time of first occurrence of Cmax
Tmeff1
follistatin like domains 1
ULN
upper limit of normal
C
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WBC
white blood cell
14.1.5 Corporate Identification 
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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


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


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16.0
REFERENCES
1. Burg JM, Link JE, Morgan BS, Heller FJ, Hargrove AE, McCafferty DG. KDM1 class 
flavin-dependent protein lysine demethylases. Biopolymers 2015;104(4):213-46.
2. Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism 
spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial 
dysfunction and environmental toxicant exposures. Mol Psychiatry 2012;17(4):389-401.
3. National Institute of Mental Health. Autism Spectrum Disorder. Published 2016. Accessed 11 
August 2016. Available at: 
http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd/index.shtml.
4. Frye RE, Rossignol DA. Identification and Treatment of Pathophysiological Comorbidities of 
Autism Spectrum Disorder to Achieve Optimal Outcomes. Clin Med Insights Pediatr 
2016;10:43-56.
5. Kubota T, Mochizuki K. Epigenetic Effect of Environmental Factors on Autism Spectrum 
Disorders. Int J Environ Res Public Health 2016;13(5).
6. Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, et al. Insights 
into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron 
2015;87(6):1215-33.
7. Mbadiwe T, Millis RM. Epigenetics and autism. Autism Res Treat 2013;2013:826156.
8. Shen E, Shulha H, Weng Z, Akbarian S. Regulation of histone H3K4 methylation in brain 
development and disease. Philos Trans R Soc Lond B Biol Sci 2014;369(1652).
9. Peter CJ, Akbarian S. Balancing histone methylation activities in psychiatric disorders. Trends 
Mol Med 2011;17(7):372-9.
10.
 
 
11. Dere E, Spade DJ, Hall SJ, Altemus A, Smith JD, Phillips JA, et al. Identification of sperm 
mRNA biomarkers associated with testis injury during preclinical testing of pharmaceutical 
compounds. Toxicol Appl Pharmacol 2017;320:1-7.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research trials 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 trial.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the trial in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that trial related procedures, including trial specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations.
6. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial 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 trial, 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 
trial. 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 trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 


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


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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the trial 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 trial.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the trial.
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 trial.
17. The anticipated expenses, if any, to the subject for participating in the trial.
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 may discontinue 


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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 trial.
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 trial 
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 trial. 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 trial medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical trials;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial 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 trial results are 
published.


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25. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening, throughout the duration of the trial, and for 5 half-lives plus 90 days after last dose 
of trial medication. If the partner or wife of the subject is found to be pregnant during the trial, 
the investigator will offer the subject the choice to receive unblinded treatment information. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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


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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Female Subjects and Their Male Partners
Female subjects of childbearing potential are excluded from this trial; there are no requirements 
for contraception or pregnancy avoidance.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 half-lives PLUS 
90 days after the last dose of trial drug, male subjects who are sexually active with a female partner 
of childbearing potential must use barrier contraception (eg, condom with or without spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. Females 
of childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception below.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this trial, where medications and devices containing hormones are included, 
females of childbearing potential who are partners of male subjects are advised to use 
additional contraception chosen from the list below: 

Nonhormonal methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion.

Hormonal methods: 
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of trial drug.

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of trial drug.

Oral.

Injectable.

Implantable.
2. Since genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the 
investigational drug, additional effective methods of contraception (there may be a higher than 
1% failure rate) that may be chosen by the female partner of a male subject are: 


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
Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Male subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy and 
sperm donation during the course of the trial.
5. Male subjects will receive continued guidance with respect to the avoidance of pregnancy and 
sperm donation as part of the trial procedures. Such guidance should include a reminder of the 
following:

Contraceptive requirements of the trial.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of subject compliance through questions such as
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit?


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Appendix E
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 01 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Modified study design to delete the MRD part of the study and associated assessments, 
and clarified the SRD part.
Initial 
wording:
This is an FIH, randomized, double-blind, placebo-controlled trial to evaluate the 
safety, tolerability, and PK of TAK-418. The trial will also explore the PD of 
TAK-418 and its effects on selected biomarkers following single and multiple doses in 
healthy adult subjects.
The trial is composed of 2 parts: Part 1 (SRD) and Part 2 (MRD). Both Parts 1 and 2 
are sequential panel design in healthy subjects.
-----
Part 1: SRD in Healthy Subjects
Part 1 consists of 5 cohorts of subjects, sequentially paneled, with a double-blind 
design. Each cohort will consist of 8 subjects, where 6 subjects will be randomized to 
receive TAK-418 and 2 subjects will be assigned to receive matching placebo. The 
trial population for Part 1 will be approximately 40 healthy subjects. Additional 
cohorts may be studied if deemed necessary to fully characterize the 
pharmacologically active exposure range. For Cohort 3, there will be at least 7 days of 
washout between dose administration in the fasted and fed states.
The planned dose levels of TAK-418 to be evaluated in Cohorts 1 to 5 are outlined in 
Table 6.a.
[Table 6.a Part 1: Schematic and Planned Doses of Trial DesignCohorts 1 to 5]
(a) An additional cohort may be studied if deemed necessary to fully characterize the 
pharmacologically active exposure range.
(b) Doses planned to be administered range from 5 to 180 mg, but the actual doses administered after 
the first dose will be based on emerging safety and tolerability data from the previous doses. The 
highest dose administered will have a predicted mean area under the concentration-time curve (AUC) 
that does not exceed the monkey AUC at the no-observed-adverse-effect level (NOAEL) or mean Cmax
that does not exceed one-tenth of the monkey Cmax at the NOAEL.
(c) Cohorts 3A and 3B will be evaluated with the same subjects for the assessment of food effect on 
TAK-418. Only Cohort 3B will be administered TAK-418 under fed condition with a high fat/high 
calorie breakfast. 
Part 2: MRD in Healthy Subjects
Part 2 will consist of 3 cohorts of subjects, sequential multiple-dose panels, with a 
double-blind design. Three dose cohorts, Cohorts 6, 7, and 8, are considered adequate 
to explore the pharmacologically active exposure range. Each cohort will be 
comprised of 8 subjects, where 6 subjects will be randomized to receive TAK-418 and 
2 subjects will be assigned to receive matched placebo. The trial population for Part 2 


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will be comprised of approximately 24 healthy subjects. Part 2 may commence after 
completion of SRD Cohort 3A in Part 1, in which the starting dose will not exceed the 
dose tested in Cohort 3A from Part 1. 
It is planned that subjects will receive once-daily (QD) dosing of TAK-418 or 
matching placebo for 7 days to achieve steady-state. The mean terminal disposition 
phase half-life (t1/2z) of TAK-418 from Part 1 will inform the duration of dosing 
required in Part 2 to achieve steady-state. 
Two wearable digital devices, an actigraphy device and an ECG device, will be 
applied from Day -1 in subjects who consent to be in this additional exploratory part 
of the trial. Both devices will be used continuously through the dosing procedures, the 
postdosing period while subjects are in the unit, and for approximately 6 days after the 
subjects’ discharge from the unit. Subjects will return the devices to the unit at the 
follow-up visit.
The trial schedule is detailed in Table 6.c.
[Table 6.c
Part 2: Trial Schedule]
Amended 
or new 
wording:
This is an FIH, randomized, double-blind, placebo-controlled trial to evaluate the 
safety, tolerability, and PK of TAK-418 in healthy adult subjects. The trial will also 
explore the PD of TAK-418 and its effects on selected biomarkers following single
and multiple oral doses in healthy adult subjects. 
The trial is composed of 2 parts: Part 1 (SRD) and Part 2 (MRD). Both Parts 1 and 2 
are sequential panel design in healthy subjects.
-----
Part 1: SRD in Healthy Subjects
Part 1 This study consists of 5 cohorts of subjects, sequentially paneled, with a 
double-blind design. Each cohort will consist of 8 subjects, where 6 subjects will be 
randomized to receive TAK-418 and 2 subjects will be assigned to receive matching 
placebo. A minimum of 4 male subjects will be enrolled in each cohort. The trial 
population will be approximately 40 healthy subjects. Additional cohorts may be 
studied if deemed necessary to fully characterize the pharmacologically active 
exposure range. For Cohort 3, there will be at least 7 days of washout between dose 
administration in the fasted and fed states.
The planned dose levels of TAK-418 to be evaluated in Cohorts 1 to 5 are outlined in 
Table 6.a. 
[Table 6.a
Schematic and Planned Doses of Trial DesignCohorts 1 to 5]
(a) An Additional cohorts may be studied if deemed necessary to fully characterize 
the pharmacologically active exposure range.
(b) Doses planned to be administered range from 5 to 180 mg, but the actual doses 


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administered after the first dose will be based on emerging safety and tolerability data 
from the previous doses. If needed, a dose higher than 180 mg but less than 300 mg 
may be evaluated providing its predicted exposure does not exceed the following 
exposure levels. The highest dose administered will have a predicted mean area under 
the plasma concentration-time curve (AUC) that does not exceed the monkey AUC at 
the no-observed-adverse-effect level (NOAEL; males) from the 13-week toxicology 
study or mean maximum observed concentration (Cmax) that does not exceed 
one-tenth of the monkey Cmax from the 4-week toxicology study.
(c) Cohorts 3A and 3B will be evaluated with the same subjects for the assessment of food effect on 
TAK-418. Only Cohort 3B will be administered TAK-418 under fed condition with a high fat/high 
calorie breakfast.
Subjects in Cohort 3 will receive 2 doses (under fasted state [Cohort 3A] and 
with food [Cohort 3B]), with at least 7 days of washout between dose 
administrations. Subjects enrolled in Cohort 3A will return to the site to 
complete Cohort 3B and will be administered TAK-418/placebo under fed 
condition with a high fat/high calorie breakfast, which must start 30 minutes 
before the dose is administered. All assessments from Day -1 to Day 4 in Cohort
3B will be same as in Cohort 3A; however, there will be no follow-up for 
 
after Cohort 3A and the Day 14 follow-up assessment for Cohort 3B. 
For male subjects, 
 days will be adjusted based on dosing in 
Cohort 3B.
Part 2: MRD in Healthy Subjects
Part 2 will consist of 3 cohorts of subjects, sequential multiple-dose panels, with a 
double-blind design. Three dose cohorts, Cohorts 6, 7, and 8, are considered adequate 
to explore the pharmacologically active exposure range. Each cohort will be 
comprised of 8 subjects, where 6 subjects will be randomized to receive TAK-418 and 
2 subjects will be assigned to receive matched placebo. The trial population for Part 2 
will be comprised of approximately 24 healthy subjects. Part 2 may commence after 
completion of SRD Cohort 3A in Part 1, in which the starting dose will not exceed the 
dose tested in Cohort 3A from Part 1. 
It is planned that subjects will receive once-daily (QD) dosing of TAK-418 or 
matching placebo for 7 days to achieve steady-state. The mean terminal disposition 
phase half-life (t1/2z) of TAK-418 from Part 1 will inform the duration of dosing 
required in Part 2 to achieve steady-state. 
Two wearable digital devices, an actigraphy device and an ECG device, will be 
applied from Day -1 in subjects who consent to be in this additional exploratory part 
of the trial. Both devices will be used continuously through the dosing procedures, the 
postdosing period while subjects are in the unit, and for approximately 6 days after the 
subjects’ discharge from the unit. Subjects will return the devices to the unit at the 
follow-up visit.
CCI
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The trial schedule is detailed in Table 6.c.
[Table 6.c
Part 2: Trial Schedule]
Rationale for Change:
Change in study design to exclude MRD part of the study, include male subjects with normal 
, and to provide additional clarification.
The following sections also contain this change:
∀
Title Page
∀
Section 1.0 STUDY SUMMARY
∀
Section 2.0 Trial Schematic
∀
Section 3.0 Schedule of Trial Procedures
∀
Section 5.1.1 Primary Objective
∀
Section 5.1.2 Secondary Objective
∀
Section 5.1.3 Exploratory Objectives
∀
Section 6.2 Dose Escalation
∀
Section 6.3 Justification for Trial Design, Dose, and Endpoints
∀
Section 6.3.3.1 Safety and PK
∀
Section 6.3.3.2 Exploratory Endpoints
∀
Section 6.4 Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
∀
Section 6.5.3 Definition of Trial Completion
∀
Section 9.2.7 Trial Drug Administration
∀
Section 9.3 Biomarker, PK, PD, and PGx, Samples
∀
Section 9.3.1 PK Measurements
∀
Section 9.3.5 Confinement
∀
Section 11.1.3 PK Analysis
∀
Section 11.1.6 Safety Analysis
∀
Section 11.3 Determination of Sample Size
CCI


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Protocol Incorporating Amendment No. 01 
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CONFIDENTIAL
Change 2: Added objectives relating to 
.
The primary change occurs in 5.1 Objectives
Added text:5.1.3 Exploratory Objectives
Rationale for Change:
The following sections also contain this change:
∀
Section 1.0 STUDY SUMMARY
∀
Section 4.3 Benefit/Risk Profile
∀
Table 6.b Trial Schedule
∀
Section 6.2 Dose Escalation
∀
Section 6.3.2 Dose
∀
Section 9.3 Biomarker, PK, PD, and PGx, Samples
∀
Section 9.3.2.3
∀
Section 9.3.3.2 Biological Sample Retention and Destruction
∀
Section 10.2.9.1 Collection Period
CCI
CCI
CCI
CCI


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Change 3: Added inclusion and exclusion criteria based on 
 
 in male subjects.
This primary change occurs in 7.1 Inclusion Criteria and 7.2 Exclusion Criteria
Added text 7.1 Inclusion Criteria
8. Male subjects must have
 
7.2 Exclusion Criteria
10. Male subjects who have serum 
 levels that are 
clinically abnormal.
Rationale for Change:
To ensure that male subjects with normal 
function are enrolled.
The following sections also contain this change:
∀
Section 1.0 STUDY SUMMARY
∀
Section 3.0 Schedule of Trial Procedures
∀
Table 6.b Trial Schedule
∀
Section 9.2.11.2 Diagnostic Screening
Change 4: Added biomarkers.
This primary change occurs in Section 5.1.3 Exploratory Objectives
Added text:
∀
To collect plasma samples for possible exploratory biomarker analysis 
including but not limited to brain-derived neurotrophic factor (BDNF).
∀
Rationale for Change:
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CCI
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CONFIDENTIAL
The following sections also contains this change:
∀
Section 5.2.3 Exploratory Endpoints
∀
Section 6.3.3.3 Biomarkers
∀
Section 9.3.2.2 Plasma Samples for Circulating Biomarkers
∀
Section 10.2.9.6 Exploratory Biomarkers and Data From Wearable Devices
∀
Section 11.1.5 Biomarker Analysis
Change 5: Added preliminary data from 13-week toxicology study.
This primary change occurs in Section 4.3 Benefit/Risk Profile
Initial wording:
Amended or 
new wording:
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Protocol Incorporating Amendment No. 01 
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CONFIDENTIAL
Rationale for Change:
To provide observed 
 toxicity in nonclinical study and management of potential risk.
The following sections also contains this change.
∀
Section 1.0 STUDY SUMMARY
∀
Section 6.1 Trial Design
∀
Section 6.2 Dose Escalation
CCI
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CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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CCI


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title:  Randomized, Double-Blind, Placebo-Controlled, Ascending Oral Single Dose Trial to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-418 in Healthy Subjects
NCT Number: NCT03228433
SAP Approve Date: 07 December 2017
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 information or 
company confidential information. 
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-418-1001
A Randomized, Double-Blind, Placebo-Controlled, Ascending Oral Single Dose Trial to
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-418 in Healthy Subjects
PHASE 1
Version: Final
Date: 07 December 2017
Prepared by:
Based on:
Protocol Version: Amendment 01
Protocol Date: 07 July 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


TAK-418-1001
Page 2 of 29
Statistical Analysis Plan Final
07 December 2017
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


TAK-418-1001
Page 3 of 29
Statistical Analysis Plan Final
07 December 2017
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
List of Appendices ................................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.2
Analysis Sets ...........................................................................................................14
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................16
7.8
Efficacy Analysis.....................................................................................................16
7.9
Pharmacokinetic/ Pharmacodynamic Analysis .........................................................16
7.9.1
Pharmacokinetic Analysis ..................................................................................16
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................18
7.11
Safety Analysis........................................................................................................18
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................21
8.0
REFERENCES..............................................................................................................22


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LIST OF IN-TEXT TABLES
Table 4.a
Schematic Doses for Cohorts 1 through 5.............................................................8
Table 4.b
Trial Schedule......................................................................................................9
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................23
Appendix B
Criteria for Abnormal Changes from Baseline of Vital Signs..............................24
Appendix C
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters ......25
Appendix D
Schedule of Trial Procedures..............................................................................26


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
AUC
area under the concentration-time curve
AUC24
area under the serum concentration-time curve from time 0 to 24 hours
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration 
BDNF
brain-derived neurotrophic factor
BL-VAS
Bond-Lader Visual Analogue Scale
BMI
body mass index
CI
confidence interval
Cmax
maximum observed concentration
CPAP
Clinical Pharmacology Analysis Plan
C-SSRS
Columbia Suicide Severity Rating Scale
%CV
coefficient of variation
DBP
diastolic blood pressure
ECG
Electrocardiogram
eCRF
electronic case report form
F
free base
FAD
flavin adenine dinucleotide
F-FAD
formyl-flavin adenine dinucleotide
FIH
first-in-human
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
heart rate
MAV
Markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
messenger RNA
miRNA
micro RNA
NOAEL
no-observed-adverse-effect level
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamic(s)
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
PTE
Pretreatment adverse event
QTcF
QT interval with Fridericia correction method
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CI


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RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
Standard deviation
SOC
system organ class
SRD
single rising dose
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
WBC
white blood cell


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of this trial is to evaluate the safety and tolerability of TAK-418 following 
single oral doses in healthy subjects.
4.2
Secondary Objectives
The secondary objective of this trial is to evaluate the PK of TAK-418 free base (F) following a 
single oral dose (under fasted and fed states) in healthy subjects.
4.3
Exploratory Objectives
Exploratory objectives of the trial include:
4.4
Study Design
The study is a first-in-human (FIH), randomized, double-blind, placebo-controlled trial to 
evaluate the safety, tolerability, and PK of TAK-418 in healthy adult subjects aged from 18 to 
55 years, inclusive. The study will also explore the PD of TAK-418 and its effects on selected 
biomarkers following single oral doses in healthy adult subjects.
This study will involve 40 subjects, equally divided among 5 sequential cohorts of 8 subjects 
each (with a minimum of 4 male subjects), as shown in Table 4.a. In each cohort, 6 subjects will 
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receive TAK-418 and 2 will receive matching placebo. To ensure adequate safety and 
tolerability, sentinel dosing will be used for Cohort 1 with only 2 subjects dosed on Day 1 
(1 receiving TAK-418 and 1 receiving placebo). The remaining 6 subjects will be dosed in 
2 groups of 3 subjects each after a review of 72-hour postdose safety and tolerability data of the 
previous group. A staggered dosing regimen will be used for Cohorts 2 to 5. Each cohort will be 
divided by 2 groups (3 active: 1 placebo), and the second group will be dosed 48 hours after the 
first group, following assessment of safety and tolerability data. 
Additional cohorts may be studied if deemed necessary to fully characterize the 
pharmacologically active exposure range.
Table 4.a
Schematic Doses for Cohorts 1 through 5
Dose 5 mg
Dose 15 mg
Dose 30 mg
Dose 40 mg
Dose 60 mg
Cohort 1
(n=8; 6 active: 
2 placebo)
Cohort 2
(n=8; 6 active: 
2 placebo)
Cohort 3A and 3B
(n=8; 6 active: 
2 placebo)
Cohort 4
(n=8; 6 active: 
2 placebo)
Cohort 5
(n=8; 6 active: 
2 placebo)
TAK-418 and placebo will be administered orally in capsule formulation and will be prepared
and dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site personnel.
Doses planned to be administered range from 5 to 180 mg, but the actual doses administered 
after the first dose will be based on emerging safety and tolerability data from the previous 
doses. If needed, a dose higher than 180 mg but less than 300 mg may be evaluated providing its 
predicted exposure does not exceed the following exposure levels. The highest dose administered 
will have a predicted mean area under the plasma concentration-time curve (AUC) that does not 
exceed the monkey AUC at the no-observed-adverse-effect level (NOAEL; males) from the 13-
week toxicology study or mean maximum observed concentration (Cmax) that does not exceed 
one-tenth of the monkey Cmax from the 4-week toxicology study.
Subjects in Cohort 3 will receive 2 doses (under fasted state [Cohort 3A] and fed state [Cohort 
3B]), with at least 7 days washout between dose administrations. Subjects enrolled in Cohort 3A 
will return to the site to complete Cohort 3B and will be administered TAK-418/placebo under 
fed condition with a high fat/high calorie breakfast, which must be consumed within 30 minutes 
and the dose given within 5 minutes after the end of the meal. All assessments from Day -1 to 
Day 4 in Cohort 3B will be same as in Cohort 3A; however, there will be no follow-up for 
 
after Cohort 3A and the Day 14 follow-up assessment for Cohort 3B. For male subjects, 
 days will be adjusted based on dosing in Cohort 3B.
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The trial schedule is detailed in Table 4.b.
Table 4.b
Trial Schedule
Screening 
Period
Pretreatment 
(a)
Treatment
Posttrial (c)
Dose Administration (b)
Postdose Procedures (b)
Days -28 to -2
Day -1
Day 1
Days 1 to 4
Day 14 (±2) (c)
Days 91, 93, 182, 
and 184 (±7)
(a) 
(b) Subjects will remain in the phase 1 unit for a minimum of 48 hours following the dose of trial drug and may be 
released after 48 hours and complete the 72 hour and later procedures at an outpatient visit. Subjects may be kept in 
the clinic for longer time at PI's discretion.
(c)
 
 
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint of the study is a composite of safety variables and dose-limiting effects of 
TAK-418 that will be evaluated after dosing on Day 1 by the number and percentage of subjects 
who:
!
Experience at least 1 treatment-emergent adverse event (TEAE).
!
Discontinue because of an adverse event (AE).
!
Meet the markedly abnormal criteria for neurological assessment measurements at least once 
postdose.
!
Meet the markedly abnormal criteria for safety laboratory tests at least once postdose.
!
Meet the markedly abnormal criteria for vital sign measurements at least once postdose.
!
Meet the markedly abnormal criteria for safety 12-lead ECG parameters at least once 
postdose.
5.2
Secondary Endpoints
The secondary endpoints include:
Evaluation of the following PK parameters in healthy subjects after dosing on Day 1: 
!
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).
!
Area under the concentration-time curve from time 0 to infinity (AUC∞).
!
Maximum observed concentration (Cmax).
!
Time of first occurrence of Cmax (tmax).
5.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters in healthy subjects after 
dosing on Day 1: 
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size of 8 subjects per cohort (6 active: 2 placebo) chosen is based upon precedents 
from other FIH trials rather than a formal assessment of statistical power.
Subjects who drop out for nonsafety reasons may be replaced on a case-by-case basis at the 
discretion of the sponsor in consultation with the investigator. Subjects who replace dropouts 
will be allocated to the same dose as the subject they replace. Subjects who drop out for safety 
reasons will not be replaced.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percentage of subjects (N[%]) for each category, where applicable. Missing values 
will be categorized separately where deemed appropriate and necessary. 
Baseline values are defined as the last observed values before the first dose of study drug, unless 
otherwise stated; baseline values for Cohort 3 are defined as the last observed values before the 
first dose of study drug in each period.
In general, the presentation of decimal points will follow the following rules as appropriate: 
minimum and maximum values will be presented using the same number of decimal places as 
the recorded data. Arithmetic means, geometric means, and medians will be presented to 1 more 
decimal place than the recorded data, and SDs will be presented to 2 more decimal places than 
the recorded data. The confidence interval (CI) for a parameter estimate will be presented using 
the same number of decimal places as the parameter estimate. Percentage will be presented to 1 
decimal place (eg, 80.1%). All p-values will be rounded to 3 decimal places prior to assessment 
of statistical significance.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
As applicable, summaries for the study will be presented by pooled placebo, each TAK-418 dose 
level, TAK-418 overall and overall total. Data from the food effect cohort (Cohort 3) will be 
summarized separately by placebo fed, placebo fasted, TAK-418 fed, and TAK-418 fasted.
All statistical analyses will be performed using the SAS System® Version 9.4 or higher.
7.1.1
Study Definitions
There are no study-specific definitions.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) dosing page. Other study days are defined relative to Study Day 1, with 
Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. Study days prior to the 
first dose of study drug will be calculated as: {date of assessment/event – date of first dose of 
study drug}. Study days on or after the first dose of study drug will be calculated as: {date of 
assessment/event – date of first dose of study drug + 1}. 
7.1.3
Definition of Study Visit Windows
There will be no visit windowing.


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7.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.
7.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.
7.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data.
Plasma or urine concentrations that are below the limit of quantification (< BLQ) will be treated 
as zero in the summarization of concentration values and derivation of PK parameters.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data: 
!
Safety Set: The safety set will consist of all subjects who receive at least 1 dose of trial drug. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
!
Pharmacokinetic (PK) Set: The PK set will consist of all subjects who receive at least 1 dose 
of trial drug and have at least 1 measurable plasma concentration or amount of drug in the 
urine for TAK-418. All subjects with valid PK parameter estimates will be included in the 
summaries and analyses for that parameter.
!
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in 
the PK and PD analyses; however, data for all subjects will be presented in the data listings.
7.3
Disposition of Subjects
Disposition of all screened failure subjects will be summarized according to the primary reason 
for screen failure. Additionally, disposition information for screen failures will be listed. 
Disposition of all randomized subjects will be summarized by pooled placebo, each TAK-418 
dose level, TAK-418 overall and overall. The categories will include:
!
Subjects who were randomized but not treated, if applicable.
!
Subjects who completed the study drug.
!
Subjects who prematurely discontinued the study drug.
!
Subjects who completed all study visits.
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
Subjects who prematurely discontinued study visits.
Primary reasons for discontinuing study drug and/or visits, as recorded on the eCRF, will be 
summarized. 
Disposition information for randomized subjects will be listed. The status of blind for 
randomized subjects will also be listed. A listing of inclusion/exclusion criteria not met will be 
provided for randomized subjects who did not meet at least one inclusion criterion.
Significant protocol deviations captured on the eCRF will be listed and summarized. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for subjects in the Safety Set.
Summaries will be presented by pooled placebo, each TAK-418 dose level, TAK-418 overall, 
and overall total. Summary statistics (number of subjects, mean, SD, median, minimum, and 
maximum) will be presented for continuous variables (eg, age, weight, and BMI), and the 
number and percentage of subjects within each category will be presented for categorical 
variables (eg, sex, ethnicity, and race). Individual subject demographic and baseline 
characteristic data will be provided in the data listings.
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized overall for subjects who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, any available safety data and reason for 
screen failures will also be presented in the data listing.
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant conditions or 
diseases that are present or ongoing at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 19 or higher) coding system.
Medical history and concurrent medical conditions will be listed by site and subject number. The 
listing will contain subject identifier, treatment, system organ class (SOC), preferred term (PT), 
whether there was any medical history or concurrent condition, and, if yes, a detail of the 
medical history or concurrent condition.
There will be no inferential analysis of medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medications are recorded on 
the eCRF and include any medications, other than study drug, taken at any time from signing of 
informed consent through the end of the study.


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All medication history and concomitant medications will be listed by site and subject number. 
The listings will contain subject identifier, treatment, World Health Organization Drug 
Dictionary (WHODrug) preferred medication name, dose, unit, frequency, route, start date, stop 
date, whether the medication was ongoing, and reason for use. No inferential statistics will be 
presented. 
Medication history and concomitant medications will be coded using the WHODrug Version 01 
March 2016 or higher.
7.7
Study Drug Exposure and Compliance
Each subject will be given a single dose as per the study design. Since all doses of study 
medication will be administered during confinement, study drug compliance will not be 
summarized. Dosing administration as well as study drug concentration data will be provided by 
subject and visit in the listings. Meal time and meal consumption will be listed as collected on 
the eCRF.
There will be no inferential analysis of study drug exposure.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/ Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
All PK summaries and analyses will be based on the PK Set. PK parameters of TAK-418 will be 
derived using noncompartmental analysis methods and will be determined from the 
concentration-time data for all evaluable subjects. Actual sampling times, rather than scheduled 
sampling times, will be used in all PK computations involving sampling times for plasma PK 
parameters. Nominal time intervals will be used for computations of urine PK parameters.
PK blood and urine samples for TAK-418F concentrations will be collected as specified in the 
Schedule of Trial Procedures (See Appendix D). Plasma and urineTAK-418F concentrations will 
be measured by liquid chromatography with tandem mass spectrometry method.
Plasma concentrations of TAK-418F will be summarized by dose over each scheduled sampling 
time using descriptive statistics. The amount of TAK-418F excreted in urine will also be 
summarized by dose using descriptive statistics. Subjects randomized to placebo will not be 
included in these summarizes but will be listed. Individual plasma concentration and urine 
concentration versus time and PK parameters will be presented in a data listing. 


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The following pharmacokinetic parameters will be calculated for plasma concentration values of 
TAK-418F:
Symbol/Term
Definition 
tmax
Time of first occurrence of Cmax.
Cmax
Maximum observed concentration.
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable
concentration
AUC∞
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
Descriptive statistics (N, arithmetic mean, SD, %CV, median, minimum, and maximum) will be 
used to summarize the plasma PK parameters for TAK-418 by dose. In addition, geometric mean 
will be computed for Cmax and AUCs. Individual plasma PK parameters will be presented in a 
data listing.
The following pharmacokinetic parameters of TAK-418 will be derived from urine 
concentrations of TAK-418F:
Symbol/Term
Definition
Descriptive statistics (N, arithmetic mean, SD, median, minimum, and maximum) will be used to 
summarize the urine PK parameters for TAK-418. Individual urine PK parameters will be 
presented in a data listing.
Specific or additional PK parameters may be added as appropriate per the Clinical Pharmacology 
Analysis Plan (CPAP).
If sufficient data are available, the does proportionality for cohorts (fasted cohorts only) on Day 
1 for key PK parameters (Cmax and AUCs) will be assessed using the power model. The power 
model can be described by the following equation:
ln( 	
	
) =  +  ln() + 
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where  is the intercept and  is the slope with random error ε. Dose proportionality will be 
declared if the 90% confidence interval (CI) for  lies entirely within the critical region,
1 + ln(0.80)
ln(
)
, 1 + ln(1.25)
ln(
)  
where 
 is the ratio of the highest and the lowest dose in the study. [3]
For evaluation of potential food effect on TAK-418F PK, log-transformed Cmax and AUC values 
for Cohort 3 will be compared between the treatments (Reference=fasting administration; 
Test=fed administration) using an analysis of variance (ANOVA) with fixed effect for treatment 
and a random effect for subject. The geometric mean for relative bioavailability and 90% CIs of 
geometric mean ratio for Cmax, AUClast, and AUC∀will be calculated.
7.9.2
Pharmacodynamic Analysis
PD samples will be collected as specified in the Schedule of Trial Procedures (See Appendix D).
Additional analyses will be performed if useful and appropriate. 
7.10
Other Outcomes
Additional analyses will be performed if useful and appropriate. Detailed statistical methods for 
biomarker will be specified in a separate biomarker analysis plan. 
7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory parameters, vital sign results, 12-lead ECG 
results, and other safety parameters. The Safety Set will be used for all summaries of safety 
parameters. These summaries will be presented by pooled placebo, each TAK-418 dose level, 
and TAK-418 overall (as appropriate). These summaries will not contain data from the fed 
portion. Data from the food effect cohort will be summarized separately by placebo fed, placebo 
fasted, TAK-418 fed, and TAK-418 fasted.
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7.11.1 Adverse Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation.
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.  
A TEAE is defined as any sign, symptom, syndrome, or new illness, regardless the relationship 
to study drug, which occurs on or after the administration of the study drug and no more than 
30 days after receiving the last dose of study drug (onset data-last date of dose +1 ≤30). A TEAE 
may also be a pretreatment AE or a concurrent medical condition diagnosed prior to the date of 
first dose of study drug that increases in severity after the start of dosing. Any event with 
partially or completely missing onset date information will be considered treatment emergent 
unless the available information indicates that the onset occurred outside the window (onset 
data-last date of dose +1 ≤30).
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA, version 19 or higher). 
TEAEs are recorded in the eCRF as being related or not related to study drug and study 
procedure. TEAEs that are recorded as related to study drug and/or study procedure will be 
summarized separately. TEAEs will also be presented by intensity/severity (mild, moderate, and 
severe). Serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to 
death will also be summarized using SOC and PT.
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
TEAEs will be presented by pooled placebo, each TAK-418 dose level and TAK-418 overall. 
The tables will include the number and percentage (N[%]) of subjects. The following summary 
tables will be generated: 

Overviews of TEAEs, including number of subjects and events.

TEAEs by SOC and PT, including number of subjects and events.

Subject mappings for TEAEs by SOC and PT.

TEAEs by PT.


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!
Serious TEAEs by SOC and PT.
!
Relationship of TEAEs to study drug by SOC and PT.
!
Drug related TEAEs by SOC and PT.
!
Drug related TEAEs by PT.
!
Intensity of TEAEs by SOC and PT.
!
Intensity of drug related TEAEs by SOC and PT.
!
Pretreatment Adverse Events (PTE) by SOC and PT.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
SAEs, and AEs that resulted in death.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. Refer to Appendix D for 
scheduled clinical laboratory test measurements.
The central laboratory will perform laboratory tests, including hematology, urinalysis, chemistry 
and other tests. 
For hematology, urinalysis and chemistry tests, descriptive statistics (N, mean, median, SD, 
minimum and maximum) will be summarized for baseline, post-baseline, and change from 
baseline values by treatment regimen and study visit. Only the scheduled measurements will be 
included in the summary. 
Individual results for hematology and chemistry laboratory tests will be evaluated against the 
Takeda predefined laboratory markedly abnormal value (MAV) criteria (see Appendix A) using 
the result and criteria in SI units. All subjects with results that meet the MAV criteria will be 
presented in a data listing. The number and percentage of subjects with at least one post dose 
markedly abnormal laboratory test result will also be summarized. The mapping of the subjects 
who meet the MAV criteria after dosing will be listed as a table. All postdose observations, 
including scheduled and unscheduled measurements will be included in the MAV summaries. 
Listings of all clinical safety laboratory data will be provided and will be presented in both SI 
and CV units. Laboratory data outside of the normal reference range will be indicated in the 
listings. In addition, MAVs will be flagged. The listing will include site number, subject 
identifier, age (at informed consent), gender, treatment group, study visit, and sample collection 
date.
 parameters will be listed separately.
7.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
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to each post-baseline visit. Summaries will be presented by pooled placebo and each TAK-418 
dose level.
Individual results of vital signs that meet Takeda’s markedly abnormal criteria (see Appendix B) 
will be summarized and provided in the data listings. If a subject has a MAV for a particular vital 
sign parameter, all visits for that subject for that parameter will be listed. The number and 
percentage of subjects with at least 1 postdose MAV signs measurement will be summarized by 
pooled placebo, each TAK-418 dose level and TAK-418 overall. The mapping of the subjects 
who meet the MAV criteria will be listed as a table. All observations, including ones at 
unscheduled visits, will be included in the MAV evaluation and summaries.
All vital sign results for all subjects in the Safety Set will be listed by subject in the data listings 
and markedly abnormal values will be flagged.
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix D. The ECG 
parameters include heart rate, PR-interval, QRS-duration, QT-interval, and QTcF interval, and 
the interpretation of the ECG profile by the principal investigator.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters will 
be presented for baseline, each post-baseline visit, and changes from Baseline in quantitative 
ECG parameters to each post-baseline visit. Only the scheduled measurements will be included 
in the summary. No inferential statistics will be presented.
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria (see Appendix C) will be summarized and provided in the 
data listings. Shift tables will be generated to show the investigator’s ECG interpretations at each 
postdose collection by the interpretation at Baseline.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings. 
7.11.5 Other Observations Related to Safety
Physical examination findings will be presented in the data listings.
Columbia-Suicide Severity Rating Scale results will be presented in the data listings.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
Not applicable.


TAK-418-1001
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CONFIDENTIAL
8.0
REFERENCES
1.
A Randomized, Double-Blind, Placebo-Controlled, Ascending Oral Single Dose Trial to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-418 in Healthy Subjects, 
Takeda Development Center Americas, Inc., Amendment 01, Trial No. TAK-418-1001, 
dated 07 July, 2017.
2.
 
 
3. Brian P. Simith, etc. (2000), Confidence Interval Criteria for Assessment of Dose 
Proportionality, Pharmaceutical Research; Vol 17, No. 10, pp 1278-1283.
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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 × LLN
>1.5 × ULN
Platelet count
Conventional
<75 × 103/L
>600 × 103/L
SI
<75 × 109/L
>600 × 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Alkaline Phosphatase
Both
--
>3 × ULN
ALT
Both
--
>3 × ULN
AST
Both
--
>3 × ULN
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Calcium
Conventional
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
Carbon dioxide (Bicarbonate)
Conventional
<8.0 mEq/L
--
SI
<8.0 mmol/L
--
Chloride
Both
<75 × LLN
>126 × ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 mol/L
Glucose
Conventional
<50 mg/dL
>350 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Gamma-glutamyl transferase
Both
--
>3 ×  ULN
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Total protein
Both
<0.8 ×  LLN
>1.2 ×  ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, LLN=lower limit of normal, ULN=upper limit of 
normal.


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


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CONFIDENTIAL
Appendix C
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters
Parameter
Unit
Lower Criteria
Upper Criteria
HR
bpm
<50 
>120 
QT-interval
msec
≤50
≥460 
QTcF-interval
msec
≤50
≥500 OR
≥30 change from baseline and
≥450 


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CONFIDENTIAL
Appendix D
Schedule of Trial Procedures
Schedule of Activities
Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
-28 to 
-2
-1
Hours
Days
Screen 
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 182, 
184 (±7)
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/ 
demographics
X
Prior and concomitant 
medication review
X--------------------------------------------------------Continuous Review--------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X (d)
X
Neurological examination
X
X (d)
X
X
X
Height
X
Weight
X
X
X
X
BMI
X
Semirecumbent vital signs 
(HR, SBP, and DBP)
X
X (e)
X
X
X
X
Vital signs (respiratory rate, 
oral [at the floor of the 
mouth]/tympanic 
temperature)
X
X (e)
X
X
X
X
12-lead ECG
X
X
X (e)
X
X
X
X
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CONFIDENTIAL
Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
-28 to 
-2
-1
Hours
Days
Screen 
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 182, 
184 (±7)
TAK-418/placebo 
administration
X
C-SSRS
X
X
X
X
X
X
BL-VAS
X
X
X
AE monitoring
X-------------------------------------------------------------Continuous Monitoring----------------------------------------------------X
Laboratory Procedures/Assessments
Hematology
X
X
X
X
Urinalysis
X
X
X
X
Serum chemistry
X
X
X
X
hCG (females) 
X
X
X
X
Urine/breath alcohol test (j)
X
X
Hepatitis screen
X
HIV
X
PK Evaluations
Blood for plasma PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for PK (k)
X----------------------------------------------------------------------------------------------X
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CONFIDENTIAL
Day(s) (a)
Scheduled Time (a)
Follow-
up/ ET 
(b)
-28 to 
-2
-1
Hours
Days
Screen 
ing
Predose 
Day 1
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
14 
(±2) 
91, 93, 182, 
184 (±7)
Biomarker Evaluations
PGx Evaluations
Blood sample for DNA PGx 
(n)
X
Blood sample for RNA PGx 
(o)
X
X
Other
Confinement
X-----------------------------------------------------------------------------------------------X
Footnotes are on the last table page.
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TAK-418-1001
Page 29 of 29
Statistical Analysis Plan Final
07 December 2017
CONFIDENTIAL
AE=adverse event, BL-VAS=Bond-Lader Visual Analogue Scale, BMI=body mass index, C-SSRS=Columbia–Suicide Severity Rating Scale, DBP=diastolic blood pressure, 
ECG=electrocardiogram, ET=early termination, F-FAD=formyl-flavin adenine dinucleotide, 
, hCG=human chorionic gonadotropin, 
HIV=human immunodeficiency virus, HR=heart rate, 
, PBMC=peripheral blood mononuclear cell, PGx=pharmacogenomics, PK=pharmacokinetic, 
SBP=systolic blood pressure.
(a) For Cohort 3, there will be a 7 day washout between Cohorts 3A and 3B, starting from TAK-418 administration on Day 1 for Cohort 3A. For Cohort 3B, all assessments on 
Days -1 through Day 4 will be same as Cohort 3A. 
(b)
 
(c) 
(d) Predose physical and neurological examinations may be done within approximately 24 hours predose.
(e) Vital signs and a 12-lead ECG will be performed within approximately 1 hour predose on Day 1.
(f) 
 
(g) 
(h) 
(i) 
 
(j) A urine alcohol test may be performed at the discretion of the investigator.
(k) Urine sample for TAK-418F concentrations may be collected at a dose level projected to produce therapeutic exposure at the following time intervals: Predose (spot collection), 
0 to 12 hours, 12 to 24 hours, 24 to 48 hours.
(l)
 
(n) Blood for DNA PGx will be collected within 60 minutes predose.
(o) Blood for RNA PGx will be collected within 60 minutes predose and 24 hours postdose.
(p)
 
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