Clinical trial NCT04202497
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2019-12-18; Completion date: 2020-03-19
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine brain LSD1 enzyme occupancy and the relationship of occupancy to TAK-418 dose and plasma exposure after single oral dosing of TAK-418 in healthy participants using \[18F\]MNI-1054 positron emission tomography (PET) imaging.

Detailed description:
The drug being tested in this study is called TAK-418. TAK-418 is being tested to determine the relationship between brain LSD1 enzyme occupancy and TAK-418 plasma concentration. This study will utilize the PET radiotracer \[18F\]MNI-1054 to evaluate the brain LSD1 enzyme occupancy of TAK-418 after single dose oral administration in healthy adult participants.

The study will enroll approximately 16 participants. The TAK-418 starting dose is 1.5 mg, given on Day 1. Each participant will receive one dose of TAK-418 and up to 3 dynamic \[18F\]MNI-1054 PET scans to assess enzyme occupancy on baseline, Day 1 and Day 2 or 3 post-TAK-418 dosing.

This single center trial will be conducted in the United States. The overall time to participate in this study is 62 days. Participants will be followed up on Day 14 for follow-up safety assessments.

Arms: arm 1: TAK-418 1.5 milligram (mg), orally, once on Day 1. Participants will also receive 10 millicurie (mCi) of \[18F\]MNI-1054 injection intravenously, prior to each PET scans on Day -1, Day 1, and either on Day 2 or 3. Dose levels for subsequent participants may vary based on available review of imaging and pharmacokinetics (PK) data.
Interventions: intervention 1: TAK-418 intervention 2: [18F]MNI-1054 (radiotracer)
Intervention descriptions: intervention 1: TAK-418 orally. intervention 2: \[18F\]MNI-1054 injection.

Protocol documents:
Prot_000.pdf: 



Title: A PHASE 1, OPEN-LABEL, POSITRON EMISSON TOMOGRAPHY (PET) STUDY WITH 
[18F]MNI-1054 TO DETERMINE LYSINE-SPECIFIC DEMETHYLASE 1A (LSD1) BRAIN 
ENZYME OCCUPANCY OF TAK-418 AFTER SINGLE-DOSE ORAL ADMINISTRATION IN 
HEALTHY SUBJECTS
NCT Number: NCT04202497
Protocol Approve Date: 5 March 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-label, Positron Emission Tomography Study With [18F]MNI-1054 to 
Determine Lysine-Specific Demethylase 1A Brain Enzyme Occupancy of TAK-418 After 
Single-Dose Oral Administration in Healthy Subjects
Study Identifier:
TAK-418-0004
Compound:
TAK-418
Date:
05 March 2020
Amendment Number:
2
Amendment History:
Date
Amendment Number
Region
27 September 2019
Initial version
United States
25 October 2019
1
United States
05 March 2020
2
United States
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TAK-418
Study No. TAK-418-0004 
Page 2 of 83
Protocol Amendment 2
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
1.1
Protocol Amendment 2 Summary of Changes..........................................................10
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.1.1
TAK-418 ...........................................................................................................15
4.1.2
[18F]MNI-1054...................................................................................................20
4.2
Rationale for the Proposed Study.............................................................................21
4.3
Benefit-Risk Profile .................................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................25
5.1
Hypothesis...............................................................................................................25
5.2
Study Objectives......................................................................................................25
5.2.1
Study Primary Objective ....................................................................................25
5.2.2
Study Secondary Objectives...............................................................................25
5.3
Endpoints.................................................................................................................25
5.3.1
Primary Endpoints .............................................................................................25
5.3.2
Secondary Endpoints..........................................................................................26
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................27
6.1
Study Design ...........................................................................................................27
6.2
Dose Selection.........................................................................................................27
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................27
6.3.1
Rationale of Study Design..................................................................................27
6.3.2
Rationale for Dose .............................................................................................28
6.3.3
Rationale for Endpoints......................................................................................28
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............28
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.5
Study Beginning and End/Completion .....................................................................30
6.5.1
Definition of Beginning of the Study..................................................................30
6.5.2
Definition of End of the Study ...........................................................................30
6.5.3
Definition of Study Discontinuation...................................................................30
6.5.4
Criteria for Premature Termination or Suspension of the Study..........................31
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............32
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Study No. TAK-418-0004 
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7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................33
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products.........34
7.3.1
Concomitant Medications...................................................................................34
7.3.2
Fruit Juice ..........................................................................................................35
7.3.3
Alcohol..............................................................................................................35
7.3.4
Caffeine .............................................................................................................35
7.3.5
Smoking ............................................................................................................35
7.4
Diet, Fluids, and Activity.........................................................................................35
7.4.1
Diet and Fluids...................................................................................................35
7.4.2
Activity..............................................................................................................36
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................36
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................37
7.7
Subject Replacement................................................................................................37
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................38
8.1
Clinical Study Drug .................................................................................................38
8.1.1
Clinical Study Drug Labeling.............................................................................38
8.1.2
Clinical Study Drug Inventory and Storage ........................................................38
8.1.3
Clinical Study Drug Blinding.............................................................................38
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs...............................38
8.2
Ancillary Supplies ...................................................................................................38
9.0
STUDY PROCEDURES...............................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent...............................................................................................39
9.1.2
Inclusion and Exclusion Criteria.........................................................................39
9.1.3
Medical History, Demographics, and Prior and Concomitant Medications .........40
9.2
Clinical Procedures and Assessments.......................................................................40
9.2.1
Full Physical Examination..................................................................................40
9.2.2
Neurologic Examination ....................................................................................40
9.2.3
Height and Weight .............................................................................................40
9.2.4
BMI ...................................................................................................................40
9.2.5
Vital Signs .........................................................................................................40
9.2.6
Assessment of Suicidal Ideation and Behavior ...................................................41
9.2.7
12-Lead ECG.....................................................................................................41
9.2.8
Study Drug Administration ................................................................................42
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9.2.9
MRI ...................................................................................................................42
9.2.10 [18F]MNI-1054 PET Imaging .............................................................................42
9.2.11 AE Monitoring...................................................................................................43
9.3
Laboratory Procedures and Assessments..................................................................43
9.3.1
Hematology .......................................................................................................43
9.3.2
Chemistry ..........................................................................................................43
9.3.3
Urinalysis...........................................................................................................44
9.3.4
Diagnostic Screening .........................................................................................44
9.4
PK Samples .............................................................................................................45
9.4.1
PK Evaluations ..................................................................................................45
9.4.2
PK Measurements..............................................................................................46
9.5
C-SSRS ...................................................................................................................46
9.6
Confinement ............................................................................................................46
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions and Elements of AEs .............................................................................47
10.1.1 SAEs..................................................................................................................49
10.1.2 Special Interest AEs...........................................................................................50
10.2
AE Procedures.........................................................................................................50
10.2.1 Assigning Severity/Intensity of AEs...................................................................50
10.2.2 Assigning Causality of AEs................................................................................51
10.2.3 Start Date...........................................................................................................51
10.2.4 End Date............................................................................................................51
10.2.5 Pattern of AE (Frequency) .................................................................................51
10.2.6 Action Taken With Study Treatment..................................................................51
10.2.7 Outcome ............................................................................................................52
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................52
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....54
11.0
STATISTICAL METHODS..........................................................................................56
11.1
Statistical and Analytical Plans ................................................................................56
11.1.1 Analysis Sets......................................................................................................56
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................56
11.1.3 PK Analysis .......................................................................................................56
11.1.4 PET Analysis .....................................................................................................57
11.1.5 Safety Analysis ..................................................................................................57
11.2
Interim Analysis and Criteria for Early Termination ................................................58
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11.3
Determination of Sample Size..................................................................................58
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
12.1
Study-Site Monitoring Visits ...................................................................................59
12.2
Protocol Deviations..................................................................................................59
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................60
13.1
IRB and/or IEC Approval ........................................................................................60
13.2
Subject Information, Informed Consent, and Subject Authorization .........................61
13.3
Subject Confidentiality ............................................................................................62
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................62
13.4.1 Publication and Disclosure.................................................................................62
13.4.2 Clinical Trial Registration..................................................................................63
13.4.3 Clinical Trial Results Disclosure ........................................................................63
13.5
Insurance and Compensation for Injury....................................................................63
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................64
14.1
Administrative Information......................................................................................64
14.1.1 Study Contact Information .................................................................................64
14.1.2 INVESTIGATOR AGREEMENT......................................................................65
14.1.3 List of Abbreviations .........................................................................................66
15.0
DATA HANDLING AND RECORDKEEPING............................................................68
15.1
eCRFs......................................................................................................................68
15.2
Record Retention .....................................................................................................68
16.0
REFERENCES..............................................................................................................70
17.0
APPENDICES...............................................................................................................71
LIST OF IN-TEXT TABLES
Table 4.a
Summary of TAK-418F Plasma PK Parameters From TAK-418-1001...............17
Table 4.b
Summary of Single-Dose TAK-418F Plasma PK Parameters From Study 
TAK-418-1003 Cohort 1....................................................................................18
Table 4.c
Plasma PK Parameters of TAK-418F Following Single and Multiple Dose Oral 
Administration of TAK-418 20 mg, 60 mg, and 160 mg to Non-Japanese 
Subjects From Study TAK-418-1003 .................................................................19
Table 9.a
Primary Specimen Collections ...........................................................................46
Table 10.a
Takeda Medically Significant AE List................................................................50
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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................71
Appendix B
Elements of the Subject Informed Consent.........................................................73
Appendix C
Investigator Consent to the Use of Personal Information ....................................76
Appendix D
Pregnancy and Contraception.............................................................................77
Appendix E
Detailed Description of Amendments to Text.....................................................80
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TAK-418
Study No. TAK-418-0004 
Page 7 of 83
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceuticals USA (TPUSA)
95 Hayden Avenue
Lexington, MA 02421
Compound:
TAK-418
Study Identifier: TAK-418-0004
Phase: 1
Protocol Title: A Phase 1, Open-label, Positron Emission Tomography Study With [18F]MNI-1054 to Determine 
Lysine-Specific Demethylase 1A Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in 
Healthy Subjects
Study Design:
This is a positron emission tomography (PET) imaging study with a single oral dose of TAK-418 and up to 
3 administrations of intravenous microdoses of the lysine-specific demethylase 1 (LSD1) PET radiotracer 
[18F]MNI-1054. The primary objective is to determine brain LSD1 enzyme occupancy and the relationship of 
occupancy to TAK-418 dose and plasma exposure after single oral dosing of TAK-418 in healthy subjects.
A maximum of 16 evaluable subjects are planned to participate in this study. Within that total number of subjects, up 
to 5 dose levels may be evaluated with up to 6 subjects per dose level, although typically there will be 2 to 3 subjects 
per dose level. 
Each subject will receive up to 3 dynamic [18F]MNI-1054 PET scans (up to 180 minutes with intermittent breaks) to 
assess enzyme occupancy and turnover in humans (1 baseline scan and 2 scans after a single dose of TAK-418). There 
will be 2 confinement periods: 1 for the baseline PET scan and 1 for the treatment period PET scans. Plasma samples 
will be taken at prescribed intervals to assess the peripheral pharmacokinetics (PK) of TAK-418. A brain magnetic 
resonance imaging (MRI) scan without gadolinium contrast will be performed as part of the screening visit and used to 
delineate the anatomical regions of interest for individual PET images. 
This study will have an adaptive design such that the TAK-418 dose and timing of postdose imaging for subsequent 
subjects will be based on the data from the previous subjects and determined with input from the sponsor and the 
clinical site team. For the first 2 subjects, the postdose PET scans will be performed at approximately 6 hours after 
TAK-418 dosing, and at approximately 26.5 hours after TAK-418 dosing.
Study Primary Objective:
The primary objective of the study is to determine the relationship between the occupancy of LSD1 by TAK-418, 
following administration of a single oral dose, and the TAK-418 plasma concentration in healthy subjects using 
[18F]MNI-1054 PET imaging.
Secondary Objectives:

To estimate the LSD1 enzyme turnover rate. 

To acquire safety data following administration of a single oral dose of TAK-418. 

To acquire safety data following injection of [18F]MNI-1054.
Study Subject Population: Healthy male or female subjects.
Planned Number of Subjects:
Up to 16 evaluable subjects
Planned Number of Sites:
1
Dose Levels:
Up to 5
Route of Administration:
Oral (TAK-418); intravenous ([18F]MNI-1054)
Duration of Treatment:
Single dose
Planned Study Duration:
Approximately 62 days (Screening: ~30 days + Baseline 
Period Check-in and PET scan: ~15 days + Treatment 
Period: 3 days + Follow-up: ~14 days)
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TAK-418
Study No. TAK-418-0004 
Page 8 of 83
Protocol Amendment 2
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Main Criteria for Inclusion:
To be eligible for study participation: 
!
The subject must understand the study procedures and agree to participate by providing written informed 
consent.
!
The subject must be willing and able to comply with all study procedures and restrictions.
!
The subject is male or female and aged 18 to 65 years, inclusive, at the screening visit.
!
The subject must have a body mass index ≥18.5 and ≤30.0 kg/m2 at the screening visit
!
The subject must 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, and vital sign 
measurements performed at the screening visit and before the first dose of study drug or first invasive procedure.
!
The subject has adequate circulation to both hands for safe placement of arterial lines (as determined by Allen’s 
test).
!
A female subject is EITHER of nonchildbearing potential or, if of childbearing potential, is using at least 1 highly 
effective method of contraception with low user dependency (as defined in the protocol and informed consent) 
from screening, throughout the entire duration of the study, and for 31 days after study drug administration. In 
addition, female subjects must agree not to donate ova during this period.
!
Male subjects who are non-sterilized and sexually active with a partner of childbearing potential must use 
adequate contraception (as defined in the protocol and informed consent) from screening, throughout the entire 
duration of the study, and for 91 days after study drug administration. In addition, male subjects must agree not to 
donate sperm during this period.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if he or she: 
!
Has contraindications to undergoing MRI examination including but not limited to implants such as implanted 
cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted 
neural stimulators, central nervous system aneurysm clips and other medical implants that have not been certified 
for MRI, or history of claustrophobia in MRI.
!
Has participated in other research protocols or clinical care in the last year in addition to the radiation exposure 
expected from participation in this clinical study, such that radiation exposure exceeds the effective dose of 
50 mSv, which would be above the acceptable annual limit established by the United States Federal Guidelines. 
!
Has clinically significant abnormal findings on brain MRI that in the opinion of the investigator may interfere 
with the interpretation of the PET imaging.
!
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 12 months before screening.
!
Has luteinizing hormone, follicle-stimulating hormone, or estradiol levels that are clinically abnormal.
!
Is in the opinion of the investigator, unsuitable in any other way to participate in this study.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are:
!
Quantitative estimates of binding of [18F]MNI-1054 based on appropriate PET radiotracer kinetic models (eg, 
inhibitory constant (Ki) from irreversible 2-tissue compartmental model). The modeling approach will be 
informed by the data from the first-in-human radiotracer validation study TAK-418-0002 (
).
!
Percent enzyme occupancy calculated from quantitative estimates of binding (= 100 × [baseline –
postdose]/baseline).
!
Plasma PK parameters including, if feasible, but not limited to:
–
Maximum observed concentration.
–
Area under the concentration-time curve from time 0 to time t. 
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TAK-418
Study No. TAK-418-0004 
Page 9 of 83
Protocol Amendment 2
05 March 2020
–
Area under the concentration-time curve from time 0 to time infinity.
The secondary endpoints will be assessed through evaluation of the following parameters: 

The relationship between percent receptor occupancy calculated from first and second postdose scans.

Summary of safety observations, including but not limited to:
–
Number and percentage of participants with 1 or more adverse events.
–
Number and percentage of participants with 1 or more serious adverse events.
–
Number and percentage of participants with clinically defined abnormal laboratory values.
–
Number and percentage of participants with clinically defined abnormal vital signs.
Statistical Considerations:
Enzyme Occupancy from PET: 
Descriptive summaries for PET radiotracer binding (eg, Ki from irreversible 2-tissue compartment model) and target 
occupancy will be provided. Enzyme occupancy of brain LSD1 by TAK-418 in brain regions including the cerebellum 
will be calculated from the percent reduction of binding by comparing the baseline and postdose imaging values. The 
relationship between enzyme occupancy and drug exposure will be modeled using a maximum drug-induced effect 
model, or similar, and presented as an enzyme occupancy versus TAK-418 drug exposure curve. The relationship 
between enzyme occupancy and administered dose will also be assessed.
Safety: 
Descriptive statistics will be provided for safety, demographics, and subject disposition data by dose level. Descriptive 
statistics for continuous data will include means, medians, SDs, and ranges, while categorical data may be 
summarized using frequency counts and percentages. 
PKs: 
TAK-418 concentrations will be tabulated using descriptive statistics during the imaging period for each dose of 
TAK-418. Appropriate PK endpoints will be used to model the relationship between plasma exposure and enzyme 
occupancy.
Sample Size Justification: 
No formal statistical sample size calculation was performed. The sample size of up to 5 dose levels and up to 
6 subjects per dose level within the limit of 16 total evaluable subjects is based on precedents of other PET occupancy 
studies and is considered to be sufficient for evaluation of target occupancy, duration of occupancy, safety, 
tolerability, and the relationship between occupancy and TAK-418 plasma exposure.
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TAK-418
Study No. TAK-418-0004 
Page 10 of 83
Protocol Amendment 2
05 March 2020
1.1
Protocol Amendment 2 Summary of Changes 
This section describes the changes in reference to the Protocol incorporating Amendment 2.
There are 2 main purposes of this amendment. One is to clarify in the Schedule of Study 
Procedures that there will be 2 confinement periods, one for the baseline period and one for the 
treatment period. Second, statements were removed that would necessitate including data for 
subjects who do not receive study drug in the eCRFs or in tables, listings and figures. Other minor 
changes in procedures are proposed. Minor grammatical and editorial changes were made for 
clarification purposes only. 
For descriptions and locations of text changes listed below, as well as rationales for these changes, 
see Appendix E.
Changes in Amendment 2:
1. Clarified that there will be 2 separate confinement periods. 
2. Allen’s test was added to Day 2-3 procedures.
3. Corrected terminology referring to the 2 versions of the Columbia-Suicide Severity Rating 
Scale (C-SSRS).
4. Modified text to remove any requirement to complete eCRFs or produce statistical tables, 
listings or figures for subjects who do not receive study drug (TAK-418 or [18F]MNI-1054).
5. Updated serious adverse event (SAE) reporting guidance.
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Study No. TAK-418-0004 
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Protocol Amendment 2
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2.0
STUDY SCHEMATIC
Figure 2.a
Adaptive Design Evaluation - Evaluation of First 2 Subjects to Optimize 
Timing of PET Scan With [
18F]MNI-1054 and TAK-418 Oral Dosing Before 
Enrolling Additional Subjects (14)
PET: positron emission tomography.
a Baseline and Day 1 visit may occur over 1 or 2 calendar days. 
Screening 
Baseline PET Scan with 18F]MNI-1054 a
Day 1 PET scan with [18F]MNI-1054 and 
TAK-418 oral dosing a
Day 2-3 PET scan  with [18F]MNI-1054
Subject safety follow-up visits Day 14 (4)
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Study No. TAK-418-0004
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Protocol Amendment 2
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CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES 
Screening
Baseline (BL) Period a
Treatment Period a
ET
Follow-up
Study Day:
Days -45 to 
BL Check-in
Check-in 
Day -15 to 
Day -3
PET Scan 
Days -14 to -2
Check-in
Day -1
Day 1
Day 2-3
Day 14
(±4)
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Medical history/demographics
X
Prior and concomitant medication review
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Full physical examination
X
X
X
X
X
X
X
X
Neurological examination
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Body mass index
X
Semirecumbent vital signs (heart rate, systolic 
and diastolic blood pressure)
X
X b
X b
X b
X b
X
X
X
Vital signs (respiratory rate, oral temperature)
X
X
X
X
X
X
X
X
Standard 12-lead ECG 
X
X b
X b
X b
X b
X
X
X
Allen’s test (source only)
X
X
X
X
Brain MRI
X
C-SSRS c
X
X
X
X
X
X
X
X
PTE assessment d
X
X
AE assessment e
X
X
X
X
X
X
Insertion of arterial catheter f
X
X
X
Insertion of venous catheters 
X
X
X
Study drug (TAK-418) administration g
X (t = 0)
Laboratory Procedures/Assessments
Hematology h
X
X 
X 
X 
X 
X 
X
X
Chemistry h
X
X 
X 
X 
X 
X
X
X
Urinalysis h
X
X 
X 
X 
X 
X
X
X
Hepatitis screen
X
HIV screen
X
PT and PTT
X
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Study No. TAK-418-0004
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Protocol Amendment 2
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CONFIDENTIAL
Screening
Baseline (BL) Period a
Treatment Period a
ET
Follow-up
Study Day:
Days -45 to 
BL Check-in
Check-in 
Day -15 to 
Day -3
PET Scan 
Days -14 to -2
Check-in
Day -1
Day 1
Day 2-3
Day 14
(±4)
Serum hCG/ i
X
X
X
X
X
Urine dip stick pregnancy test i
X
X
X
Urine drug screen
X
X
X
X
X
Alcohol screen
X
X
X
Cotinine screen
X
X
X
PK Evaluations
Plasma sample for TAK-418 PK
X j
X j
X
PD-Related Evaluations
[18F]MNI-1054 PET radiotracer injection l
X
X
X
PET brain imaging l, m
X 
X 
X 
Arterial blood sampling for [18F]MNI-1054 radio 
equivalents f
X
X
X
Other
Standardized meals
X
X
X
X
X
AE: adverse event; BL, baseline; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; ET: early termination; FSH: follicle-stimulating hormone; hCG: 
human chorionic gonadotropin; LH: luteinizing hormone-releasing hormone; MRI: magnetic resonance imaging; PD: pharmacodynamic; PET: positron emission tomography; PK: 
pharmacokinetic; PT: prothrombin time; PTE: pretreatment event; PTT: partial prothrombin time.
a There will be 2 confinement periods. The baseline confinement period is from the day before the baseline PET scan through completion of all baseline assessments. The treatment 
confinement period is from Day -1 until completion of Day 2 or 3 assessments.
b Will be obtained as described in Sections 9.2.5 (Vital Signs) and 9.2.7 (12-Lead ECG). 
c C-SSRS: The current C-SSRS Screening/Baseline will be administered at screening. The current C-SSRS Since Last Visit assessment will be administered on all other days.
d PTEs will be collected from signing of informed consent up until first administration of [18F]MNI-1054 radiotracer.
e AEs will be collected from the time of first administration of [18F]MNI-1054 radiotracer up until the Day 14 (±4) follow-up visit.
f The arterial catheter may be inserted as described in Section 9.2.10. 
g Subjects will fast for at least 8 hours before TAK-418 dosing on Day 1 and will continue to fast for an additional 4 hours after dosing. The single oral dose of TAK-418 will be 
administered with approximately 240 mL of water (see Section 7.4.1 for additional dietary information). 
h For details of hematology, chemistry and urinalysis assessments, refer to Sections 9.3.1, 9.3.2 and 9.3.3, respectively. Prior to imaging on Day 1. subjects will have chemistry, 
hematology, and urinalysis performed if they have not been confined since prior safety labs. For other visits that include PET scans, labs are to be performed within approximately 1 
hour after each PET scan. 
i For women of childbearing potential (see Appendix D for definition). To be performed before any administration of study drug or PET scan. Results from urine dip stick pregnancy 
tests may be used if results from serum hCG pregnancy tests are not available in time for study procedures or study drug administration.
j Will occur pre-dose, approximately 0.5, 1, and 3 hours after TAK-418 administration, immediately before and immediately after the Day 1 PET scan. Subjects will fast for at least 8 
hours before the pre-dose PK sample is collected and will continue to fast for an additional 4 hours after TAK-418 dosing (Section 7.4.1). On Day 2 (or Day 3), PK samples will be 
collected within 30 minutes before and within 30 minutes after the follow-up Day 2 (or Day 3) PET scan (Section 9.4.1).
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CONFIDENTIAL
k On Day 1, subjects will fast for at least 8 hours before the pre-dose PK sample is collected and will continue to fast for an additional 4 hours after TAK-418 dosing (Section 7.4.1). 
On Day 2 (or Day 3), PK samples will be collected within 30 minutes before and within 30 minutes after the follow-up Day 2 (or Day 3) PET scan (Section 9.4.1). Fasting is not 
required on non-dosing days (Day 2-3 and end of treatment).
l Flexibility of approximately ±1 hour is permissible in scan timing. Deviations of greater than this (eg, due to logistical issues, such as radiotracer production delays) are permissible 
if agreed with the sponsor.
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4.0
INTRODUCTION
4.1
Background
4.1.1
TAK-418
Lysine-specific demethylase 1 (LSD1), a member of the lysine-specific demethylase (KDM) 
family, is involved in a wide variety of cellular processes and pathologies, including signal 
transduction, transcriptional regulation, viral pathogenesis, cell proliferation, cancer, and 
metastasis, cell development, cell differentiation, and chromatin remodeling [1]. As such, LSD1 
has emerged as a potential therapeutic target for development disorders involving chromatin 
remodeling defects, such as autism spectrum disorder (ASD) and other neurodevelopmental 
disorders [2].
One of the modifications that has been extensively studied in patients with ASD is methylation of 
lysine in position 4 of type 3 histone (H3K4) [3], and LSD1 is an important regulator of H3K4 
methylation. LSD1 uses a flavin adenine dinucleotide (FAD) 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, and subsequently 
additional specific substrates have been identified [4].
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CONFIDENTIAL
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Please refer to the current TAK-418 Investigator’s Brochure for additional background 
information.
4.1.2
[18F]MNI-1054
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The TAK-418-0002 study results indicate that [18F]MNI-1054 is a suitable PET radiotracer for 
measuring LSD1 occupancy in human studies.
4.2
Rationale for the Proposed Study
This study will yield a mathematical relationship between the plasma levels of TAK-418 and the 
degree of enzyme occupancy in the brain (target engagement). This will enable doses to be chosen 
for subsequent studies with an understanding of the corresponding occupancy of the TAK-418 
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binding site in the brain. This relationship is not expected to be different in any of the potential 
patient populations under consideration for TAK-418; thus, a healthy subject population is deemed 
appropriate.
 
 
 
An objective of this study is thus to achieve both a predicted and measured enzyme 
occupancy, at the first postdose scan time point, that will exceed 90% and correspond to 
near-maximal inhibition within the range of doses to be tested. The second postdose PET scan will 
provide information on the LSD1 enzyme turnover rate in humans.
4.3
Benefit-Risk Profile
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
At 1 or more doses tested, TAK-418 will produce ≥90% occupancy of LSD1 enzyme in at least 2 
subjects per dose level, in human brain region(s) of high receptor binding (eg, cerebellum).
5.2
Study Objectives
5.2.1
Study Primary Objective
The primary objective of the study is to determine the relationship between the occupancy of 
LSD1 by TAK-418, following administration of a single oral dose, and the TAK-418 plasma 
concentration in healthy subjects using [18F]MNI-1054 PET imaging.
5.2.2
Study Secondary Objectives
The secondary objectives of the study are:
1. To estimate the LSD1 enzyme turnover rate. 
2. To acquire safety data following administration of a single oral dose of TAK-418. 
3. To acquire safety data following injection of [18F]MNI-1054.
5.3
Endpoints
5.3.1
Primary Endpoints
The primary endpoints of the study are:
!
Quantitative estimates of binding of [18F]MNI-1054 based on appropriate PET radiotracer 
kinetic models (eg, Ki from irreversible 2-tissue compartmental model). The modeling 
approach will be informed by the data from the ongoing FIH radiotracer validation study 
TAK-418-0002 (
.
!
Percent enzyme occupancy calculated from quantitative estimates of binding (= 100 × 
[baseline – postdose]/baseline).
!
Plasma PK parameters including, if feasible, but not limited to:
–
Cmax.
–
Area under the concentration-time curve from time 0 to time t (AUCt).
–
AUC∞.
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5.3.2
Secondary Endpoints 
Secondary endpoints include: 
1. The relationship between percent receptor occupancy calculated from first and second 
postdose scans. 
2. Summary of safety observations, including but not limited to:
–
Number and percentage of participants with 1 or more AEs.
–
Number and percentage of participants with 1 or more SAEs.
–
Number and percentage of participants with clinically defined abnormal laboratory values.
–
Number and percentage of participants with clinically defined abnormal vital signs.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a PET imaging study with a single oral dose of TAK-418 and up to 3 administrations of 
intravenous microdoses of the LSD1 PET radiotracer [18F]MNI-1054. The primary objective is to 
determine brain LSD1 enzyme occupancy and the relationship of occupancy to TAK-418 dose and 
plasma exposure after single oral dosing of TAK-418 in healthy subjects.
A maximum of 16 evaluable male or female subjects are planned to participate in this study. 
Within that total number of subjects, up to 5 dose levels may be evaluated in up to 6 subjects per 
dose level, although typically there will be 2 to 3 subjects per dose level. 
Each subject will receive up to 3 dynamic [18F]MNI-1054 PET scans (up to 180 minutes with 
intermittent breaks) to assess enzyme occupancy and turnover in humans (1 baseline scan and 
2 scans after a single dose of TAK-418). It is anticipated that there will be 2 confinement periods 
as described in the Schedule of Study Procedures (Section 3.0): 1 for the baseline PET scan and 1 
for the treatment period PET scans. Plasma samples will be taken at prescribed intervals to assess 
the peripheral PK of TAK-418. A brain magnetic resonance imaging (MRI) scan without 
gadolinium contrast will be performed as part of the screening visit and used to delineate the 
anatomical regions of interest (ROIs) for individual PET images. 
This study will have an adaptive design such that the TAK-418 dose and timing of postdose 
imaging for subsequent subjects will be based on the data from the previous subjects and 
determined with input from the sponsor and the clinical site team. For the first 2 subjects, the 
postdose PET scans will be performed at approximately 6 and 26.5 hours after TAK-418 dosing. 
Flexibility of approximately ±1 hour is permissible in scan timing. Deviations of greater than this 
(eg, due to logistical issues such as radiotracer production delays) are permissible if agreed with 
the sponsor. 
6.2
Dose Selection
The starting dose in this study will be 1.5 mg (see Section 6.3.2). Dose levels for subsequent 
subjects may be lower or higher than this and will be selected based on review of the imaging and 
PK data available at that point to enable an accurate determination of the exposure-occupancy 
relationship. Only doses lower than or equal to those that have been tested in the phase 1 safety 
studies and determined to be safe and well-tolerated will be assessed in this study. The maximum 
dose of TAK-418 evaluated in phase 1 safety study was 160 mg.
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
The study design is typical for phase 1 receptor- or enzyme-occupancy studies and considered 
appropriate for the objectives of this study. The adaptive nature of the design ensures that doses are 
selected over sufficient range that the exposure-occupancy relationship is determined with 
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sufficient accuracy to inform dose selection, and that the number of subjects exposed to the 
investigational compound and ionizing radiation is minimized.
6.3.3
Rationale for Endpoints
6.3.3.1
Efficacy Endpoints 
This is a phase 1 biomarker study designed to quantify target engagement after single doses in 
healthy subjects; no efficacy endpoints are included.
6.3.3.2
Safety Endpoints
Safety assessments are included to ensure adequate monitoring of the safety and tolerability of 
TAK-418 and of [18F]MNI-1054 in this study.
6.3.3.3
PK Endpoints
The PK analyses will provide measures of TAK-418 exposure in plasma so that their relationship 
to enzyme occupancy in the brain can be determined.
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the administration of [18F]MNI-1054 and TAK-418, collection of PET imaging data 
and PK sampling are the critical procedures.
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
At any time point following the administration of [18F]MNI-1054 and TAK-418, collection of 
PET imaging data and PK sampling should be performed as close to scheduled time as 
possible.

All other procedures should be performed as close as possible (either before or after) the 
scheduled times.

ECG and vital signs measurements should be performed before the nominal time of the 
administration of [18F]MNI-1054 and TAK-418, collection of PET imaging data, and PK 
sampling if scheduled together.

The order of priority can be changed during the study with joint agreement of the investigator 
and the sponsor.

Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 1 assessment of [18F]MNI-1054 and TAK-418 in adult men and women, and the 
PK, PD, and safety profiles of the compounds are still being elucidated. This protocol is written 
with some flexibility to accommodate the inherent dynamic nature of phase 1 clinical studies. 
Subjects will receive a single oral dose of TAK-418 administered with approximately 240 mL of 
water on Day 1 (Sections 7.4.1 and 9.2.8). Modifications to the doses, dosing regimen, and/or 
clinical or laboratory procedures, as outlined below, may be required to achieve the scientific goals 
of the study objectives and/or to ensure appropriate safety monitoring of the study subjects.
As such, the following alterations from the currently outlined dose and/or dosing regimen may be 
permitted on the basis of newly available data, but the maximum daily dose/exposure may not 
exceed that currently outlined in Section 6.3.2:

A subject will receive a single dose of TAK-418. If the critical procedures cannot be performed 
(eg, in the case of synthesis failure of [18F]MNI-1054 or PET scanner malfunction), the same 
subject will not be used for a repeat dose and a backup subject will receive that dose. However, 
a subject already dosed may, at the discretion of the investigators, be scanned later the same 
day (first postdose scan) or within the window of Days 2 to 3 (second postdose scan) if the 
technical issues are resolved in time (eg, resynthesis of [18F]MNI-1054).

The number of days in the study may be increased on the basis of emerging information.

Instructions to take study drug with or without food or drink may be modified on the basis of 
newly available data.

The PK/PD sampling scheme may be modified during the study on the basis of newly available 
PK or PD data (eg, to obtain data closer to the time of first occurrence of Cmax). If indicated, 
these collected samples may also be assayed in an exploratory manner for metabolites and/or 
additional PD markers.
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
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECGs, 
safety laboratory tests) may be modified during the study on the basis of newly available 
safety, tolerability, PK, or PD data (eg, to obtain data closer to the time of first occurrence of 
Cmax). These changes will not increase the number of study procedures for a given subject 
during her participation in the entire study.

Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information.

It is understood that the current study may employ some or none of the alterations previously 
described. Any alteration made to this protocol to meet the study objectives must be detailed 
by the sponsor in a letter to the study file and forwarded to the investigator for retention. The 
letter may be forwarded to the institutional review board (IRB)/independent ethics committee 
(IEC) at the discretion of the investigator.
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.5.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit, discontinues from the study, or is lost to follow-up 
(ie, the investigator is unable to contact the subject).
6.5.3
Definition of Study Discontinuation
Study discontinuation because of nonsafety reasons, such as the following:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical study 
using the study treatment(s) results in the study being stopped for a nonsafety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Study discontinuation because of safety reasons:

Early study termination because of unanticipated concerns of safety to the study subjects 
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s) 
of the same class, or methodology(ies) used in this study.
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6.5.4
Criteria for Premature Termination or Suspension of the Study
6.5.4.1
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
or is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement.
6.5.4.2
Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Sites
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
1. The subject must understand the study procedures and agree to participate by providing written 
informed consent.
2. The subject must be willing and able to comply with all study procedures and restrictions.
3. The subject is male or female and aged 18 to 65 years, inclusive, at the screening visit.
4. The subject must have a body mass index (BMI) ≥18.5 and ≤30.0 kg/m2 at the screening visit.
5. The subject must be a current nonsmoker at screening as demonstrated by negative cotinine 
test.
6. The subject must be judged to be in good health by the investigator, on the basis of clinical 
evaluations including laboratory safety tests, medical history, physical examination, ECG, and 
vital sign measurements performed at the screening visit and before the first dose of study drug 
or first invasive procedure.
The subject has adequate circulation to both hands for safe placement of arterial lines (as 
determined by Allen’s test [source documentation only]).
7. A female subject is EITHER of nonchildbearing potential* OR, if of childbearing potential*, is 
using at least 1 of the following highly effective methods of contraception with low user 
dependency* from screening, throughout the entire duration of the study, and for 31 days after 
study drug administration and follow necessary precautions listed in Appendix D.
a.
Intrauterine device (IUD).
b. Intrauterine hormone-releasing system (IUS).
In addition, female subjects must also agree not to donate ova during this period.
*Definitions and acceptable methods of contraception are provided in Appendix D.
8. Male subjects who are non-sterilized* and sexually active with a partner of childbearing 
potential* must use adequate contraception from screening, throughout the duration of the 
study, and for 91 days after study drug administration and follow necessary precautions listed 
in Appendix D. 
In addition, male subjects must agree not to donate sperm during this period.
*Definitions and acceptable methods of contraception are provided in Appendix D.
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7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has participated in another investigational study within 4 weeks (or based on local 
regulations) before the screening visit. The 4-week window will be derived from the date of the 
last study procedure and/or AE related to the study procedure in the previous study to the 
screening visit of the current study.
2. The subject is an employee of the sponsor or study site or immediate family member (eg, 
spouse, parent, child, sibling) of the sponsor or study site.
3. The subject has a history of cancer (malignancy).
4. The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerance to prescription or 
nonprescription drugs or food.
5. Has a known hypersensitivity to any component of the formulation of TAK-418 or related 
compounds, including [18F]MNI-1054.
6. The subject has a positive alcohol or drug screen.
7. The subject has a positive pregnancy test.
8. The subject is a lactating/nursing female.
9. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or human immunodeficiency antibody/antigen, at the screening visit. Note: 
Subjects with positive hepatitis B virus (HBV) or HCV serology may be enrolled if 
quantitative polymerase chain reaction for HBV or HCV RNA is negative.
10. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before the screening visit.
11. The subject is unable to refrain from or anticipates using any concomitant medications other 
than those allowed per Section 9.1.3 beginning approximately 7 days before administration of 
the first dose of study drug, throughout the study, until the final follow-up visit.
12. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on 
average (1 glass is approximately equivalent to the following: beer [354 mL/12 oz], wine [118 
mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day).
13. The subject 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. The subject has a substance abuse disorder.
15. The subject cannot tolerate venipuncture or has poor venous access that would cause difficulty 
in collecting blood samples.
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16. The subject has contraindications to undergoing MRI examination including but not limited to 
implants, such as implanted cardiac pacemakers or defibrillators, insulin pumps, cochlear 
implants, metallic ocular foreign body, implanted neural stimulators, central nervous system 
aneurysm clips, and other medical implants that have not been certified for MRI, or history of 
claustrophobia in MRI.
17. The subject has prior participation in other research protocols or clinical care in the last year in 
addition to the radiation exposure expected from participation in this clinical study, such that 
radiation exposure exceeds the ED of 50 mSv, which would be above the acceptable annual 
limit established by the United States Federal Guidelines. 
18. The subject has clinically significant abnormal findings on brain MRI scan that in the opinion 
of the investigator may interfere with the interpretation of the PET imaging.
19. The subject has experienced an acute illness within 10 days before the screening visit.
20. The subject has a risk of suicide according to the investigator’s clinical judgment per the 
C-SSRS at screening or has made a suicide attempt in the 12 months before screening.
21. The subject has luteinizing hormone, FSH, or estradiol levels that are clinically abnormal.
22. The subject has an ECG at the screening visit, baseline or pre-dose on Day 1 that reveals a QT 
interval with Fridericia correction method (QTcF) >450 milliseconds for males and 470 
milliseconds for females.
23. The subject has a clinically significant resting heart rate outside of the range of 50 to 100 beats 
per minute, confirmed on repeat testing within a maximum of 30 minutes, at the screening 
visit, baseline or pre-dose on Day 1. 
24. The subject has existing skin rashes that can be diagnosed as dermatitis.
25. Subject is in the opinion of the investigator, unsuitable in any other way to participate in this 
study.
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products
7.3.1
Concomitant Medications
Throughout the study, contraception (IUD or IUS; Appendix D) and the occasional use of 
acetaminophen (approximately <1 g/day) are the only concomitant medications allowed.
The use of concomitant medications (see Section 9.1.3) from the day of the baseline PET scan 
(occurring between Day -14 to Day -1 per the Schedule of Study Procedures in Section 3.0) until 
the final follow-up visit (Day 14 ±4) is not permitted. Subjects must be instructed not to take any 
medications without first consulting with the investigator. Any concomitant medication use must 
first be discussed with the sponsor, unless the investigator or designee considers immediate 
administration is necessitated.
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7.3.2
Fruit Juice
Subjects will refrain from consuming grapefruit juice, grapefruits, and products containing 
grapefruit beginning approximately 2 weeks before administration of the first dose of 
[18F]MNI-1054 and TAK-418, throughout the study and until 1 week after administration of 
TAK-418.
Subjects also will refrain from consuming all juices 24 hours before and after administration of 
each dose of [18F]MNI-1054 and TAK-418 on PK sampling days. Consumption of all fruits other 
than grapefruit is allowed on all other days of the study.
7.3.3
Alcohol
Subjects will refrain from consuming alcohol 7 days before the screening visit and from 7 days 
before TAK-418 dosing on Day 1 until the last PK blood sample has been collected. During study 
participation, when permitted, alcohol consumption is limited to no more than approximately 2 
alcoholic beverages or equivalent (1 alcoholic beverage is approximately equivalent to: beer 
[354 mL/12 oz], wine [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz]) per day.
7.3.4
Caffeine
Subjects will refrain from consuming caffeinated beverages 72 hours before each PET scan and for 
7 days after administration of TAK-418, and from 24 hours before the first and until the last PK 
blood sample has been collected. During study participation when permitted, caffeinated 
beverages or xanthine-containing products will be limited to amounts of no more than 6 units per 
day (1 unit = 120 mg of caffeine).
7.3.5
Smoking
Smoking is not permitted during the study.
7.4
Diet, Fluids, and Activity
7.4.1
Diet and Fluids
Subjects will fast for at least 8 hours before the pre-dose PK sample and will continue to fast for an 
additional 4 hours after dosing. Subjects will receive a single oral dose of TAK-418 administered 
with approximately 240 mL of water on Day 1. Subjects may consume water ad libitum except for 
1 hour before and 1 hour after study drug administration.
During the confinement periods, subjects will be given a standard menu that includes 3 meals and 
an evening snack. The meals served on the day of TAK-418 dosing may differ from the standard 
menu because of fasting requirements but should be similar in nutritional content for each subject 
in the study. Subjects will fast from all food and drink except water between meals and snacks. The 
caloric content and composition of meals will be similar for all subjects.
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7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the screening visit until administration of the initial dose of study drug, throughout 
the study (including washout intervals between treatment periods), and for 7 days after 
administration of TAK-418,
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver function test (LFT) Abnormalities
Administration of TAK-418 and [18F]MNI-1054 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 10.2.8.4), if the 
following circumstances occur at any time during study drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 times the 
upper limit of normal (ULN), or
–
ALT or AST >5 times the ULN and persists for more than 2 weeks, or
–
ALT or AST >3 times the ULN in conjunction with elevated total bilirubin >2 times the 
ULN or international normalized ratio >1.5, or
–
ALT or AST >3 times the ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of [18F]MNI-1054 and/or 
TAK-418 that the subject failed to meet protocol entry criteria or did not adhere to protocol 
requirements, and continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category). 
5. Study termination. The sponsor or IRB terminates the study.
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6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit.
7.7
Subject Replacement
If a subject discontinues from the study, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The study site should contact the sponsor for the 
replacement of subject’s treatment assignment and allocation number.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
Details regarding the dosage form description and strengths, or composition for the 
extemporaneous preparation, of the active drug can be found in the pharmacy manual or in the 
referenced compounding manual when applicable. Study drug will be packaged to support 
enrollment and replacement of subjects as required.
8.1.1
Clinical Study Drug Labeling
A clinical label will be affixed to study drug containers in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and must remain in the original container until dispensed. The temperature 
excursion information can be found in the pharmacy manual or in the referenced compounding 
manual when applicable. Receipt and dispensing of study drug must be recorded by authorized 
personnel at the study site.
8.1.3
Clinical Study Drug Blinding
This is an open-label study.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the study drug (TAK-418) and 
[18F]MNI-1054 precursor (
) received from the sponsor or designee, the amount 
dispensed to and returned by the subjects, and the amount remaining at the end of the study. For all 
study sites, the local country sponsor personnel or designee will provide appropriate 
documentation that must be completed for study drug accountability, return, and destruction.
8.2
Ancillary Supplies
All ancillary supplies will be provided by either the study site or the sponsor or designee, 
depending upon availability. The list of ancillary supplies and source information can be found in 
the pharmacy manual or in the referenced compounding manual when applicable. If provided by 
the sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the 
sponsor or designee.
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9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the Schedule of Study Procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, per the 
discretion of the investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Appendix B. 
9.1.1.1
Assignment of Screening Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur. Each subject will be assigned only 1 screening number. 
Screening numbers must not be reused 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 receive a unique number. The unique number identifies the subject for all 
procedures occurring after meeting admission criteria. Once a unique number is assigned to a 
subject, it can never be reassigned to another subject. A single subject cannot be assigned more 
than 1 unique number.
9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned to receive a number in ascending numerical order at the 
clinical site. Each subject will be dispensed and TAK-418, labeled with his/her unique number, 
throughout the study.
Subjects will be assigned to receive a 4-digit number. For dose level X, the sequence number will 
be X001 to X006. For example, the sequence numbers will be 1001 to 1006 if there are 6 subjects 
for dose level 1, and 2001 to 2006 if there are 6 subjects for dose level 2, etc. This 4-digit number 
will be used by the clinical site to facilitate the prelabeling of PK samples, as applicable, and will 
be the only subject identifier used on all PK sample collections. It should also be contained on the 
PK transport vials shipped to the bioanalytical laboratory and will be used by the laboratory to 
report the subject data results. This 4-digit number should only be used for the purposes described 
in this section. It does not replace the 3-digit subject number that is assigned at the time the 
informed consent is obtained and that is used for all other procedures to identify the subjects 
throughout the study.
9.1.2
Inclusion and Exclusion Criteria
Each subject will be assessed, according to the eligibility criteria provided in Section 7.0.
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9.1.3
Medical History, Demographics, and Prior and Concomitant Medications
At screening, qualified site personnel will collect the subject’s significant medical history (past 
and concurrent medical conditions), per the clinical site’s standard of care and appropriate clinical 
judgment, and subject demographics. Throughout the study, contraception (IUD or IUS; Appendix 
D) and the occasional use of acetaminophen (approximately <1 g/day; Section 7.3.1) are the only 
concomitant medications allowed.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
A complete physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, extremities, and 
musculoskeletal system. Rectal, breast, and genital examinations are not required as part of this 
examination.
9.2.2
Neurologic Examination
A neurologic examination will be performed and collected in the eCRF. This will include testing 
mental status, gait, cerebellar function, cranial nerves, motor function (including strength and 
reflexes), and sensation.
9.2.3
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and any jacket or coat 
removed. Height will only be obtained only at the screening visit. 
9.2.4
BMI
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI = kg/m2). 
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) 
thermometer.
Subjects should rest in a semirecumbent position for at least 5 minutes before vital signs are 
measured. Vital signs will include pulse rate, respiratory rate, and systolic and diastolic blood 
pressure. The same method (eg, same size cuff, manual or automated) must be used for all 
measurements for each individual subject and should be the same for all subjects. 
These vital signs will be obtained 1 hour before each [18F]MNI-1054 injection, within 
approximately 1 hour after each PET scan, within approximately 1 hour before TAK-418 
administration, at approximately 1, 2, and 24 hours after TAK-418 administration.
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9.2.6
Assessment of Suicidal Ideation and Behavior
The current C-SSRS Screening/Baseline will be administered at screening. The current C-SSRS 
Since Last Visit assessment will be administered at all other timepoints. The C-SSRS was 
developed by researchers at Columbia University as a tool to help systematically assess suicidal 
ideation and behavior in subjects during participation in a clinical trial of centrally acting drugs.
The C-SSRS is composed of 3 questions addressing suicidal behavior and 5 questions addressing 
suicidal ideation, with subquestions assessing the severity. The tool is administered via interview 
with the subject.
9.2.7
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 
measurement.
QTcF intervals will be calculated in this study.
A standard 12-lead ECG will be obtained 1 hour before each [18F]MNI-1054 injection, within 
approximately 3 hours after each PET scan, within approximately 1 hour before TAK-418 
administration, at approximately 1, 2, and 24 hours after TAK-418 administration.
The pre-dose ECG will be obtained within approximately 1 hour before study drug dosing. This 
measurement will be used as the baseline assessment. The principal investigator should arrange to 
have a study cardiologist available as needed to review ECG abnormalities.
If a subject demonstrates an increase in QTcF interval ≥40 milliseconds compared with a pre-dose 
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 milliseconds, the subject will continue to 
be monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours or until the QTcF 
interval is within 40 milliseconds of the baseline value. If prolongation of the QTcF interval ≥40 
milliseconds persists, a consultation with a study cardiologist may be appropriate and the sponsor 
should be notified.
If the QTcF interval is ≥500 milliseconds, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be monitored by telemetry (until the QTcF interval 
is <500 milliseconds) 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 by 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy.
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If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: heart rate, PR interval, QRS interval, QT 
interval, QTcF interval, and the interpretation of the ECG profile by the principal investigator.
9.2.8
Study Drug Administration
On Day 1, a single oral dose of study drug (TAK-418) will be administered with approximately 
240 mL of water as described in Sections 6.4 and 7.4.1. As described in Section 9.2.10, 
[18F]MNI-1054 will be administered on Day -1, Day 1, and either Day 2 or 3. 
9.2.9
MRI
As part of the screening visit, eligible subjects will undergo a 3-dimensional high-resolution T1 
MRI scan without gadolinium contrast on a 1.5T or 3T MRI scanner. 
9.2.10 [18F]MNI-1054 PET Imaging
Venous catheters will be placed in the forearm. For the baseline PET scan (once between Days -14 
and -1), there will be 1 venous catheter for [18F]MNI-1054 administration. For the postdose PET 
scans (on Days 1 and 2-3), 2 venous catheters will be placed, 1 for [18F]MNI-1054 administration 
and a second for blood PK collections.
An arterial catheter may be inserted, and arterial sampling done, for all 3 PET scans. Optionally 
(eg, if quantification methods are developed that do not require arterial sampling), some or all the 
PET scans may be performed without arterial sampling.
Each subject will receive an intravenous injection not exceeding 10 mCi of [18F]MNI-1054 over 
3 minutes using an infusion pump. Serial PET imaging will commence immediately following 
injection. Serial dynamic imaging (6 × 30-second, 4 × 1-minute, 4 × 2-minute PET frames, with 
the remainder comprising 5-minute PET frames) will be obtained over a total duration of up to 180 
minutes. 
If performed, arterial sampling (up to 5 mL blood per sample during the PET scan) will be 
obtained throughout the course of the imaging for radioactive metabolite analysis to determine the 
percent parent fraction of [18F]MNI-1054 in plasma. In addition, 3 samples (approximately 5 mL 
per sample) will be drawn before [18F]MNI-1054 injection for estimation of the free fraction (not 
bound to protein) of parent [18F]MNI-1054 in plasma. Blood samples will be analyzed by 
high-performance liquid chromatography at the study site. The arterial catheter may be inserted, 
and arterial sampling done, for all 3 PET scans. Optionally (eg, if quantification methods are 
developed that do not require arterial sampling), some or all the PET scans may be performed 
without arterial sampling.
If the critical procedures cannot be performed (eg, in the case of synthesis failure of 
[18F]MNI-1054 or PET scanner malfunction), the same subject will not be used for a repeat dose 
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and backup subject will receive that dose. However, a subject already dosed may, at the discretion 
of the investigators, be scanned later the same day (first postdose scan) or within the Days 2 to 3 
window (second postdose scan) if the technical issues are resolved in time (eg, resynthesis of 
[18F]MNI-1054).
9.2.11 AE Monitoring
PTE monitoring begins after signing of the informed consent form until [18F]MNI-1054 dose and 
AE monitoring begins after that. Changes in subject health status from the baseline assessment 
until study 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.
9.3
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Fasting is not required for safety labs (Sections 9.3.1, 9.3.2, and 9.3.3), but fasting status must be 
documented. Fasting is only required for the collection of Day 1 PK samples (Section 9.4).
It is anticipated that the total blood volume drawn, including PK samples (Section 9.4), will be
approximately 318 mL for each subject. 
9.3.1
Hematology
The hematology assessment will include the following tests:
Erythrocytes (red blood cells)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells) with absolute differential
9.3.2
Chemistry
The chemistry assessment will include the following tests:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatinine
Glucose
-glutamyl transferase
Sodium 
Potassium
Bilirubin (total); if above the ULN total bilirubin will be fractionated
Protein (total)
PT and PTT a
Serum FSH/LH/estradiol b
ALT: alanine aminotransferase; AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; LH: luteinizing 
hormone; PT: prothrombin time; PTT: partial thromboplastin time; ULN: upper limit of normal.
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a Test will be performed only at the screening visit.
b On Day 1, this test will be performed within 24 hours of TAK-418 dose.
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, -glutamyl transferase, and international 
normalized ratio) should be performed 48 to 72 hours after the abnormality was noted.
If ALT or AST remains elevated >3 times the ULN on these 2 consecutive occasions, the 
investigator must contact the medical monitor for consideration of additional testing, close 
monitoring, possible discontinuation of study drug, and discussion of the relevant subject details 
and possible alternative etiologies. The abnormality should be recorded as an AE.
Please refer to Section 7.5 for subject discontinuation criteria regarding abnormal LFT results and 
Section 10.2.8.4 for guidance on reporting abnormal LFT results.
9.3.3
Urinalysis
The urinalysis assessment will include the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cells/high-power field, white blood cells/high-power field, and casts.
9.3.4
Diagnostic Screening
9.3.4.1
Serum
The serum diagnostic screening assessment will include the following tests:
HIV
Hepatitis screen (HBsAg, HCV antibody)
HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus.
9.3.4.2
Alcohol Screen
A urine alcohol test will be performed as indicated in the Schedule of Study Procedures (Section 
3.0) and at the discretion of the investigator.
9.3.4.3
Urine
The urine drug screening assessment will include the following tests:
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Amphetamines
3,4-methylenedioxy-methamphetamine
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Tetrahydro cannabinoids
Phencyclidine
Cocaine/metabolites
Cotinine
9.3.4.4
Serum Human Chorionic Gonadotropin/Urine Dipstick
A urine dipstick or serum human chorionic gonadotropin (hCG) pregnancy test will be 
administered to women of childbearing potential (see Appendix D for definition) before any 
administration of study drug or PET scan, as indicated in the Schedule of Study Procedures 
(Section 3.0).
9.4
PK Samples
9.4.1
PK Evaluations
Samples for PK analysis will be collected at the time points stipulated in the schedule of 
procedures (Section 3.0). PK samples will be collected at pre-dose, approximately 0.5, 1, and 3 
hours after TAK-418 administration, immediately before and after the Day 1 PET scan, and within 
30 minutes before and within 30 minutes after the Day 2 (or Day 3) PET scan.
On Day 1 only, subjects must be fasting overnight for at least 8 hours before collection of the 
pre-dose PK sample and will continue to fast for an additional 4 hours after TAK-418 dosing, for a 
total of approximately 12 hours. PK samples will be collected pre-dose, approximately 0.5, 1, and 
3 hours after TAK-418 administration, and immediately before and after the Day 1 PET scan.
On Day 2 (or Day 3), PK samples will be collected within 30 minutes before and within 30 minutes 
after the PET scan. Fasting is not required on non-dosing days (Day 23 and at end of treatment).
Please refer to the laboratory manual for information on the collection, processing, and shipment 
of samples to the central laboratory.
The decision as to which collected samples will be assayed for evaluation of PK will be 
determined by the sponsor. If indicated, these samples may also be assayed and/or pooled to 
measure metabolites in an exploratory manner.
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Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary Specimen
Description of 
Intended Use
Sample Collection
Plasma sample for 
TAK-418 PK
Plasma
Pharmacokinetic 
measurements
Mandatory
9.4.2
PK Measurements
The PK parameters of TAK-418 will be determined from the concentration-time profiles for all 
evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be used in 
all computations involving sampling times.
The following PK parameters will be calculated from plasma concentrations of TAK-418 when 
feasible, unless otherwise specified:

Cmax.

AUCt.

AUC∞.
Additional PK parameters may be calculated as appropriate. A detailed PK analysis plan will be 
prepared before PK parameter computation.
9.4.2.1
Plasma for PK Measurements
Blood samples for PK analysis of TAK-418 will be collected into chilled blood collection tubes 
(vacutainer) containing the anticoagulant K2EDTA. 
The actual time of sample collection will be recorded on the source document and eCRF. Sampling 
time points may be adjusted based on the preliminary emerging concentration data collected from 
prior subject(s), but the total number of samples collected per subject should not exceed the 
planned number.
9.5
C-SSRS 
The C-SSRS will be completed at every visit, including screening, as indicated in the Schedule of 
Study Procedures (Section 3.0).
9.6
Confinement 
There will be 2 confinement periods. Subjects will be confined overnight before the baseline PET 
scan and again before the Day 1 PET scan and will leave after completion of study-related 
procedures for Day 2-3. At the discretion of the investigator, subjects may be requested to remain 
at the clinical site 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 study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters may be considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
a study procedure. However, if the subject experiences a worsening or complication of such a 
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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 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.
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
All cases of overdose (with or without associated AEs) will be documented in 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.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.2.5 Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment
Drug withdrawn or study procedures stopped: a study medication or [18F]MNI-1054 PET 
scans stopped due to the particular AE.

Dose not changed: the particular AE did not require stopping a study medication or study
procedures.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a study medication or study procedure was stopped for a reason other than the 
particular AE (eg, the study has been terminated, the subject died, dosing with study 
medication had not yet started, or dosing with study medication was already stopped before the 
onset of the AE).

Dose reduced: the dose was reduced due to the particular AE.

Dose increased: the dose was increased due to the particular AE.
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
Drug interrupted: the dose was interrupted due to the particular AE.
10.2.7 Outcome 

Recovered/resolved: subject returned to first assessment status with respect to the AE.

Recovering/resolving: the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to the baseline value; the subject died from a cause other than 
the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved: there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/resolved with sequelae: the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal: an AE that is considered as the cause of death.

Unknown: the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
PTE monitoring begins after signing of the informed consent form until [18F]MNI-1054 dose;
subsequently, collection of AEs (ie, AEs, SAEs, special interest AEs, and abnormal LFTs) begins. 
Routine collection of AEs will continue through the Day 14 (±4) safety follow-up safety visit. For 
subjects who discontinue before the administration of study medication, AEs will be followed 
until the subject discontinues study participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE 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 until 
there is a satisfactory explanation for the change. Nonserious AEs that begin before the first 
exposure to investigational product, related or unrelated to the study procedure, need not be 
followed up for the purposes of the protocol.
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All subjects experiencing AEs, whether considered associated with the use of the study 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 end date and time.

Pattern of AE (frequency).

Severity/intensity.

Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
The paper SAE forms should be submitted via fax (preferred method). In case of fax, site 
personnel need to confirm successful transmission of all pages and include an email address on the 
fax cover sheet so that an acknowledgment of receipt (AOR) can be returned via email within 1 
business day.
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Email submission of SAE forms with a PDF attachment should only be used in the case where fax 
is not possible within 24 hours of receiving the event. In case of email, site personnel need to 
confirm successful transmission by awaiting an AOR via email within 1 business day. 
If SAE forms are submitted via fax or email, a confirmation of receipt will be sent to the sites 
indicating that the SAE has been received. It is the site’s responsibility to ensure an AOR has been 
obtained when email or fax are used. If AOR is not received within 1 business day, the site
investigator should escalate it immediately to their clinical research associate.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 times the ULN on 2 consecutive occasions, 
the abnormality should be recorded as an AE. In addition, an LFT increase eCRF must be 
completed to provide additional information on relevant recent history, risk factors, clinical signs 
and symptoms, and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 times the ULN and total bilirubin >2 times the ULN 
for which an alternative etiology has not been identified, the event should be recorded as an SAE 
and reported per Section 10.2.8.3. The investigator must contact the medical monitor for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
hepatitis A or B or other acute liver disease. Follow-up laboratory tests as described in Section 9.3
must also be performed. In addition, the relevant eCRF(s) must be completed and transmitted with 
the Takeda SAE form (per Section 10.2.9). 
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
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and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety analysis set will consist of all subjects who are enrolled and receive an investigational 
drug ([18F]MNI-1054 or TAK-418) as part of this study. Subjects in this analysis set will be used 
for demographic, baseline characteristics, and safety summaries.
11.1.1.2 PK Set
The PK set will consist of all subjects who receive study drug (TAK-418) and have at least 
1 measurable plasma concentration of TAK-418.
11.1.1.3 PET Set
The PET target occupancy set will consist of all subjects who receive study drug (TAK-418) and 
have a technically adequate baseline PET scan and at least 1 technically adequate post–TAK-418 
dose PET scan. 
If any subjects are found to have incomplete data, a decision will be made on a case-by-case basis 
as to their inclusion in the analysis but will be presented in the subject listings.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous demographic variables and baseline characteristics variables (eg, age, height, weight, 
and BMI) for TAK-418 dose level, and overall. The number and percentage of subjects in each 
class of the categorical demographic variables and baseline characteristics variables (eg, sex, 
ethnicity, race, smoking status) will also be tabulated. Individual subject demographic and 
baseline characteristics data will be listed. 
11.1.3 PK Analysis
The concentrations of TAK-418 in plasma will be summarized by dose level over each scheduled 
sampling time point (each of the 2 post–TAK-418 dose PET scans) using descriptive statistics. 
Individual plasma concentration data versus time will be presented in a data listing.
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PK parameters of TAK-418 will be summarized using descriptive statistics.
A more detailed analysis will be presented in the SAP.
11.1.4 PET Analysis 
11.1.4.1 PET Enzyme Occupancy and Brain Kinetics for TAK-418
Dynamic uptake and washout of [18F]MNI-1054 will be evaluated. The MRI and PET images will 
be coaligned for anatomy-based definition of ROIs for analysis of regional [18F]MNI-1054 
binding. Analysis will focus on the decay-corrected time activity data in brain regions of high 
uptake (eg, cerebellum). Imaging data will be analyzed with modeling approaches appropriate for 
irreversible binding that will be informed by the ongoing FIH validation study TAK-418-0002 
(I
) (eg, irreversible 2-tissue compartment model). The primary imaging outcome 
measure for [18F]MNI-1054 is expected to be a parameter from such a model. 
LSD1 enzyme occupancy in ROI after a single dose of TAK-418 will be obtained from the model 
binding parameter (eg, inhibitory constant [Ki]) for the first postdose scan as follows:
Occupancy (1st postdose) = (Ki [baseline] - Ki [1st postdose]) / Ki (baseline)
The second postdose scan will be used to assess the rate of enzyme turnover in humans. The data 
will be analyzed like the first postdose scan to calculate an apparent occupancy value:
Apparent occupancy (2nd postdose) = (Ki [baseline] - Ki [2nd postdose]) / Ki (baseline).
Descriptive summaries for modeled binding parameters and target occupancy will be provided. 
11.1.4.2 Relationship of PET Enzyme Occupancy to Plasma TAK-418 Levels
Modeling will be performed to assess the relationship between target occupancy and TAK-418 
plasma exposure. The relationship between LSD1 enzyme occupancy and TAK-418 exposure 
measures will be graphically explored. If appropriate, linear or nonlinear models may be used to 
quantify this information. The TAK-418 plasma exposure and dose required for LSD1 occupancy 
of at least 90% will be established.
11.1.5 Safety Analysis
AEs will be presented in listings, and TEAEs will be summarized.
Individual results of laboratory tests (hematology, serum chemistry, and urinalysis), vital signs and 
ECG parameters will be listed. Baseline, postdose, and change from baseline to postdose 
laboratory data, vital signs, and ECG parameters will be summarized. All safety summaries will be 
performed for [18F]MNI-1054 and each TAK-418 dose level.
Physical examination findings, visual examinations, and suicidal assessments will be presented in 
data listings.
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
No formal statistical sample size calculation was performed. The sample size of up to 5 dose levels 
and up to 6 subjects per dose level within the limit of 16 total evaluable subjects is based on 
precedents of other PET occupancy studies and is considered to be sufficient for evaluation of 
target occupancy, duration of occupancy, safety, tolerability, and the relationship between 
occupancy and TAK-418 plasma exposure.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator guarantees access for quality assurance auditors 
to all study documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council for Harmonisation (ICH) Harmonised Tripartite Guideline 
for GCP. Each investigator will conduct the study according to applicable local or regional 
regulatory requirements and align his or her conduct in accordance with the “Responsibilities of 
the Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through 
the protocol and through appendices containing requirements for informed consent and 
investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor 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 study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a pharmacogenomic sample for DNA and 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 study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
13.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda policy/standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
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 study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
PPD
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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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14.1.3 List of Abbreviations
%ID
Percent injected dose
AE
adverse event
ALT
alanine aminotransferase
AOR
acknowledgment of receipt
ASD
autism spectrum disorder
AST
aspartate aminotransferase
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUC∞
area under the concentration-time curve from time 0 to infinity
AUCt
area under the concentration-time curve from time 0 to time t
BMI
body mass index
CFR
Code of Federal Regulations
Cmax
maximum observed concentration
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
ED
effective dose
FAD
flavin adenine dinucleotide
FDA
Food and Drug Administration
F-FAD
formylated flavin adenine dinucleotide
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
H3K4
lysine in position 4 of type 3 histone
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
ICH
International Council for Harmonisation
ICRP
International Commission on Radiological Protection
IEC
independent ethics committee
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
Ki
inhibitory constant
LFT
liver function test
LSD1
lysine-specific demethylase 1A, also known as KDM1A
MRD
multiple-rising dose 
MRI
magnetic resonance imaging
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NOAEL
no-observed-adverse-event-level
PD
pharmacodynamic(s)
PET
positron emission tomography
PK
pharmacokinetic(s)
PTE
pretreatment event
QD
once daily
QTcF
QT interval with Fridericia correction method
rem
Roentgen equivalent man
ROI
regions of interest
SAE
serious adverse event
SAP
statistical analysis plan 
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
TAC
time-activity curve
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities. Drugs will be coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who receives any investigational drug 
([18F]MNI-1054 or TAK-418) as part of this study.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms),
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
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enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the clinical study site agreement 
between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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16.0
REFERENCES
1. 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. 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.
3. 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).
4. Rudolph T, Beuch S, Reuter G. Lysine-specific histone demethylase LSD1 and the dynamic 
control of chromatin. Biol Chem 2013;394(8):1019-28.
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17.0
APPENDICES
CCI
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CCI
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Appendix B
Elements of the Subject Informed Consent
CCI
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CCI
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roperty of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
the Applicable Terms of Use


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Appendix C
Investigator Consent to the Use of Personal Information
CCI
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Appendix D
Pregnancy and Contraception
CCI
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CCI
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CCI
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For Non-Commercial Use Only and Subject to the Applicable Terms of Us


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Appendix E
Detailed Description of Amendments to Text
CCI
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CCI
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CCI
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PPD
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A PHASE 1, OPEN-LABEL, POSITRON EMISSON TOMOGRAPHY (PET) STUDY WITH 
[18F]MNI-1054 TO DETERMINE LYSINE-SPECIFIC DEMETHYLASE 1A 
(LSD1) BRAIN ENZYME OCCUPANCY OF TAK-418 AFTER SINGLE-DOSE ORAL 
ADMINISTRATION IN HEALTHY SUBJECTS
NCT Number: NCT04202497
SAP Approve Date: 19 February 2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-418_0004
A PHASE 1, OPEN-LABEL, POSITRON EMISSON TOMOGRAPHY (PET) STUDY 
WITH [18F]MNI-1054 TO DETERMINE LYSINE-SPECIFIC DEMETHYLASE 1A 
(LSD1) BRAIN ENZYME OCCUPANCY OF TAK-418 AFTER SINGLE-DOSE ORAL 
ADMINISTRATION IN HEALTHY SUBJECTS
PHASE 1 TAK-418 SINGLE DOSE PET TARGET OCCUPANCY STUDY
Version: Final
Date: 19 February 2020
Prepared by:
PPD
Property of Takeda: Fo
Property of
nly and Subject to the Applicable Terms of Use
Y (PET
Y (PE
METH
METH
SINGL
NG
ECTS
CTS
GET OC
ET O
Final
inal
Februar
Februar
Commercial Use O
For Non-Co


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Statistical Analysis Plan
19 February 2020
2.0
APPROVAL SIGNATURES
Study Title:
A Phase 1, Open-Label, Positron Emission Tomography (PET) Study 
with [18F]MNI-1054 to Determine Lysine-specific demethylase 1A 
(LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral 
Administration in Healthy Subjects
Takeda Approval:
Date
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
udy 
dy 
1A 
1A 
Dose O
ose O
ly and Subject to t


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Statistical Analysis Plan
19 February 2020
3.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
APPROVAL SIGNATURES...........................................................................................2
3.0
TABLE OF CONTENTS.................................................................................................3
4.0
LIST OF ABBREVIATIONS..........................................................................................5
5.0
OBJECTIVES .................................................................................................................6
5.1
Primary Objective......................................................................................................6
5.2
Secondary Objectives.................................................................................................6
5.3
Study Design .............................................................................................................6
5.4
Dose Selection...........................................................................................................6
6.0
ANALYSIS ENDPOINTS...............................................................................................8
6.1
Primary endpoints......................................................................................................8
6.2
Secondary endpoints..................................................................................................8
7.0
DETERMINATION OF SAMPLE SIZE.........................................................................9
8.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
8.1
General Principles....................................................................................................10
8.1.1
Missing Data......................................................................................................10
8.1.2
Derived Datasets and Variables..........................................................................10
8.1.3
Definition of Study Days and Baseline...............................................................10
8.2
Analysis Sets ...........................................................................................................11
8.3
Disposition of Subjects ............................................................................................11
8.4
Demographic and Baseline Characteristics...............................................................11
8.5
Medical History and Concurrent Medical Conditions...............................................11
8.6
Medication History and Concomitant Medications...................................................12
8.7
Study Drug Exposure and Compliance.....................................................................12
8.8
Efficacy Analysis.....................................................................................................12
8.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................12
8.9.1
Analysis of Pharmacokinetic Parameters............................................................13
8.9.2
Pharmacodynamic Analysis ...............................................................................13
8.10
Other Outcomes.......................................................................................................15
8.11
Safety Analysis........................................................................................................15
8.11.1 Adverse Events ..................................................................................................15
8.11.2 Clinical Laboratory Evaluations .........................................................................16
8.11.3 Vital Signs .........................................................................................................16
8.11.4 Physical Examinations .......................................................................................17
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8.11.5 12-Lead ECGs ...................................................................................................17
8.11.6 Other Observations Related to Safety.................................................................17
8.12
Interim Analysis ......................................................................................................17
8.13
Changes in the Statistical Analysis Plan...................................................................17
9.0
REFERENCES..............................................................................................................18
LIST OF IN-TEXT FIGURES
Figure 5.a
Schematic of Study Design ..................................................................................7
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................19
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................21
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms.........................22
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4.0
LIST OF ABBREVIATIONS
LSD1
lysine-specific demethylase 1A, also known as KDM1A
ADaM
Analysis Data Model
AE
adverse event
AUC
area under the plasma concentration-time curve
AUCscan
area under the plasma concentration-time curve for TAK-418 during each PET scan
AUECt
area under the effect-time curve from time 0 to last sampling time point
BLQ
below the limit of quantification
BMI
body mass index
Cave(scan)
average plasma concentration during each PET scan period following TAK-418 dosing
Cmax
maximum observed plasma concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
CTS
Clinical and Translational Science
DLRM
dose level review meeting
ECG
electrocardiogram
Emax
maximum observed effect
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
PT
preferred term
ROI
region of interest
SAE
serious adverse event
SOC
system organ class
SRD
single rising dose
TEAE
treatment-emergent adverse event
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5.0
OBJECTIVES
5.1
Primary Objective
The primary objective of the study is to determine the relationship between the occupancy of 
LSD-1 by TAK-418, following administration of a single oral dose, and the TAK-418 plasma 
concentration in healthy subjects using [18F]MNI-1054 PET imaging.
5.2
Secondary Objectives
The secondary objective(s) of the study are:
1. To estimate the LSD1 enzyme turnover rate. 
2. To acquire safety data following administration of a single oral dose of TAK-418. 
3. To acquire safety data following injection of [18F]MNI-1054.
5.3
Study Design
This is a PET imaging study with a single oral dose of TAK-418 and up to 3 administrations of 
intravenous microdoses of the LSD1 PET radiotracer [18F]MNI-1054. The primary objective to 
determine brain LSD1 enzyme occupancy and the relationship of occupancy to TAK-418 dose 
and plasma exposure after single oral dosing of TAK-418 in healthy subjects.
A maximum of 16 evaluable male or female subjects are planned to participate in this study. 
Within that total number of subjects, up to 5 dose levels may be evaluated with up to 6 subjects 
per dose level, although typically there will be 2 to 3 subjects per dose level. 
Each subject will receive up to 3 dynamic [18F]MNI-1054 PET scans (up to 180 minutes with 
intermittent breaks) to assess enzyme occupancy and turnover in humans (1 baseline scan and 
2 scans after a single dose of TAK-418). It is anticipated that there will be at least a 3-night stay 
at the overnight confinement unit. Plasma samples will be taken at prescribed intervals to assess 
the peripheral pharmacokinetics (PK) of TAK-418. A brain magnetic resonance imaging (MRI) 
scan without gadolinium contrast will be performed as part of the screening visit and used to 
delineate the anatomical regions of interest (ROIs) for individual PET images. 
This study will have an adaptive design such that the TAK-418 dose and timing of postdose 
imaging for subsequent subjects will be based on the data from the previous subjects and 
determined with input from the sponsor and the clinical site team. For the first 2 subjects, the 
postdose PET scans will be performed at approximately 6 and 26.5 hours after TAK-418 dosing. 
Flexibility of approximately ±1 hour is permissible in scan timing. Deviations of greater than this 
(eg, due to logistical issues such as radiotracer production delays) are permissible if agreed with 
the sponsor.
5.4
Dose Selection
The starting dose in this study will be 1.5 mg. Dose levels for subsequent subjects may be lower 
or higher than this and will be selected based on review of the imaging and PK data available at 
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Statistical Analysis Plan
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that point to enable an accurate determination of the exposure-occupancy relationship. Only 
doses lower than or equal to those that have been tested in the phase 1 safety studies and 
determined to be safe and well-tolerated will be assessed in this study. The maximum dose of 
TAK-418 evaluated in phase 1 safety study was 160 mg.
Figure 5.a
Schematic of Study Design
PET: positron emission tomography.
a Baseline and Day 1 visit may occur over 1 or 2 calendar days. 
A schedule of assessments and their timing during the study is listed in Protocol TAK-418-0004 
[1].
Screening 
Baseline PET Scan with 18F]MNI-1054 a
Day 1 PET scan with [18F]MNI-1054 and 
TAK-418 oral dosing a
Day 2-3 PET scan  with [18F]MNI-1054
Subject safety follow-up visits Day 14 (4)
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6.0
ANALYSIS ENDPOINTS
6.1
Primary endpoints
The primary endpoints of the study are:

Quantitative estimates of binding of [18F]MNI-1054 based on appropriate PET radiotracer 
kinetic models (eg, Ki from irreversible 2-tissue compartmental model). 

Percent enzyme occupancy calculated from quantitative estimates of binding (= 100 × 
[baseline – postdose]/baseline).

Plasma PK parameters including, if feasible, but not limited to:
–
Cmax.
–
Area under the concentration-time curve from time 0 to time t (AUCt).
–
AUC∞.
6.2
Secondary endpoints
Secondary endpoints include: 
1. The relationship between percent receptor occupancy calculated from first and second 
postdose scans. 
2. Summary of safety observations, including but not limited to:
–
Number and percentage of participants with 1 or more AEs.
–
Number and percentage of participants with 1 or more SAEs.
–
Number and percentage of participants with clinically defined abnormal laboratory 
values.
–
Number and percentage of participants with clinically defined abnormal vital signs.
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7.0
DETERMINATION OF SAMPLE SIZE
No formal statistical sample size calculation was performed. The sample size of up to 5 dose 
levels and up to 6 subjects per dose level within the limit of 16 total evaluable subjects is based 
on precedents of other PET occupancy studies and is considered to be sufficient for evaluation of 
target occupancy, duration of occupancy, safety, tolerability, and the relationship between 
occupancy and TAK-418 plasma exposure.
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8.0
METHODS OF ANALYSIS AND PRESENTATION
8.1
General Principles
All study-related raw data, including derived data, will be presented in data listings. Continuous 
data will be summarized using: number of subjects (N), mean, SD, median, minimum, and 
maximum, where appropriate. Where indicated, 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 for each category where appropriate.
8.1.1
Missing Data
There will be no imputation of incomplete or missing data. Decisions regarding inclusion or 
exclusion of data from an analysis for subjects who are noncompliant with the dose schedule, or
who have incomplete data, will be made on a case-by-case basis, but the data will be presented in 
data listings regardless. 
Plasma concentrations that are below the limit of quantification (BLQ) will be given a value of 0
in the summarized concentration values and derived PK parameters. These values will be flagged 
in the data listings, and deviations from this convention may be considered on a case-by-case 
basis as deemed appropriate.
8.1.2
Derived Datasets and Variables
Derived datasets will be generated according to CDISC guidance documents: Analysis Data 
Model (ADaM) Implementation Guide, Version 1.0 (17 Dec 2009); ADaM Data Structure for 
Adverse Event Analysis, Version 1.0 (10 May 2012).
8.1.3
Definition of Study Days and Baseline
For all safety endpoints, Baseline will be defined as the last observation before the first dose of 
any study drug unless otherwise specified. Study day prior to the first dose of treatment will be 
calculated as: date of assessment/event – date of treatment; study day on or after the date of first 
dose of treatment will be calculated as: date of assessment/event – date of treatment + 1.
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8.2
Analysis Sets
Safety Set
The Safety Analysis Set consists of all enrolled subjects who 
receive [18F]MNI-1054 or TAK-418 as part of this study. 
Subjects in this analysis set will be used for demographic, 
baseline characteristics, and safety summaries.
Pharmacokinetic (PK) Set
The PK Analysis Set will consist of all subjects who receive 
study drug (TAK-418) and have at least 1 measurable plasma 
concentration for TAK-418.
Pharmacodynamic (PD)
Set
The PD Analysis Set will consist of all subjects who receive 
study drug (TAK-418) and have at least 1 analyzable PET scan
following TAK-418 administration.
If any subjects are found with incomplete data, a decision will be made on a case-by-case basis 
as to their inclusion in the analysis but will be presented in the subject listings.
8.3
Disposition of Subjects
The number and percentage of subjects who complete study drug and study visits, and those who 
prematurely discontinue study drug and study visits will be summarized by Baseline 
[18F]MNI-1054, each TAK-418 dose level, and TAK-418 overall for subjects in the Safety Set. 
In addition, the number and percentage of subjects will be summarized for reasons of study drug 
discontinuation and study visits by Baseline [18F]MNI-1054, each TAK-418 dose level, and 
TAK-418 overall. Subjects’ study completion data, including reasons for premature termination, 
will be listed.
The number and percentage of subjects comprising each analysis set will be summarized by 
Baseline [18F]MNI-1054, each TAK-418 dose level, and TAK-418 overall. 
8.4
Demographic and Baseline Characteristics
Demographic characteristics will be summarized and listed. Summary statistics (N, mean, SD, 
median, minimum, and maximum) will be generated for continuous variables (eg, age, height, 
weight and BMI) for Baseline [18F]MNI-1054, each TAK-418 dose level, and TAK-418 overall, 
and the number and percentage of subjects within each category will be presented for categorical 
variables (eg, gender, race, and ethnicity). 
Individual demographic characteristics, date of informed consent, any available safety data will 
also be presented in the data listings.
8.5
Medical History and Concurrent Medical Conditions
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to informed consent. Concurrent medical conditions are those 
significant ongoing conditions or diseases that are present at signing of informed consent.
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Statistical Analysis Plan
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Medical history and concurrent medical condition verbatim reported terms will be coded using
the Medical Dictionary for Regulatory Activities (MedDRA). No summary statistics for medical
history and concurrent medical conditions will be provided. All medical history and concurrent
medical conditions will be listed.
8.6
Medication History and Concomitant Medications
Medication history information obtained includes any medication stopped at or within 30 days
prior to signing of informed consent. Medications used from signing of informed consent 
through the end of study will be considered as concomitant medications.
Medication history and concomitant medications will be coded using World Health Organization
Drug Dictionary (WHO Drug). No summary statistics for medication history and concomitant
medications will be provided. All medication history and concomitant medications data will be
listed.
8.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing. No summary 
statistics for the extent of exposure to study drug or compliance calculations will be performed 
for this study.
8.8
Efficacy Analysis
Not applicable.
8.9
Pharmacokinetic/Pharmacodynamic Analysis
Serial blood samples for determination of TAK-418 will be collected at approximately 0.5, 1, 
and 3 hours after TAK-418 administration, immediately before and after the Day 1 PET scan, 
and within 30 minutes before and within 30 minutes after the Day 2 (or Day 3) PET scan. 
Analyte
Matrix
Day
Scheduled Time (hours)
TAK-418
Plasma
1
At approximately 0.5, 1, and 3 hours after TAK-418 administration, 
immediately before and immediately after the Day 1 PET scan
TAK-418
Plasma
2 (or 3)
within 30 minutes before and within 30 minutes after the follow-up PET 
scan
The plasma concentration of TAK-418 will be summarized by TAK-418 dose level and PET 
scan period over each scheduled sampling time using descriptive statistics (N, mean, SD, %CV, 
median, minimum, and maximum) where appropriate. 
Individual plasma concentration data versus time will be presented in a data listing.
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8.9.1
Analysis of Pharmacokinetic Parameters
The PK parameters of plasma TAK-418 will be determined from the concentration-time profiles 
for all evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be 
used in all computations. The following PK parameters will be calculated if feasible.
Symbol/Term
Definition
Plasma
AUCt
Area under the plasma concentration-time curve from time 0 to 
Cmax 
Maximum observed plasma concentration
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity
Cavg
Average plasma concentrations
Cavg(scan)
Average plasma concentration for TAK-418 during PET scan period
AUC(scan)
AUC of TAK-418 during the PET scan period
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
Descriptive statistics (N, mean, SD, %CV, median, minimum, and maximum) will be used to 
summarize the plasma PK parameters for TAK-418 by TAK-418 dose level and PET scan period
where appropriate. 
All plasma PK parameters will be presented in a data listing. 
Additional parameters may be calculated if necessary. 
8.9.2
Pharmacodynamic Analysis
LSD1 binding parameter (Ki) data obtained from each PET scan before (Day -1) and after 
TAK-418 dosing (Day 1, and Day 2 or 3) will be summarized by relative time to the TAK-418 
dosing, TAK-418 dose level and brain regions of interest using descriptive statistics (N, mean, 
SD, CV%, minimum, maximum, median) where appropriate.
Individual LSD1 Ki values will be presented in a data listing.
LSD1 occupancy data obtained after TAK-418 dosing (Day 1, and Day 2 or 3) will be 
summarized by relative time to the TAK-418 dosing, TAK-418 dose level and brain regions of 
interest using descriptive statistics (N, mean, SD, CV%, minimum, maximum, median) where 
appropriate. 
Individual LSD1 occupancy results will be presented in a data listing.
The relationships between LSD1 occupancy and TAK-418 dose level and PK parameters will be 
evaluated using scatter plots and Emax models for:
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Statistical Analysis Plan
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
LSD1 occupancy (%) vs. TAK-418 dose, AUC, Cavg(scan) and Cmax for the Day 1 PET 
scans.

LSD1 occupancy (%) vs. TAK-418 dose, AUC, Cavg(scan) and Cmax for the Day 2 or 3 (if 
acquired) PET scans, if appropriate to be combined.
The following  model will be used:
 = 
 × 

 + 
,
where:
E=Observed LSD1 occupancy (%) in a brain region of interest;
Exposure = Observed TAK-418 dose, TAK-418 AUC, or TAK-418 Cavg(scan);
=Maximum LSD1 Occupancy in the brain region of interest;
=Exposure or TAK-418 dose level which related to the 50% of the Maximum LSD1
occupancy in the brain region of interest.
When modeling Day 1 and Day 2 data separately,  and will be estimated as fixed
parameters. When modeling Day 1 and Day 2 together, random effect model will be explored.
Model parameter estimates (and ) and their 95% confidence intervals will be provided.
Results from a simple  model in which  set to be 100% , will also be presented. 
Other models will also be explored if deemed appropriate.
Enzyme turnover will be quantified for each subject by modeling the recovery in PET signal 
between Day 2 or 3 and Day 1, from to the relationship.
 =  + ( −)1 −( ! ") #$
⁄
&
where: 
S0 = the PET signal (e.g., Ki) in the region of interest at baseline
S1 = the PET signal (e.g., Ki) in the region of interest from the Day 1 scan
S2 = the PET signal (e.g., Ki) in the region of interest from the Day 2 or 3 scan
t1 = the time in hours post-TAK-418-dose of the Day 1 scan
t2 = the time in hours post-TAK-418-dose of the Day 2 or 3 scan
TR = the turnover rate (half-life) in hours. 
Accordingly, the enzyme turnover rate (half-life) can be estimated for each subject as:
'( = −
( −)
ln + −
 −,
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Statistical Analysis Plan
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Other models will also be explored if deemed appropriate.
Individual turnover rates will be presented in a data listing and graphed in scatterplots vs. 
TAK-418 dose, exposure measures and Day 1 occupancy. If appropriate, enzyme turnover rates 
will be summarized using descriptive statistics (N, mean, SD, CV%, minimum, maximum, 
median).
8.10
Other Outcomes
PET data collected on the eCRF will be included in listings.
The imaging analysis will be conducted by an outside vendor and are not included in this SAP.
8.11
Safety Analysis
The safety endpoints including AEs, clinical laboratory parameters, vital sign parameters, 
12-lead ECG parameters will be summarized and described in data listings. The Safety Set will 
be used for all summaries of safety parameters. Physical examination and C-SSRS will be 
described in data listings.
8.11.1 Adverse Events
A treatment-emergent AE (TEAE) is defined as an AE or a SAE that occurs or gets worse after 
receiving the first dose of study drug (either Baseline [18F]MNI-1054 or TAK-418), and within 
30 days (onset date – last date of dose + 1 ≤30) after the last dose of study drug. A TEAE may 
also be a pretreatment adverse event 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. Adverse events 
data with onset occurring more than 30 days after last dose of study drug (AE start date – last 
dose date >30) will be listed, but not included in the summary tables. 
Adverse event verbatim reported terms will be coded by system organ class (SOC), high-level 
term and preferred term (PT) using MedDRA.
The TEAE summary tables will present the number and percentages of subjects experiencing at 
least 1 TEAE by SOC and PT and will be tabulated for Baseline [18F]MNI-1054, each TAK-418
dose level, and TAK-418 overall. TEAEs tabulated under Baseline [18F]MNI-1054 are defined as 
TEAEs starting after first [18F]MNI-1054 injection during Baseline Imagining Period and prior to 
TAK-418 dosing whereas TEAEs tabulated under TAK-418 dose levels are defined as TEAEs 
starting after TAK-418 dosing.
The following is a list of AE summary tables to be generated: 

Overview of TEAEs.

TEAEs by SOC and PT at subject and event level.

Subject Mappings for TEAEs.

TEAEs by PT.
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Statistical Analysis Plan
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
Non-Serious TEAEs by PT.

Relationship of TEAEs to Study Drug by SOC and PT.

Drug-Related TEAEs by SOC and PT.

Intensity of TEAEs by SOC and PT.

Intensity of Drug-Related TEAEs by SOC and PT.

Pretreatment Events by SOC and PT.
Additional AE summary tables may be added as appropriate. 
A subject with 2 or more different AEs within the same level of MedDRA term and regimen will 
be counted only once in that level using the most extreme intensity for the intensity tables, and 
relationship to study drug for the causality tables.
Data listings will be provided for all AEs (including pretreatment events for enrolled subjects),
and for AEs leading to study drug discontinuation and leading to study visit discontinuation, 
SAEs, and AEs resulting in death.
8.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include clinical chemistry, hematology, and urinalysis. The 
samples for these tests will be collected following a minimum 8-hour overnight fast (for details 
of hematology, chemistry and urinalysis assessments). For visits that include PET scans, labs are 
to be performed within approximately 1 hour after each PET scan.
Individual results for hematology and chemistry laboratory tests will be evaluated against the 
Takeda predefined laboratory MAV criteria (Appendix A) using the result and criteria in SI 
units. All subjects with at least 1 post dose laboratory result that meet the MAV criteria will be 
presented in a data listing. The number and percentage of subjects with at least 1 postdose 
markedly abnormal laboratory test result will also be summarized for Baseline [18F]MNI-1054 
and each TAK-418 dose level. Subjects who meet the MAV criteria will be mapped to their 
respective qualifying laboratory result. All post dose clinical lab MAV results, including 
scheduled and unscheduled measurements will be included in the MAV summaries. 
All clinical laboratory data will be presented in both SI and conventional units in the listings.
8.11.3 Vital Signs
Vital signs will include oral temperature, pulse rate, respiratory rate, and systolic and diastolic 
blood pressure. These vital signs will be obtained 1 hour before each [18F]MNI-1054 injection, 
within approximately 1 hour after each PET scan, within approximately 1 hour before TAK-418 
administration, at approximately 1, 2, and 24 hours after TAK-418 administration.
All individual vital signs that meet Takeda’s predefined criteria for MAVs (Appendix B) will be 
listed. The number and percentage of subjects with at least 1 postdose markedly abnormal vital 
sign measurement will be summarized for Baseline [18F]MNI-1054 and each TAK-418 dose 
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Statistical Analysis Plan
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level. Subjects who meet the MAV criteria will be mapped to their respective qualifying vital 
sign result. All post dose MAV vital signs, including both scheduled and unscheduled 
measurements, will be included in the MAV summaries.
Individual subject vital signs will be presented in data listings. 
8.11.4 Physical Examinations
Physical examination is performed at Screening, Check-in (Day -15 to Day-2), Baseline PET 
Scan (Day-14 to Day -1), Day 1, Study Exit (Day 3) or Early Termination and Follow-up 
(Day 14 ±4).
The physical examination findings will be presented in data listings. No summary tables will be 
provided.
8.11.5 12-Lead ECGs
ECG measurements include heart rate, PR interval, QRS interval, QT interval, QTcF interval, 
and the interpretation of the ECG profile by the principal investigator. The samples for these 
tests are collected at the following timepoints, at 1 hour before each [18F]MNI-1054 injection, 
within approximately 3 hours after each PET scan, within approximately 1 hour before TAK-418 
administration, at approximately 1, 2, and 24 hours after TAK-418 administration. The predose 
ECG will obtained within approximately 1 hour before study drug dosing. This measurement 
will be used as the baseline assessment.
All individual ECGs that meet Takeda’s predefined criteria for MAV (Appendix B) will be 
listed. The number and percentage of subjects with at least 1postdose markedly abnormal ECG 
measurement will be summarized for Baseline [18F]MNI-1054 and each TAK-418 dose level. 
Subjects who meet the MAV criteria will be mapped to their respective qualifying ECG result. 
All post dose MAV ECGs, including both scheduled and unscheduled measurements, will be 
included in the MAV summaries.
Individual subject ECGs will be presented in data listings. 
8.11.6 Other Observations Related to Safety
All results for the neurological monitoring and the C-SSRS will be listed.
8.12
Interim Analysis
Not applicable.
8.13
Changes in the Statistical Analysis Plan 
Any changes/modifications of the statistical analyses outlined in this SAP, will be presented and 
justified in the relevant section of the CSR.
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9.0
REFERENCES
1. Protocol: A Phase 1, Open-label, Positron Emission Tomography Study With [18F]MNI-1054 
to Determine Lysine-Specific Demethylase 1A Brain Enzyme Occupancy of TAK-418 After 
Single-Dose Oral Administration in Healthy Subjects. 27 September 2019.
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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
CCI
Use
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CCI
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cable Terms of U


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CCI
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Applicable Terms of Us


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CCI
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and Subject to the Applicable Terms of Us


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