Clinical trial NCT03501069
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-05-30; Completion date: 2018-12-26
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to characterize safety and tolerability of TAK-418 in non-Japanese and Japanese healthy female participants when administered at single or multiple (once daily \[QD\]) oral doses.

Detailed description:
The drug being tested in this study is called TAK-418. This study will assess the safety, tolerability, PK and PD of single and multiple rising doses of TAK-418 in healthy Japanese or non-Japanese females.

The study will enroll approximately 48 participants in 6 cohorts and each cohort will have 8 participants. The study will include 2 parts: single rising dose (SRD) in Cohort 1 and multiple rising dose (MRD) in Cohorts 2 to 6. Cohort 3 will include cerebrospinal fluid (CSF) collection. Participants will be randomly assigned (by chance, like flipping a coin) to one of the 6 cohorts.

This two-center trial will be conducted in the United States. The overall time to participate in Cohort 1 of this study is approximately 105 days and 98 days in Cohort 2. Participants will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-418 120 milligram (mg) or TAK-418 matching placebo, capsule, orally, once on Day 1 of Period A followed by a minimum of 14 days of washout period, followed by TAK-418 160 mg or TAK-418 matching placebo, capsule, orally, once on Day 1 of Period B. The actual TAK-418 dose for Period B will be determined based on safety, tolerability, and PK data available from the previous dose in Period A. arm 2: TAK-418 20 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. arm 3: TAK-418 40 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 3 will be determined based on safety, tolerability, and PK data available from the previous doses. arm 4: TAK-418 60 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 4 will be determined based on safety, tolerability, and PK data available from the previous doses. arm 5: TAK-418 20 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 5 will be determined based on safety, tolerability, and PK data available from the previous doses. arm 6: TAK-418 40 mg or TAK-418 matching placebo, capsule, orally, once daily for 10 days. The actual TAK-418 dose for Cohort 6 will be determined based on safety, tolerability, and PK data available from the previous doses.
Interventions: intervention 1: TAK-418 intervention 2: TAK-418 Matching Placebo
Intervention descriptions: intervention 1: TAK-418 capsules. intervention 2: TAK-418 matching placebo capsules.

Protocol documents:
Prot_000.pdf: 



Title: A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in 
Healthy Female Subjects. 
NCT Number: NCT03501069
Protocol Approve Date: 20 March 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in 
Healthy Female Subjects.
Study Identifier:
TAK-418-1003
Compound:
TAK-418
Date:
20 March 2018
Version/Amendment 
Number:
Original Protocol
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418
Study ID TAK-418-1003
Page 2 of 84
Protocol 
20 March 2018
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
3.1
Schedule of Study Procedures for SRD Cohort 1 (Periods A and B).........................12
3.2
Schedule of Study Procedures for MRD Cohorts 2 to 6............................................15
3.3
Schedule for PK and Biomarker Sample Collection for MRD Cohorts 2 to 6 ...........18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................20
4.3
Benefit/Risk Profile .................................................................................................21
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................22
5.1
Trial Objectives .......................................................................................................22
5.1.1
Trial Primary Objective......................................................................................22
5.1.2
Trial Secondary Objective..................................................................................22
5.1.3
Trial Exploratory Objectives ..............................................................................22
5.2
Endpoints.................................................................................................................23
5.2.1
Primary Endpoints .............................................................................................23
5.2.2
Secondary Endpoints..........................................................................................23
5.2.3
Exploratory Endpoints .......................................................................................23
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................26
6.1
Trial Design.............................................................................................................26
6.2
Dose Escalation .......................................................................................................27
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................27
6.3.1
Rationale of Trial Design ...................................................................................27
6.3.2
Rationale for Dose .............................................................................................27
6.3.3
Rationale for Endpoints......................................................................................28
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................30
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................30
6.5
Trial Beginning and End/Completion.......................................................................31
6.5.1
Definition of Beginning of the Trial ...................................................................31
6.5.2
Definition of End of the Trial.............................................................................31
6.5.3
Definition of Trial Discontinuation ....................................................................31
6.5.4
Criteria for Premature Termination or Suspension of the Trial............................32
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Study ID TAK-418-1003
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Protocol 
20 March 2018
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............33
7.1
Inclusion Criteria .....................................................................................................33
7.2
Exclusion Criteria ....................................................................................................34
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products.........36
7.3.1
Concomitant Medications...................................................................................36
7.3.2
Fruit Juice ..........................................................................................................36
7.3.3
Alcohol..............................................................................................................36
7.3.4
Caffeine .............................................................................................................37
7.3.5
Smoking ............................................................................................................37
7.4
Diet, Fluids, and Activity.........................................................................................37
7.4.1
Diet and Fluids...................................................................................................37
7.4.2
Activity..............................................................................................................37
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................38
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................39
7.7
Subject Replacement................................................................................................39
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................40
8.1
Clinical Study Drug .................................................................................................40
8.1.1
Clinical Study Drug Labeling.............................................................................40
8.1.2
Clinical Study Drug Inventory and Storage ........................................................40
8.1.3
Clinical Study Drug Blinding.............................................................................40
8.1.4
Randomization Code Creation and Storage ........................................................40
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................40
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................41
8.2
Ancillary Supplies ...................................................................................................41
9.0
STUDY PROCEDURES...............................................................................................42
9.1
Administrative Procedures.......................................................................................42
9.1.1
Informed Consent Procedure..............................................................................42
9.1.2
Inclusion and Exclusion .....................................................................................42
9.1.3
Medical History and Demographics ...................................................................42
9.1.4
Prior and Concomitant Medications ...................................................................43
9.2
Clinical Procedures and Assessments.......................................................................43
9.2.1
Full Physical, Neurological, and Fundoscopic Examinations..............................43
9.2.2
Height and Weight .............................................................................................43
9.2.3
BMI ...................................................................................................................43
9.2.4
Vital Signs .........................................................................................................43
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Study ID TAK-418-1003
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20 March 2018
9.2.5
12-Lead ECG.....................................................................................................43
9.2.6
Study Drug Administration ................................................................................45
9.2.7
..............................................................................................................45
9.2.8
..........................................................................................................45
9.2.9
.................................................................45
9.2.10 Actigraphy.........................................................................................................46
9.2.11 AE Monitoring...................................................................................................46
9.3
Laboratory Procedures and Assessments..................................................................46
9.3.1
Clinical Laboratory Tests...................................................................................46
9.3.2
Diagnostic Screening .........................................................................................48
9.4
PK, PD, Biomarker, and Pharmacogenomic Evaluations..........................................48
9.4.1
PK, PD, Biomarker, and Pharmacogenomic Samples .........................................48
9.4.2
PK Measurements..............................................................................................49
9.4.3
PD Measurements..............................................................................................51
9.4.4
Biomarker Measurements...................................................................................52
9.4.5
PGx Measurements ............................................................................................53
9.4.6
Confinement ......................................................................................................54
10.0
ADVERSE EVENTS ....................................................................................................55
10.1
Definitions and Elements of AEs .............................................................................55
10.1.1 SAEs..................................................................................................................57
10.2
AE Procedures.........................................................................................................57
10.2.1 Assigning Severity/Intensity of AEs...................................................................57
10.2.2 Assigning Causality of AEs................................................................................58
10.2.3 Start Date...........................................................................................................58
10.2.4 End Date............................................................................................................58
10.2.5 Pattern of Adverse Event (Frequency)................................................................58
10.2.6 Action Taken With Study Treatment..................................................................58
10.2.7 Outcome ............................................................................................................59
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs............................59
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....61
11.0
STATISTICAL METHODS..........................................................................................62
11.1
Statistical and Analytical Plans ................................................................................62
11.1.1 Analysis Sets......................................................................................................62
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................62
11.1.3 PK Analysis .......................................................................................................63
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Study ID TAK-418-1003
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11.1.4 PD Analysis .......................................................................................................63
11.1.5 Exploratory Biomarker Analysis ........................................................................63
11.1.6 Safety Analysis ..................................................................................................63
11.2
Interim Analysis and Criteria for Early Termination ................................................64
11.3
Determination of Sample Size..................................................................................64
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................65
12.1
Study-Site Monitoring Visits ...................................................................................65
12.2
Protocol Deviations..................................................................................................65
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................65
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................66
13.1
IRB and/or IEC Approval ........................................................................................66
13.2
Subject Information, Informed Consent, and Subject Authorization .........................66
13.3
Subject Confidentiality ............................................................................................68
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................68
13.4.1 Publication and Disclosure.................................................................................68
13.4.2 Clinical Trial Registration..................................................................................69
13.4.3 Clinical Trial Results Disclosure ........................................................................69
13.5
Insurance and Compensation for Injury....................................................................69
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................70
14.1
Administrative Information......................................................................................70
14.1.1 Study Contact Information .................................................................................70
14.1.2 INVESTIGATOR AGREEMENT......................................................................71
14.1.3 List of Abbreviations .........................................................................................72
15.0
DATA HANDLING AND RECORDKEEPING............................................................74
16.0
REFERENCES..............................................................................................................75
17.0
APPENDICES...............................................................................................................76
LIST OF IN-TEXT TABLES
Table 4.a
Summary of Preliminary Plasma PK Parameter Estimates of TAK-418F 
(TAK-418 as Free Base) Following a Single Oral Dose of TAK-418 to Fasted 
Healthy Subjects ................................................................................................20
Table 6.a
Planned Dosing Regimens and Ethnicity of Subjects..........................................26
Table 9.a
Primary Specimen Collections ...........................................................................49
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TAK-418
Study ID TAK-418-1003
Page 6 of 84
Protocol 
20 March 2018
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................76
Appendix B
Elements of the Subject Informed Consent.........................................................78
Appendix C
Investigator Consent to the Use of Personal Information ....................................81
Appendix D
Pregnancy and Contraception.............................................................................82
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418
Study ID TAK-418-1003
Page 7 of 84
Protocol 
20 March 2018
1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge MA 02139
USA
Compound:
TAK-418
Study Identifier: TAK-418-1003
Phase: 1
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in Healthy Female Subjects.
Trial Design:
This phase 1, randomized, double-blind, placebo-controlled trial is designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple (once-daily [QD]) rising oral doses of 
TAK-418 (capsule formulation) in healthy adult female subjects.
Approximately 48 subjects are planned for enrollment in 6 cohorts (n=8 per cohort). In single-rising dose (SRD) 
cohort 1, subjects will receive a single oral dose of study drug (TAK-418 or matching placebo) in a double-blind 
manner in period A. After a washout interval of at least 14 days after the dose of study drug and following the review 
of the safety, tolerability, and PK data from period A, subjects in cohort 1 may receive a second single dose of study 
drug in period B. In multiple-rising dose (MRD) cohorts 2 to 6, subjects will receive study drug QD for 10 days in a 
double-blind manner. In each SRD and MRD cohort, 6 subjects will be randomly assigned to receive TAK-418 and 2 
to receive placebo. The cohorts will be enrolled in a consecutive, staggered, or parallel manner.
For all SRD and MRD cohorts, blood samples will be collected for PK (TAK-418), 
 
 and 
. For MRD cohort 3 only, serial lumbar cerebrospinal 
fluid (CSF) samples will be collected through an indwelling temporary catheter for 48 hours after the last dose of study 
drug for PK (TAK-418) and 
. Urine samples will be collected from selected 
non-Japanese MRD cohorts.
The planned TAK-418 dosing regimens and ethnicity of subjects are presented below. Non- Japanese subjects will be 
enrolled in cohorts 1 to 4 and Japanese subjects in cohorts 5 and 6. Planned 
, but the 
actual doses administered after cohort 1 (period A) and cohort 2 will be based on emerging safety, tolerability, and PK 
data available from the previous doses.
Planned Dosing Regimens and Ethnicity of Subjects
Cohort
Ethnicity
Planned TAK-418
Dosing Regimen
Comments
1 (period A)
Non-Japanes
e
single dose
Cohort 1 (period A) may receive a second single dose (period B).
1 (period B)
single dose
2
D (10 days)
Cohort 2 may be run in parallel with cohort 1 (period A or period B).
3
D (10 days)
Serial CSF samples will be collected.
4
D (10 days)
5
Japanese
D (10 days)
Cohort 5 may be run in parallel with cohort 1, 2, or 3.
6
D (10 days)
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TAK-418
Study ID TAK-418-1003
Page 8 of 84
Protocol 
20 March 2018
Trial Primary Objective:
!
To characterize the safety and tolerability of TAK-418 in non-Japanese and Japanese healthy female subjects 
when administered at single or multiple (QD) oral escalating doses.
Trial Secondary Objective:
!
To characterize the PK of TAK-418 in non-Japanese and Japanese healthy female subjects when administered at 
single or multiple (QD) oral escalating doses.
Trial Subject Population: Healthy female non-Japanese and Japanese subjects, aged 18 to 55 years, inclusive.
Planned Number of Subjects:
Approximately 48 subjects randomized
Planned Number of Sites:
Approximately 2
Dose Levels:
SRD Cohort:
TAK-418
single dose
TAK-418
single dose
Matching placebo
MRD Cohorts:
TAK-418
QD 
TAK-418
QD 
TAK-418
QD
TAK-418
QD
TAK-418
QD
Matching placebo
Route of Administration:
Oral
Duration of Treatment:
SRD Cohort: single dose
MRD Cohorts: QD for 10 Days
Planned Trial Duration:
SRD Cohort: Up to 15 weeks (including screening period, 
periods A and B, and follow-up period)
MRD Cohorts: Up to 14 weeks (including screening period 
and follow-up period)
Main Criteria for Inclusion:
To be eligible for study participation, subjects must:
For All Cohorts 
!
Be female and aged 18 to 55 years, inclusive, at the screening visit.
!
Have a body mass index (BMI) ≥18.5 and ≤30.0 kg/m2 at the screening visit. (cohorts 1 to 4 only)
!
Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine patch) for at least 
6 months before administration of the first dose of study drug or invasive procedure.
!
Be judged to be in good health by the investigator, based on clinical evaluations performed at the screening visit 
and before administration of the first dose of study drug or invasive procedure.
!
Either be of nonchildbearing potential, as defined in the protocol, or if of childbearing potential, be using at least 
1 of the highly effective methods of contraception, as defined in the protocol, during the entire duration of the 
study.
!
For MRD Cohorts 5 and 6 (Japanese Subjects) Only
!
Have a BMI ≥18.0 and ≤26.0 kg/m2, at the screening visit.
!
Have been born in Japan to a Japanese mother and father and have maternal and paternal Japanese grandparents.
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TAK-418
Study ID TAK-418-1003
Page 9 of 84
Protocol 
20 March 2018

Have not been away from Japan for more than 10 years, at the screening visit.

Have a lifestyle that did not change significantly since relocation from Japan.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
For All Cohorts:

Has a positive alcohol or drug screen.

Has a positive serum pregnancy test or is breastfeeding.

Is unable to refrain from or anticipates using any medication beginning approximately 7 days before 
administration of the first dose of study drug, throughout the trial (including washout intervals between treatment 
periods), until the final follow-up visit.

Has a substance abuse disorder.

Has a risk of suicide according to the investigator’s clinical judgment per Columbia-Suicide Severity Rating Scale 
at screening or has made a suicide attempt in the 6 months before screening.

Has a clinically significant history of head injury, trauma, or seizures (history of a seizure within 3 months prior to 
randomization).

Has a lifetime history of major psychiatric disorder, such as major depressive disorder, bipolar disorder, or 
schizophrenia.

Has luteinizing hormone, follicle-stimulating hormone, or estradiol levels that are clinically abnormal.
For MRD Cohort 3 Only (Includes CSF Sample Collection)

The subject has had CSF collection performed within 30 days before Check-in (Day -1).

The subject has a known hypersensitivity to the anesthetic or its derivatives used during CSF collection or any 
medication used to prepare the area of lumbar puncture.

The subject has significant vertebral deformities (scoliosis or kyphosis) that, in the opinion of the investigator, 
may interfere with the lumbar puncture procedure.

The subject has a history of major (lumbar) back surgery, clinically significant back pain, and/or injury, in the 
opinion of the investigator.

The subject has a local infection at the puncture site.

The subject has thrombocytopenia or other suspected bleeding tendencies noted before the procedure.

The subject has developed signs and symptoms of spinal radiculopathy, including lower extremity pain and 
paresthesia.

The subject has any focal neurological deficit that might suggest an increase in intracranial pressure.

The subject has any abnormal finding on ophthalmological assessment/fundoscopy indicative of raised 
intracranial pressure (ie, optic disc swelling/edema; or [uncontrolled] hypertensive retinopathy).

The subject regularly has moderate-to-severe headaches requiring analgesics.

The subject has any bleeding abnormality or history of bleeding abnormalities.

The subject has abnormal coagulation tests (prothrombin time/international normalized ratio, activated partial 
thromboplastin time) at screening.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are as follows:
For All Cohorts

Number and percentage of subjects with at least 1 treatment-emergent adverse event (TEAE).

Number and percentage of subjects with at least 1 serious adverse event.
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Study ID TAK-418-1003
Page 10 of 84
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20 March 2018

Number and percentage of subjects who meet the markedly abnormal criteria for clinical laboratory values at least 
once postdose.

Number and percentage of subjects who meet the markedly abnormal criteria for vital signs at least once postdose.

Number and percentage of subjects who meet the markedly abnormal criteria for safety 12-lead 
electrocardiogram (ECG) parameters at least once postdose.
The secondary endpoints of the study are as follows:
For SRD Cohort 1 (Periods A and B)

Area under the plasma concentration-time from time 0 to infinity (AUC∞) after a single dose of TAK-418.
For MRD Cohorts 2 to 6

Area under the plasma concentration-time curve during a dosing interval (AUCτ) on Day 1 and after the final dose 
following multiple (QD) dosing of TAK-418.
For All Cohorts

Maximum observed plasma concentration (Cmax).

Time of first occurrence of Cmax (tmax). 
Statistical Considerations:
TEAEs will be summarized by placebo, TAK-418 dose level, and TAK-418 overall. Individual results of clinical 
laboratory tests, vital signs, and quantitative 12-lead ECG parameters that meet Takeda’s markedly abnormal criteria 
will be listed and summarized by placebo, TAK-418 dose level, and TAK-418 overall.
TAK-418 concentrations in plasma (including trough concentrations for the MRD cohorts) will be summarized by 
dose over each scheduled sampling time point using descriptive statistics. Individual plasma concentration data versus 
time will be presented in a data listing. Descriptive statistics (arithmetic mean, SD, %CV, median, minimum, 
maximum, and/or geometric mean) will be used to summarize the plasma PK parameters for TAK-418, as appropriate.
Sample Size Justification:
The sample sizes chosen are considered sufficient for evaluation of safety, tolerability, PK, and PD of each cohort but 
are not based on statistical considerations.
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Study ID TAK-418-1003
Page 11 of 84
Protocol 
20 March 2018
2.0
STUDY SCHEMATIC
Abbreviations: MRD, multiple-rising dose; SRD, single-rising dose; QD, once daily.
Cohort 1 (Period A)
g single dose
Non-Japanese SRD Cohort 1 (Periods A and B)
Non-Japanese MRD Cohorts 2 to 4
Cohort 3
 QD (10 Days)
Cohort 5
 QD (10 Days)
Safety and tolerability assessment for 
dose escalation to cohort 6
Cohort 2 may run in parallel with cohort 1 (period A or B)
Cohort 2
 QD (10 Days)
Washout
(≥14 days)
Cohort 4
 QD (10 Days)
Safety and tolerability assessment for 
dose escalation to cohort 4
Cohort 3: Serial CSF samples will be collected
Safety and tolerability assessment for 
dose escalation to cohort 3
Cohort 1 (Period B)
g single dose
Cohort 6
QD (10 Days)
Japanese MRD Cohorts 5 and 6
Cohort 5 may run in parallel with cohorts 1, 2, 3
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TAK-418
Study ID TAK-418-1003
Page 12 of 84
Protocol 
20 March 2018
3.0
SCHEDULE OF STUDY PROCEDURES
3.1
Schedule of Study Procedures for SRD Cohort 1 (Periods A and B)
Screening
Period
Check
-in a
Treatment Period a
ET
Follow-Up Period
Study Day
-28 to -2
-1
1
2
3
4
7±
1 b
13±
2 c
30±
2 c
60±
2 c
Hour
Predose
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/ 
demographics
X
Prior and concomitant 
medication review
X------------------------------------------------------------------------Continuous Review----------------------------------------------------------------------X
Clinical Procedures/Assessments
Full physical examination
X
X d
X
X
X
X
X
X
Neurological examination
X
X d
X
X
X
X
X
X
X
Height
X
Weight
X
Body mass index
X
Semirecumbent vital signs 
(HR, SBP, DBP)
X
X e
X
X
X
X
X
X
X
X
Vital signs (respiratory rate, 
temperature)
X
X e
X
X
X
X
X
X
X
X
12-lead ECG
X
X e
X
X
X
X
X
X
X
X
Study drug (TAK-418 or 
placebo) administration
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
BL-VAS
X
X
X
X
X
Footnotes are on the last table page.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418
Study ID TAK-418-1003
Page 13 of 84
Protocol 
20 March 2018
3.1
Schedule of Study Procedures for SRD Cohort 1 (Periods A and B) (continued)
Screening
Period
Check
-in a
Treatment Period a
ET
Follow-Up Period
Study Day
-28 to -2
-1
1
2
3
4
7
±1 b
13±
2 c
30±
2 c
60±
2 c
Hour
Predose
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
Clinical Procedures/Assessments
Actigraphy g
X----------------------------------------------------------------------------------------------------X
AE monitoring
X---------------------------------------------------------------------Continuous Monitoring----------------------------------------------------------------------X
Laboratory Procedures/Assessments
Hematology
X
X d
X
X
X
X
X
X
Urinalysis
X
X d
X
X
X
X
X
X
Chemistry
X
X d
X
X
X
X
X
X
PT and aPTT
X
Serum hCG
X
X d
X
X
X
X
Serum FSH/LH/estradiol
X
X d
X
X
X
X
X
X
HIV screen
X
Hepatitis screen
X
Urine drug screen
X
X d
Alcohol test
X
X d
PK Evaluations
Plasma sample for TAK-418 
PK
X
X
X
X
X
X X X X
X
X
X
X
X
X
PD/Biomarker Evaluations
Footnotes are on the last table page.
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Property of Tak
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For non-commercial use only and subjeje
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TAK-418
Study ID TAK-418-1003
Page 14 of 84
Protocol 
20 March 2018
3.1
Schedule of Study Procedures for SRD Cohort 1 (Periods A and B) (continued)
Screening
Period
Check
-in a
Treatment Period a
ET
Follow-Up Period
Study Day
-28 to -2
-1
1
2
3
4
7±
1 b
13±
2 c
30±
2 c
60±
2 c
Hour
Predose
0
0.25
0.5
1
1.5
2
3
4
8
12
24
36
48
72
PD/Biomarker Evaluations
PGx Evaluations
Other
Confinement
X---------------------------------------------------------------------------------------------------X
Standardized meals i
X------------------------------------------------------------------------------------X
Abbreviations: AE, adverse event; aPTT, activated partial thromboplastin time; 
DBP, diastolic blood pressure; ECG, electrocardiogram; ET, Early Termination; 
 
FSH, follicle-stimulating hormone; hCG, human chorionic gonadotrophin; HR, heart rate; LH, luteinizing hormone; PD, pharmacodynamic; 
, 
pharmacokinetic(s); 
; PT, prothrombin time; SBP, systolic blood pressure; SRD, single-rising dose.
a Subjects from cohort 1 (period A) may receive a second single dose of study drug in cohort 1 (period B) after a washout interval of at least 14 days after the dose of study drug in 
period A.
b For both periods A and B.
c For period B only.
d Will be performed within approximately 24 hours before the dose of study drug in each treatment period.
e Will be performed within approximately 1 hour before the dose of study drug in each treatment period.
f For period A only.
g Optional assessment (separate informed consent).
h Will be collected within approximately 1 hour before the dose of study drug in cohort 1 (period A) only.
i Standardized meals (approximately 30% fat content relative to total calories) will be administered during confinement and only up to 24 hours after the dose of study drug in each 
treatment period. On Day 1 in each treatment period, standardized meals will be administered at 4 (lunch), 7 (snack), 10 (dinner), and 13 (snack) hours postdose. 
CCI
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Property of Takeda: For non-commercial use
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TAK-418
Study ID TAK-418-1003
Page 15 of 84
Protocol 
20 March 2018
3.2
Schedule of Study Procedures for MRD Cohorts 2 to 6
Screening
Period
Check
-in
Treatment Period
Follow-up &
Discharge
ET
Follow-up Period
Study Day
-28 to -2
-1
1
(Predose)
1
2
3
4
5
6
7
8
9
10
11
12
14
22
±2 
40
±2 
70
±2 
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
X---------------------------------------------------------Continuous Review------------------------------------------------------------------X
Clinical Procedures/Assessments
Full physical examination
X
X a
X
X
X
Neurology examination
X
X a
X
X
X
Fundoscopic examination (cohort 3 
only)
X
X
Weight
X
Height
X
Body mass index
X
Semirecumbent vital signs (HR, SBP, 
DBP)
X
X b
X
X
X
X
X
X
X
Vital signs (respiratory rate, 
temperature)
X
X b
X
X
X
X
X
X
X
12-lead ECG
X
X b
X
X
X
X
X
X
Continuous ECGs (12-lead Holter) c
X
X
X
X
Study drug (TAK-418 or placebo) 
administration d
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
BL-VAS
X
X
X
Footnotes are on the last table page.
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le
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Tak


TAK-418
Study ID TAK-418-1003
Page 16 of 84
Protocol 
20 March 2018
3.2
Schedule of Study Procedures for MRD Cohorts 2 to 6 (continued)
Screening
Period
Check
-in
Treatment Period
Follow-up
& Discharge
ET
Follow-up Period
Study Day
-28 to -2
-1
1
(Predose)
1
2
3
4
5
6
7
8
9
10
11
12
14
22
±2 
40
±2 
70
±2 
Clinical Procedures/Assessments
Actigraphy f
X-------------------------------------------------------------------------------------------------X
AE monitoring
X-------------------------------------------------------------Continuous Monitoring----------------------------------------------------------X
Laboratory Procedures/Assessments
Hematology
X
X a
X
X
X
Urinalysis
X
X a
X
X
X
Chemistry
X
X a
X
X
X
PT and aPTT
X
Serum hCG
X
X a
X
X
X
X
Serum FSH/LH/estradiol
X
X a
X
X
X
X
HIV screen
X
Hepatitis screen
X
Alcohol test
X
X a
Urine drug screen
X
X a
PK Evaluations
Plasma sample for TAK-418 PK g
X
X
X
X
X
X
X
X
X
Urine sample for TAK-418 PK (selected 
cohorts only) g
X
X
X
X
X
CSF sample for TAK-418 PK (cohort 3 
only) g
X
X
X
PD/Biomarker Evaluations
Footnotes are on the last table page.
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Takeda:


TAK-418
Study ID TAK-418-1003
Page 17 of 84
Protocol 
20 March 2018
3.2
Schedule of Study Procedures for MRD Cohorts 2 to 6 (continued)
Screening
Period
Check
-in
Treatment Period
Follow-up &
Discharge
ET
Follow-up Period
Study Day
-28 to -2
-1
1
(Predose)
1
2
3
4
5
6
7
8
9
10
11
12
14
22
±2 
40
±2 
70
±2 
PD/Biomarker Evaluations
f
a
PGx Evaluations
Other
Confinement
X------------------------------------------------------------------------------------------------X
Standardized meals d, i
X----------------------------------------------------------------------------------------X
Abbreviations: AE, adverse event; aPTT, activated partial thromboplastin time; 
CSF, cerebrospinal fluid; 
, 
 DBP, diastolic blood pressure; ET, Early Termination; 
 
 FSH, follicle-stimulating hormone; hCG, human chorionic gonadotrophin; HR, heart rate; LH, luteinizing hormone; MRD, multiple-rising dose; PD, 
pharmacodynamic(s); 
 PK, pharmacokinetic(s); 
 PT, prothrombin time; SBP, systolic blood pressure.
a Will be performed within approximately 24 hours before the first dose of study drug.
b Will be performed within approximately 1 hour before the first dose of study drug.
c Continuous Holter ECG will be performed at the following time points: On Day -1 at 23.5, 23, 22.5, 22, 21, 20, 16, and 12 hours before the first (Day 1) dose of study drug 
(time-matched to Day 1 time points); and immediately before dosing (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours after the first dose on Day 1.
d Study drug will be administered after a fast of at least 8 hours. Subjects will continue to fast for an additional 4 hours after dosing.
e Cognitive testing will be performed twice on Day 1, with a 10- to 15-minute break between administrations. The first administration is to familiarize subjects with test requirements.
f Optional assessment (separate informed consent).
g See Section 3.3 for details of collection time points.
h Will be collected 96 hours after the last dose of study drug.
i Standardized meals (approximately 30% fat content relative to total calories) will be administered during confinement and only up to 24 hours after the last dose of study drug. On 
each dosing day, standardized meals will be administered at 4 (lunch), 7 (snack), 10 (dinner), and 13 (snack) hours postdose.
CCI
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TAK-418
Study ID TAK-418-1003
Page 18 of 84
Protocol 
20 March 2018
3.3
Schedule for PK and Biomarker Sample Collection for MRD Cohorts 2 to 6
Treatment Period
Follow-up & Discharge
Study Day
1
(First Dose)
2
3
7
10
(Last Dose)
11
12
PK Evaluations
Plasma sample for TAK-418 PK
Predose and 0.25, 0.5, 
1, 1.5, 2, 3, 4, 8, and 
12 h postdose
24 h after first dose 
(before second dose)
Predose
Predose
Predose and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 8, and 12 h 
postdose
24 and 36 h 
after last dose
48 h after last 
dose
Urine sample for TAK-418 PK 
(selected cohorts only)
Predose (spot 
collection) and 0 to 6, 
6 to 12, and 12 to 24 h 
postdose
Predose (spot 
collection) and 0 to 6, 6 
to 12, and 12 to 24 h 
postdose
CSF sample for PK (cohort 3 only)
Predose and 1, 2, 4, 8, 
and 12 h postdose
24 and 36 h 
after last dose
48 h after last 
dose
PD/Biomarker Evaluations
Abbreviations:
 CSF, cerebrospinal fluid;
MRD, multiple-rising dose; PD, 
pharmacodynamic(s); PK, pharmacokinetic(s); PBMC, peripheral blood mononuclear cells.
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Property of Takeda: For 
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TAK-418
Study ID TAK-418-1003
Page 19 of 84
Protocol 
20 March 2018
4.0
INTRODUCTION
4.1
Background
Lysine-specific demethylase 1A (LSD1), a member of the lysine-specific demethylase family 1 
(KDM1), 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. 
 
. 
The first reported specific substrate of LSD1 was histone H3K4me1/2, and subsequently 
additional specific substrates have been identified [4].
TAK-418 is a novel small molecule that inhibits the activity of human LSD1, also known as 
KDM1A. 
 
 
 
 
 
 
TAK-418 is currently being evaluated in a phase 1, first-in-human clinical study in healthy 
non-Japanese adult subjects (Study TAK-418-1001); dosing for this study has been completed. 
This randomized, double-blind, placebo-controlled, single-rising dose (SRD) study is designed to 
assess the safety, tolerability, and pharmacokinetics (PK) of the oral capsule formulation of 
TAK-418. Subjects have been enrolled into 5 sequential cohorts of 8 subjects each (6 TAK-418; 2 
placebo), with a minimum of 4 male subjects per cohort. Subjects received a single dose of 
TAK-418 or placebo after an overnight fast of at least 10 hours. To allow for a preliminary 
assessment of the effect of food on the PK of TAK-418, subjects in the 30-mg cohort also received 
study drug under fed conditions (high fat/high calorie breakfast), with a washout interval of at least 
7 days between dose administrations.
The preliminary blinded safety and PK data from this single-dose study are summarized below.
!
In Study TAK-418-1001, a total of 40 subjects (in 5 cohorts) have completed treatment at 
single dose levels of up to 
mg. The following safety summary is preliminary and based on 
blinded data reported by the study investigator. Headache and nausea were the most common 
treatment-emergent adverse events (TEAEs) potentially related to study drug. All episodes of 
headache and nausea were mild in intensity and generally self-limiting. There were no 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-418
Study ID TAK-418-1003
Page 20 of 84
Protocol 
20 March 2018
concerning trends in clinical laboratory, electrocardiogram (ECG), or vital sign data. Although 
not expected, these data may change upon finalization following study monitoring, source data 
verification, and discrepancy query management prior to database lock.
!
The systemic exposure of TAK-418, as measured by mean maximum observed plasma 
concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 
infinity (AUC∀), increased approximately dose proportionally from 
. The mean
terminal disposition phase half-life (t1/2z) was short, ranging from 3.2 to 4.6 hours (Table 4.a). 
As evaluated in the 
 cohort, a standard high-fat meal significantly decreased mean Cmax
by 40.3%. There was no effect of a high-fat meal on AUC∀.
Table 4.a
Summary of Preliminary Plasma PK Parameter Estimates of TAK-418F 
(TAK-418 as Free Base) Following a Single Oral Dose of TAK-418 to Fasted 
Healthy Subjects
TAK-418
Dose
tmax
(h) a
Cmax
(ng/mL)
AUClast
(h*ng/mL)
AUC∞
(h*ng/mL)
Vz/F
(L)
CL/F
(L/h)
t1/2z
(h)
Mean (%CV)
1 (1-1)
22.7 (35)
85.4 (43)
94 (43)
279 (34)
63 (46)
3.2 (12)
1 (1-2)
63.5 (22)
311 (22)
317 (22)
313 (20)
49.2 (22)
4.43 (5)
1 (0.5-1)
166 (18)
683 (8)
693 (8)
286 (10)
43.5 (8)
4.57 (10)
1.25 (1-1.5)
162 (31)
728 (24)
735 (24)
313 (25)
57.5 (28)
3.83 (14)
1 (1-1)
324 (14)
1640 (30)
1660 (30)
218 (25)
39.3 (34)
3.92 (10)
Abbreviations: AUC∞, area under the plasma concentration-time curve from time 0 to infinity; AUClast, area under the plasma 
concentration-time curve from time 0 to time of the last quantifiable concentration; %CV, percent coefficient of variation; CL/F, 
apparent clearance after extravascular administration; Cmax, maximum observed plasma concentration; t1/2z, terminal disposition 
phase half-life; tmax, time of first occurrence of Cmax; Vz/F, apparent volume of distribution during the terminal disposition phase 
after extravascular administration.
a Median (min-max).
Note: n=6 for each dose level.
Please refer to the current TAK-418 Investigator’s Brochure for additional background 
information.
4.2
Rationale for the Proposed Study
The primary objective of the current study is to evaluate the safety, tolerability, PK, and 
pharmacodynamics (PD) of TAK-418 in healthy female subjects of non-Japanese and Japanese 
origin to support further development of TAK-418 as a potential treatment for patients with 
neurodevelopmental disorders. The available nonclinical pharmacology, PK, and toxicology data 
and the preliminary clinical data from the first-in-human (FIH) trial (TAK-418-1001) support the 
current trial and the development of TAK-418. TAK-418 has shown effects on declarative and 
emotional short-term memory tasks in rodents and social interaction in autism rodent models that 
suggest utility for the treatment of cognitive deficits in patients with ASD.
CCI
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Dose
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neurode
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and
cu


TAK-418
Study ID TAK-418-1003
Page 21 of 84
Protocol 
20 March 2018
The safety, tolerability, PK, and PD data from the current trial may inform the design of and dosing 
regimen selection for subsequent proof-of-mechanism and proof-of-concept trials in subjects of 
Japanese and non-Japanese origin.
4.3
Benefit/Risk Profile
This phase 1, randomized, double-blind, placebo-controlled trial will evaluate the safety, 
tolerability, PK, and PD of TAK-418 following single or multiple oral doses in healthy female 
subjects aged 18 to 55 years, inclusive. As this is a healthy subject trial, there is no expected 
clinical benefit to the trial participants.
TAK-418 is a potential first-in-class drug, and therefore, there are no known contraindications 
based on drug class. Potential risks are based on the mechanism of action and nonclinical findings. 
Potential risks include adverse effects on hematologic parameters, cardiovascular effects, 
hepatotoxicity, convulsions, and effects on embryo-fetal development. The potential risks related 
to hematology, cardiovascular effects, and hepatotoxicity can be monitored clinically and/or with 
laboratory tests and have been considered when determining the stopping rules for this clinical 
trial. 
 
 
 
 
 
 
 
 
 
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TAK-418
Study ID TAK-418-1003
Page 22 of 84
Protocol 
20 March 2018
5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Trial Objectives
5.1.1
Trial Primary Objective
!
To characterize the safety and tolerability of TAK-418 in non-Japanese and Japanese healthy 
female subjects when administered at single or multiple (once daily [QD]) oral escalating 
doses.
5.1.2
Trial Secondary Objective
!
To characterize the PK of TAK-418 in non-Japanese and Japanese healthy female subjects 
when administered at single or multiple (QD) oral escalating doses.
5.1.3
Trial Exploratory Objectives
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Study ID TAK-418-1003
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5.2 Endpoints
5.2.1
Primary Endpoints
For All Cohorts
!
Number and percentage of subjects with at least 1 TEAE.
!
Number and percentage of subjects with at least 1 serious adverse event (SAE).
!
Number and percentage of subjects who meet the markedly abnormal criteria for clinical 
laboratory values at least once postdose.
!
Number and percentage of subjects who meet the markedly abnormal criteria for vital signs at 
least once postdose.
!
Number and percentage of subjects who meet the markedly abnormal criteria for safety 
12-lead ECG parameters at least once postdose.
5.2.2
Secondary Endpoints 
For SRD Cohort 1 (Periods A and B)
!
AUC∞after a single dose of TAK-418.
For MRD Cohorts 2 to 6
!
Area under the plasma concentration-time curve during a dosing interval (AUCτ) on Day 1 and 
after the final dose following multiple (QD) dosing of TAK-418.
For All Cohorts
!
Cmax.
!
Time of first occurrence of Cmax (tmax).
5.2.3
Exploratory Endpoints
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Study ID TAK-418-1003
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Study ID TAK-418-1003
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5.2.3.3
Exploratory Biomarker Endpoints
5.2.3.4
Other Exploratory Endpoints
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Study ID TAK-418-1003
Page 26 of 84
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This phase 1, randomized, double-blind, placebo-controlled trial is designed to evaluate the safety,
tolerability, PK, and PD of single and multiple (QD) rising oral doses of TAK-418 (capsule 
formulation) in healthy adult female subjects.
Approximately 48 subjects are planned for enrollment in 6 cohorts (n=8 per cohort). In SRD 
cohort 1, subjects will receive a single oral dose of study drug (TAK-418 or matching placebo) in 
a double-blind manner in period A. After a washout interval of at least 14 days after the dose of 
study drug and following the review of the safety, tolerability, and PK data from period A, subjects 
in cohort 1 may receive a second single dose of study drug in period B. In multiple-rising dose 
(MRD) cohorts 2 to 6, subjects will receive study drug QD for 10 days in a double-blind manner. 
In each SRD and MRD cohort, 6 subjects will be randomly assigned to receive TAK-418 and 2 to 
receive placebo. The cohorts will be enrolled in a consecutive, staggered, or parallel manner (see 
Section 2.0).
For all SRD and MRD cohorts, blood samples will be collected for PK (TAK-418), 
 
and 
. For MRD cohort 3 only, serial lumbar CSF samples will 
be collected through an indwelling temporary catheter for 48 hours after the last dose of study drug 
for PK (TAK-418) and 
. Urine samples will be collected from 
selected non-Japanese MRD cohorts.
The planned TAK-418 dosing regimens and ethnicity of subjects are presented in Table 6.a. 
Non-Japanese subjects will be enrolled in cohorts 1 to 4 and Japanese subjects in cohorts 5 and 6. 
Planned doses range from 
 mg, but the actual doses administered after cohort 1 (period A) 
and cohort 2 will be based on emerging safety, tolerability, and PK data available from the 
previous doses (see Section 6.3.2 for dose selection rationale).
Table 6.a
Planned Dosing Regimens and Ethnicity of Subjects
Cohort
Ethnicity
Planned TAK-418
Dosing Regimen
Comments
1 (period A)
Non-Japanese
single dose
Cohort 1 (period A) may receive a second single dose 
(period B).
1 (period B)
single dose
2
D (10 days)
Cohort 2 may run in parallel with cohort 1 (period A or 
period B).
3
D (10 days)
Serial CSF samples will be collected.
4
D (10 days)
5
Japanese
D (10 days)
Cohort 5 may run in parallel with cohort 1, 2, or 3.
6
D (10 days)
Abbreviations: CSF, cerebrospinal fluid; QD, once daily.
The trial may be conducted at multiple phase 1 units to support both CSF collection and 
recruitment of Japanese subjects.
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Study ID TAK-418-1003
Page 27 of 84
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6.2
Dose Escalation
Dose escalation and subsequent dose levels will be based on a blinded review of available safety,
tolerability, and PK data from the previous dose levels and will only occur following agreement 
between the investigator and the sponsor.
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design 
This phase 1 trial is designed to characterize the safety, tolerability, PK, and PD of single and 
multiple rising oral doses of TAK-418 in healthy female subjects of non-Japanese and Japanese 
origin. The safety and tolerability of single and multiple TAK-418 doses will be evaluated, some 
of which may exceed doses anticipated to be therapeutically effective. However, it should be noted 
that the trial is not intended to determine the maximum tolerated dose.
Only female subjects will be enrolled because of nonclinical findings of testicular toxicity and 
pending results from the long-term (13- and 26-week) testicular health analyses in the FIH trial 
(TAK-418-1001). Healthy female Japanese subjects will be included to investigate any ethnic 
differences in the safety, tolerability, and PK of TAK-418.
The randomized, double-blind, placebo-controlled design employed is considered adequate to 
characterize the safety, tolerability, and PK of TAK-418. Subjects will be confined during dosing 
up until at least 48 hours after the last dose of study drug to ensure adherence to study procedures 
and to monitor safety and tolerability.
For SRD cohort 1, a washout interval of at least 14 days between dosing in periods A and B is 
considered adequate to ensure washout of TAK-418, given the mean t1/2z of 3.2 to 4.6 hours 
estimated in Study TAK-418-1001.
 
 For MRD 
cohort 3 only, additional CSF samples will be collected to characterize TAK-418 exposure in the 
CNS.
6.3.2
Rationale for Dose
Planned doses for the current study range from 
 mg, but the actual doses administered 
after cohort 1 (period A) and cohort 2 will be based on emerging safety, tolerability, and PK data 
available from the previous doses. If needed, higher or lower doses may be evaluated providing the 
predicted steady-state exposure does not exceed limits set by nonclinical toxicology findings. In 
the 13-week rat and monkey toxicity studies, the monkey was the most sensitive species. NOAELs 
in the 13-week monkey toxicity study was 4 mg/kg/day in males based on potential 
treatment-related testicular findings at ≥20 mg/kg/day, and 60 mg/kg/day in females based on 
convulsions, inappetence, and body weight changes at ≥75 mg/kg/day. 
 
 
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Study ID TAK-418-1003
Page 28 of 84
Protocol 
20 March 2018
 
 
 
) and cohort 1 (
; period B) were selected 
to explore the highest tolerated dose in healthy subjects, while not exceeding the exposure limits 
set by the nonclinical toxicity studies (Cmax of 1,007 ng/mL and AUCτ of 71,500 h*ng/mL for 
female subjects). Based on the population PK analysis of preliminary data from 
Study TAK-418-1001, the predicted Cmax and AUC∞are 928 ng/mL and 4,320 h*ng/mL, 
respectively, after a single 
 dose. The dose level for cohort 1 (period B) may be adjusted 
based on emerging safety, tolerability, and PK data.
The starting dose for the MRD cohorts 
 QD; cohort 2) was selected to approximate the 
predicted pharmacologically active dose (PAD) estimated based on the nonclinical pharmacology 
models. The Cmax and AUCτ at the PAD are estimated to be 156 ng/mL and 171 h*ng/mL, 
respectively; and based on the population PK analysis, the Cmax and AUCτ at 20 mg QD are 
predicted to be 86.3 ng/mL and 361 h*ng/mL, respectively. The Cmax and AUCτ at the highest 
planned MRD dose (
 QD; cohort 4) are predicted to be 320 ng/mL and 1360 h*ng/mL, 
respectively. The planned MRD dose levels may be adjusted, and additional MRD cohort(s) with 
QD or other dosing regimens may be added based on emerging safety, tolerability, and PK data to 
explore the highest tolerated dose in healthy subjects, while not exceeding the exposure limits 
(Cmax of 1,007 ng/mL and AUCτ of 71,500 h*ng/mL for female subjects). Based on the population 
PK analysis of preliminary data from Study TAK-418-1001, the predicted Cmax and AUC∞are 
1,000 ng/mL and 4,530 h*ng/mL, respectively, after 
 QD.
The lower dose planned for the Japanese MRD cohorts (
QD; cohort 5) was selected to 
evaluate the safety, tolerability, and PK of TAK-418 in Japanese subjects. The planned higher dose 
(
QD; cohort 6) may be adjusted based on the emerging safety, tolerability, and PK data in 
both non-Japanese and Japanese subjects.
6.3.3
Rationale for Endpoints
6.3.3.1
Safety Endpoints
The safety endpoints of TEAEs, clinical laboratory test results, vital signs, and 12-lead ECG 
parameters are standard methods for assessing safety and tolerability of drugs in clinical trials.
ECGs derived from Holter monitoring are not intended to be analyzed for real-time safety 
monitoring but will be used for future retrospective ECG analyses, unless an earlier analysis is 
warranted by the emerging safety data.
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Study ID TAK-418-1003
Page 29 of 84
Protocol 
20 March 2018
6.3.3.2
PK Endpoints
The PK endpoints will provide measures of TAK-418 exposure in plasma, CSF, and urine 
following single and/or multiple doses of TAK-418 and are standard parameters to assess the PK 
of drugs in clinical trials.
6.3.3.3
PD Endpoints
6.3.3.4
Exploratory Biomarker and Other Exploratory Endpoints
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TAK-418
Study ID TAK-418-1003
Page 30 of 84
Protocol 
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6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this trial, the PK blood and CSF sample collections are the critical procedures.

At any postdose time point, the PK blood and CSF sample collections need to be performed as 
close to scheduled times 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 PK 
blood and CSF sample collections, if scheduled together.

If a blood draw or any study procedure coincides with a meal, the blood draw will take 
precedence followed by the study procedure and then the meal.

The order of priority can be changed during the trial with joint agreement of the investigator 
and the sponsor.

Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This trial is a phase 1 assessment of TAK-418 in humans, and the PK, PD, and safety profiles of 
the compound are still being elucidated. This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of phase 1 clinical trials. Modifications to the dose, 
dosing regimen, and/or clinical or laboratory procedures, as outlined below, may be required to 
achieve the scientific goals of the trial objectives and/or to ensure appropriate safety monitoring of 
the trial subjects.
As such, the following alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose/exposure, will not exceed 
that currently outlined in Section 6.3.2:

The dose of study drug administered may be repeated or decreased in any given period/cohort.

Doses between cohorts/periods may be interchanged.

Entire period(s) or cohort(s) may be omitted.

The duration of study drug administration (ie, number of days) in the trial may be decreased or 
increased, but will not exceed 4 weeks in any cohort.

The dosing interval may be adjusted (eg, twice daily to QD, QD to twice or 3 times daily).

The length of the washout interval between doses may be increased.

The length of the washout interval between doses may be decreased, if supported by safety and 
PK data.
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Protocol 
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
A planned PK data review may be removed if there are no further increases in total daily dose, 
if agreed by the sponsor and investigator.

A PK data review may be added.

Instructions to take study drug with or without food or drink may be modified based on newly 
available data.

The PK/PD sampling scheme may be modified during the trial based on newly available PK or 
PD data (eg, to obtain data closer to tmax). If indicated, these collected samples may also be 
assayed in an exploratory manner for metabolites and/or additional PD markers.

Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This blood 
volume may include repeat samples or modified PK/PD time points based on emerging data. 
The total blood volume withdrawn from any single subject will not exceed the maximum 
allowable volume during his/her participation in the entire trial.

The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECGs, 
clinical laboratory tests) may be modified during the trial based on newly available safety, 
tolerability, PK, or PD data (eg, to obtain data closer to tmax). These changes will not increase 
the number of trial procedures for a given subject during his/her participation in the entire trial.

Additional clinical laboratory tests may be added to blood samples previously drawn to obtain 
additional safety data.
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the sponsor in 
a letter to the trial file and forwarded to the investigator for retention. The letter may be forwarded 
to the institutional review board (IRB)/independent ethics committee (IEC) at the discretion of the 
investigator.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.5.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
trial, or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.5.3
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as the following:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a nonsafety-related reason.
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Study ID TAK-418-1003
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Protocol 
20 March 2018

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a nonsafety-related reason.

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons:

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from clinical trials or nonclinical studies with the trial treatment(s), comparator(s), drug(s) of 
the same class, or methodology(ies) used in this trial.
6.5.4
Criteria for Premature Termination or Suspension of the Trial
6.5.4.1
Criteria for Premature Termination or Suspension of Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
or is unable to ensure adequate performance of the trial, or as otherwise permitted by the 
contractual agreement.
6.5.4.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Sites
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
trial or the participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or trial suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before the first dose of study drug.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
For All Cohorts
1. The subject understands the trial procedures and agree to participate by providing written 
informed consent.
2. The subject is willing and able to comply with all trial procedures and restrictions.
3. The subject is female and aged 18 to 55 years, inclusive, at the screening visit.
4. The subject has a body mass index (BMI) ≥18.5 and ≤30.0 kg/m2 at the screening visit. 
(cohorts 1 to 4 only)
5. The subject is a nonsmoker who has not used tobacco- or nicotine-containing products (eg, 
nicotine patch) for at least 6 months before administration of the first dose of study drug or 
invasive procedure.
6. The subject is judged to be in good health by the investigator, based on clinical evaluations, 
including laboratory safety tests, medical history, physical examination, 12-lead ECG, and 
vital sign measurements performed at the screening visit and before administration of the first 
dose of study drug or invasive procedure.
7. The subject EITHER is of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a) Is postmenopausal (defined as 12 months of spontaneous amenorrhea with serum 
follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate documentation of 
FSH levels is required.
b) Is surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
c) Had a bilateral tubal occlusion or ligation with appropriate documentation of surgical 
procedure.
d) Has a congenital condition resulting in no uterus or infertility with appropriate 
documentation.
OR, if of childbearing potential, is using at least 1 of the following highly effective methods of 
contraception with low user dependency during the entire duration of the trial:
a) Intrauterine device (IUD).
b) Bilateral tubal occlusion or ligation with appropriate documentation of surgical procedure.
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Study ID TAK-418-1003
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Protocol 
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For MRD Cohorts 5 and 6 (Japanese Subjects) Only
1. The subject has a BMI ≥18.0 and ≤26.0 kg/m2, at the screening visit.
2. The subject was born in Japan to a Japanese mother and father and has maternal and paternal 
Japanese grandparents.
3. The subject has not been away from Japan for more than 10 years, at the screening visit.
4. The subject has a lifestyle that did not change significantly since relocation from Japan.
5. The subject understands and voluntarily signs an informed consent form written in English or 
Japanese prior to any study related procedures being performed and can adhere to restrictions 
and examination schedules.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
For All Cohorts
1. The subject has participated in another investigational trial within 4 weeks before the screening 
visit. The 4-week window will be derived from the date of the last trial procedure and/or AE 
related to the trial procedure in the previous trial to the screening visit of the current trial.
2. The subject is an employee or immediate family member (eg, spouse, parent, child, sibling) of 
the clinical research unit or sponsor.
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 intolerability to prescription or 
nonprescription drugs or food.
5. The subject has a positive alcohol or drug screen.
6. The subject has a positive serum pregnancy test.
7. The subject is breastfeeding.
8. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or HIV antibody/antigen, at screening. 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.
9. The subject had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks before the screening visit.
10. The subject is unable to refrain from or anticipates using any medication (as defined in Section 
9.1.4) beginning approximately 7 days before administration of the first dose of study drug, 
throughout the trial (including washout intervals between treatment periods), until the final 
follow-up visit. Certain medications may be permitted (Section 7.3.1).
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Study ID TAK-418-1003
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11. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on 
average (1 glass is approximately equivalent to beer [354 mL/12 oz], wine [118 mL/4 oz], or 
distilled spirits [29.5 mL/1 oz] per day).
12. The subjects 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.
13. The subject has a substance abuse disorder.
14. The subject has a risk of suicide according to the investigator’s clinical judgment per the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at screening or has made a suicide attempt 
in the 6 months before screening.
15. The subject has a clinically significant history of head injury, trauma, or seizures (history of a 
seizure within 3 months prior to randomization).
16. The subject has a lifetime history of major psychiatric disorder, such as major depressive 
disorder, bipolar disorder, or schizophrenia.
17. There is any concern to the investigator regarding the safe participation of the subject in the 
trial or for any other reason the investigator considers the subject inappropriate for 
participation in the trial.
18. The subject has a history of serious skin reactions (hypersensitivity) to adhesives, metals, or 
plastic. (Only for subjects participating in the actigraphy assessment.)
19. The subject has luteinizing hormone (LH), FSH, or estradiol levels that are clinically 
abnormal.
20. The subject has an ECG at the screening visit or predose on Day 1 that reveals a QT interval 
with Fridericia correction method (QTcF) >470 milliseconds.
21. The subject has a 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 or predose 
on Day 1.
For MRD Cohort 3 Only (Includes CSF Sample Collection)
1. The subject has had CSF collection performed within 30 days before Check-in (Day -1).
2. The subject has a known hypersensitivity to the anesthetic or its derivatives used during CSF 
collection or any medication used to prepare the area of lumbar puncture.
3. The subject has significant vertebral deformities (scoliosis or kyphosis) that, in the opinion of 
the investigator, may interfere with the lumbar puncture procedure.
4. The subject has a history of major (lumbar) back surgery, clinically significant back pain, 
and/or injury, in the opinion of the investigator.
5. The subject has a local infection at the puncture site.
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6. The subject has thrombocytopenia or other suspected bleeding tendencies noted before the 
procedure.
7. The subject has developed signs and symptoms of spinal radiculopathy, including lower 
extremity pain and paresthesia.
8. The subject has any focal neurological deficit that might suggest an increase in intracranial 
pressure.
9. The subject has any abnormal finding on ophthalmological assessment/fundoscopy indicative 
of raised intracranial pressure (ie, optic disc swelling/edema; or [uncontrolled] hypertensive 
retinopathy).
10. The subject regularly has moderate-to-severe headaches requiring analgesics.
11. The subject has any bleeding abnormality or history of bleeding abnormalities.
12. The subject has abnormal coagulation tests (prothrombin time [PT]/international normalized 
ratio [INR], activated partial thromboplastin time [aPTT]) at screening.
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products
7.3.1
Concomitant Medications
The use of concomitant medications (as defined in Section 9.1.4) after randomization (ie, Day 1) 
until the final follow-up visit 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.
The occasional use of acetaminophen (approximately <1 g/day) is allowed.
7.3.2
Fruit Juice
Subjects will refrain from consuming grapefruit juice, grapefruits, and products containing 
grapefruit beginning approximately 2 weeks prior to administration of the first dose of study drug, 
throughout the trial (including any washout interval between treatment periods), and until the final 
follow-up visit.
Subjects also will refrain from consuming all juices 24 hours prior to and after administration of 
each dose of study drug on PK sampling days. Consumption of all fruits other than grapefruit is 
allowed on all days of the trial.
7.3.3
Alcohol
Subjects will refrain from consuming alcohol 7 days prior to the screening visit and each follow-up 
visit and from 7 days prior to and until the last PK blood sample has been collected. At all other 
times, 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.
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7.3.4
Caffeine
Subjects will refrain from consuming caffeinated beverages 24 hours prior to the screening visit 
and each follow-up visit and from 24 hours prior to and until the last PK blood sample has been 
collected. At all other times, 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 trial.
7.4
Diet, Fluids, and Activity
7.4.1
Diet and Fluids
During confinement and only up to 24 hours after the last dose (Days -1 to 2 for SRD cohort 1; 
Days -1 to 11 for MRD cohorts 2 to 6), subjects will be given 2 standardized meals and 
2 standardized snacks, each containing approximately 30% fat (relative to total calories). The 
meals served on dosing days should be similar in composition and caloric content for each cohort 
in the trial. Whether the standardized meals were fully consumed (100%), or if not, the percentage 
consumed (0, 25%, 50%, 75%) will be recorded on these days. For MRD cohorts 5 and 6 
(Japanese), subjects may continue with a Japanese diet provided it contains approximately 30% fat 
(relative to total calories).
After the 24-hour postdose procedures have been completed following the last dose of study drug, 
subsequent meals and snacks will be unrestricted in caloric content, composition, and timing. The 
study menu should be recorded and submitted to the study file with a copy provided to the sponsor 
prior to the start of the study.
Study drug (TAK-418 or matching placebo oral capsules) will be administered with approximately 
240 mL of water after a fast of at least 8 hours. Subjects will continue to fast for an additional 4 
hours after dosing. If a subject is unable to continue fasting for 4 hours postdose, a light snack may 
be provided no earlier than 2 hours postdose on nonintense PK collection days (Days 2 to 9 and 
Days 11 and 12 for the MRD cohorts). Subjects may consume water ad libitum except for 1 hour 
before and 1 hour after study drug administration.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling) from the screening visit, throughout the trial (including washout intervals between 
treatment periods), and until the final follow-up visit.
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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
Study drug should be discontinued immediately with appropriate clinical follow-up (including 
repeat laboratory tests, until a subject’s laboratory profile has returned to normal/baseline 
status, see Section 9.3.1), if the following circumstances occur at any time during study drug 
treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8×upper limit of 
normal (ULN), or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or INR >1.5, 
or
–
ALT or AST >3×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 postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
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, IRB/IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial when 
the subject meets the trial termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the trial. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit.
7.7
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The trial site should contact the sponsor for the 
replacement of subject’s treatment assignment and allocation number.
Replacement subjects will be allocated to the same cohort as the subject they replace. Subjects in 
cohort 1 who discontinue after receiving the first single dose (cohort 1, period A) may be replaced 
with subjects who only receive the second single dose (cohort 1, period B).
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
Details of the dosage form description and strengths, or of composition for the extemporaneous 
preparation, for the active drug and placebo, can be found in the pharmacy manual or in the 
referenced compounding manual, when applicable. Clinical study drug will be packaged to 
support enrollment and replacement subjects as required. When a replacement subject is required, 
the sponsor needs to be contacted prior to dosing.
8.1.1
Clinical Study Drug Labeling
Clinical study drug will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Clinical study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and remain in the original container until dispensed. The temperature 
excursion information can be found in the pharmacy manual or in the referenced compounding 
manual, when applicable. Receipt and dispensing of study drug must be recorded by authorized 
personnel at the trial site.
8.1.3
Clinical Study Drug Blinding
This is a double-blind trial; the investigator and subjects are blinded to treatment assignment. The 
unblinded study drug supply will be provided to an unblinded pharmacist or other qualified trial 
site personnel who will blind the study drug supplies. Treatment identity (name and strength or 
potency) will be included on the study drug container label; randomization code/disclosure 
envelopes or lists will be provided in accordance with the standard operating procedures of the 
clinical site.
8.1.4
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
The clinical study drug blind will be maintained through a randomization schedule held by the site 
unblinded pharmacist. The clinical study drug blind shall not be broken by the investigator unless 
information concerning the clinical study drug is necessary for the medical treatment of the subject. 
If possible, the medical monitor should be contacted before the study drug blind is broken. 
Unblinding will be performed per the standard operating procedures of the clinical site.
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8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical study drug received 
from the sponsor or designee, the amount dispensed to and returned by the subjects, and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country sponsor 
personnel or designee will provide appropriate documentation that must be completed for clinical 
study drug accountability, return, and destruction.
8.2
Ancillary Supplies
All ancillary supplies will be provided by either the clinical site or the sponsor or designee, based 
upon availability. The list of ancillary supplies and source information can be found in the 
pharmacy manual or in the referenced compounding manual, when applicable. If provided by 
Takeda, unused ancillary supplies will be accounted for and disposed of as directed by Takeda or a 
Takeda designee.
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9.0
STUDY PROCEDURES
The following sections describe the trial procedures to be performed and data to be collected as 
indicated in the schedules 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 points, per the 
discretion of the investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters the trial 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 and Randomization Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only one 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 be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another subject. 
A single subject cannot be assigned more than one randomization number.
9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned a randomization number in ascending numerical order at each
clinical site. The randomization number encodes the subject assignment to either TAK-418 or 
placebo, according to the randomization schedule generated before the trial. Each subject will be 
dispensed blinded study drug, labeled with his/her unique randomization number, throughout the 
trial.
9.1.2
Inclusion and Exclusion 
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
9.1.3
Medical History and Demographics
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the clinical site’s standard of care and appropriate clinical judgment, and 
also subject demographics.
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9.1.4
Prior and Concomitant Medications
Qualified site personnel will review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vaccines, supplements, nutraceuticals, and 
oral herbal preparations.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical, Neurological, and Fundoscopic Examinations
Qualified site personnel will conduct full physical and neurological examinations.
For MRD cohort 3 only, ophthalmological assessments of the retina (fundoscopy) will be 
conducted to determine whether subjects have abnormal findings suggestive of raised intracranial 
pressure.
9.2.2
Height and Weight
Body weight and height will be measured with the subject’s shoes off, and jacket or coat removed.
9.2.3
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.
9.2.4
Vital Signs
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (ie, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes before vital signs are 
measured. Vital signs will include heart 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.
Subjects should continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose except to stand for the measurement of standing vital signs (if needed) or other 
trial-related procedure.
9.2.5
12-Lead ECG
9.2.5.1
Standard 12-Lead ECGs
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before 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.
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QTcF intervals will be calculated in this trial.
For each cohort, a predose 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 trial cardiologist available as needed to review ECG tracings with 
abnormalities.
During the treatment period, if a subject demonstrates an increase in QTcF interval 
≥40 milliseconds compared with a predose baseline measurement, the ECG will be repeated 
within 5 minutes. The average value of the QTcF interval from the 2 ECGs will represent the value 
at that time point. If the average QTcF interval increase from baseline for any postdose time point 
is ≥40 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 trial 
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.
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.
9.2.5.2
Continuous 12-Lead Holter ECGs
The 12-lead Holter ECG monitoring will record a minimum of 13.5 hours of continuous cardiac 
monitoring. The Holter monitor will be connected at approximately 2 hours prior to the planned 
dosing time on Day 1 and will continuously be monitored for at least 13.5 hours with at least 
12 hours of postdose monitoring. Holter ECGs on Day -1 will start and end at the time that is 
matched to those on Day 1. Holter ECGs are not intended for real-time safety monitoring, but they 
will be used for ECG assessment by a central ECG vendor.
Triplicate 12-lead ECGs will be extracted from stored data approximately 1 minute apart from one 
another. For each time point, the best 3 consecutive complexes in Lead II will be selected for 
measurement by the central ECG reader. Lead V5 will be used when Lead II is unsuitable. The 
same lead will be used for measurements for each subject. A study-specific assessment of 
inter-reader variability will be performed. This procedure will compare the ECG heart rate and 
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Study ID TAK-418-1003
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20 March 2018
time intervals (RR, PR, QRS and QT intervals) of the first reading with an interpretation by a 
second reader.
The Holter procedure is further described in the procedure manual.
9.2.6
Study Drug Administration
For each cohort, study drug (TAK-418 or placebo) will be administered as described in Section 
7.4.1 and in accordance with the schedules of study procedures (Section 3.0).
9.2.7
9.2.8
9.2.9
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9.2.10
9.2.11 AE Monitoring
AE monitoring begins after signing of the informed consent form. 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. 
Samples will be taken following a minimum 8-hour overnight fast on the days stipulated in the 
schedules of study procedures (Section 3.0).
9.3.1
Clinical Laboratory Tests
Hematology
The hematology assessment will include the following tests:
Erythrocytes (red blood cells)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells) with absolute 
differential
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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 upper limit of normal total 
bilirubin will be fractionated
Protein (total)
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, -glutamyl transferase, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was noted.
If ALT or AST remains elevated >3×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.
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.
Other
The following additional tests will be performed:
Serum estradiol
PT
Serum LH
aPTT
Serum FSH
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9.3.2
Diagnostic Screening
Serum
The serum diagnostic screening assessment will include the following tests:
HIV 
Hepatitis screen (hepatitis B surface antigen, hepatitis C virus antibody)
hCG (pregnancy test)
hCG, human chorionic gonadotropin.
Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Urine 
The urine drug screening assessment will include the following tests:
Amphetamines
3,4-methylenedioxy-methamphetamine
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
9.4
PK, PD, Biomarker, and Pharmacogenomic Evaluations
9.4.1
PK, PD, Biomarker, and Pharmacogenomic Samples
Samples for PK, 
, and pharmacogenomic (PGx) analyses will 
be collected as specified in the schedules of study procedures (Section 3.0).
Please refer to the laboratory manual for information on the collection, processing, and shipment 
of samples to the central laboratory.
The decision as to which samples collected will be assayed for evaluation of PK, PD, 
 
s, and PGx will be determined by the sponsor. If indicated, these samples may also be 
assayed and/or pooled to measure metabolites and/or additional biomarkers in an exploratory 
manner.
It is anticipated that the total blood volume drawn for each subject in SRD cohort 1 (periods A and 
B) will be approximately 513 mL and for each subject in MRD cohorts 2 to 6 will be 
approximately 496 mL.
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Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample Collection
Plasma sample for TAK-418 PK
Blood
Plasma
Plasma sample for PK analysis
Mandatory
Urine sample for TAK-418 PK
Urine
Urine
Urine sample for PK analysis
Mandatory
CSF sample for TAK-418 PK
CSF
CSF
CSF sample for PK analysis
Mandatory
Mandatory
Mandatory
Mandatory
Mandatory
Mandatory
Mandatory
Optional
Optional
Abbreviations:
CSF, cerebrospinal fluid; 
 
 
PK, pharmacokinetic(s);
9.4.2
PK Measurements
9.4.2.1
PK Parameters
The PK parameters of TAK-418 will be determined from the concentration-time data for all 
evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be used in 
all computations involving sampling times. Nominal time intervals will be used for computations 
of urine PK parameters.
The following PK parameters will be calculated from plasma concentrations of TAK-418:
For SRD cohort 1 (periods A and B) after a single dose on Day 1
!
AUC∞
!
Cmax
!
tmax
!
AUCt
!
t1/2z
!
CL/F
!
Vz/F
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For MRD cohorts 2 to 6 on Day 1

AUC

Cmax

tmax
For MRD cohorts 2 to 6 at steady state (after the final dose)

AUC

Cmax

tmax

AUCt

t1/2z 

CL/F 

Vz/F 

Rac(AUC)

Rac(Cmax)
The following PK parameters will be calculated from urine concentrations of TAK-418:
For selected MRD cohorts after a single dose on Day 1 and at steady state (after the final dose)

Aet 

fe,t 

CLR
The following PK parameters will be calculated from CSF concentrations of TAK-418:
For MRD cohort 3 only at steady state (after the final dose)

CSF Cmax 

CSF AUC24 

CSF AUC48 

CSF AUC24:plasma AUC24

CSF AUC48:plasma AUC48
Additional PK parameters may be calculated as appropriate. A detailed PK analysis plan will be 
prepared before PK parameter computation.
9.4.2.2
Plasma for PK Measurements
Blood samples for PK analysis of TAK-418 in plasma will be collected into chilled blood 
collection tubes (vacutainer) containing the anticoagulant K2EDTA according to the schedules in 
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Section 3.0. The collected blood samples may be archived for additional analysis of potential 
metabolites.
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.
9.4.2.3
Urine for PK Measurements
Urine samples for PK analysis of TAK-418 will be collected according to the schedules in Section 
3.0. The collected urine samples may be archived for additional analysis of potential metabolites.
9.4.2.4
CSF for PK Measurements
CSF samples for PK analysis of TAK-418 will be collected, according to the schedules in Section 
3.0, using an indwelling spinal catheter inserted into the lower spinal canal by trained personnel at 
the clinical site per their standard operating procedure.
The actual time of sample collection, time since last dose was administered, and time since last 
meal will be recorded on the source document and eCRF.
9.4.2.5
PK Sample Analysis
Plasma, urine, and CSF concentrations of TAK-418 be measured by a validated high-performance 
liquid chromatography with tandem mass spectrometry assay.
9.4.3
PD Measurements
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9.4.4
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9.4.5
9.4.5.2
Biological Sample Retention and Destruction
In this trial, blood, urine, stool, and CSF samples 
 Any leftover biomarker samples, if not 
utilized, will be preserved and retained at the sponsor-selected long-term storage facility for up to 
15 years from the end of the trial. Genetic material will be initially stored at a vendor or 
comparable laboratory, under contract to Takeda, with validated procedures in place, and then 
preserved and retained at a long-term storage vendor, or a comparable laboratory, with validated 
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keda: For non-commercial use only and subject to t
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procedures in place, for up to but not longer than 15 years from the end of the trial when the trial 
report is signed, or if less, the maximum period permitted under applicable law or until consent is 
withdrawn.
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the trial will be stored securely with limited access, 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main trial but using a code that 
is different from the code attached to the health information and other clinical test results collected 
in the trial. The sample and data are linked to personal health information with code numbers; the 
samples are stripped of all personal identifying information but a key linking the samples to 
clinical analysis data exists. This link means that the subject may be identified but only indirectly. 
The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
at any time and request disposal of a stored sample. Any remaining sample that can be identified as 
coming from the subject will be destroyed. The investigator and sponsor may continue to use and 
distribute any information and test results gathered before the request to withdraw.
9.4.6
Confinement
9.4.6.1
SRD Cohort 1 (Periods A and B)
Subjects will report to the clinical site the morning before the scheduled day of study drug 
administration (Day -1) at the discretion of the investigator. Subjects will remain in the clinic until 
48 hours postdose (Day 3). At the discretion of the investigator, subjects may be requested to 
remain at the clinical site longer.
9.4.6.2
MRD Cohorts 2 to 6
Subjects will report to the clinical site the morning before the scheduled day of study drug 
administration (Day -1) at the discretion of the investigator. Subjects will remain in the clinic until 
48 hours after the last dose of study drug (Day 12). 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 preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
retest 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 
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a concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study drug or after any change in study drug, 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 drug, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented on an overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 9.2.

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.
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).
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
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10.2.2 Assigning Causality of AEs
The relationship of each AE to study drug will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE, eg, the 
study has been terminated, the subject died, dosing with study drug had not yet started or 
dosing with study drug was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
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10.2.7 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “not recovered/not 
resolved.”

Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and abnormal LFTs) will commence at the time the subject 
signs the informed consent form. For each cohort, routine collection of AEs will continue until the 
last follow-up visit. For subjects who discontinue prior to the administration of study drug, AEs 
will be followed until the subject discontinues study participation.
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug 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 
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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 drug(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of study drug 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 but 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 
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(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 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.3.1 must also be 
performed. In addition, an LFT increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9).
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subjects’ 
treatment assignments. The SAP will provide further details regarding the definition of analysis 
variables and analysis methods to address all trial objectives.
A targeted data review will be conducted prior to unblinding of subjects’ treatment assignments. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
or appropriateness of the planned statistical methods. This review may be conducted on a 
cohort-by-cohort basis.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety set will include all subjects who were enrolled and received at least 1 dose of study drug. 
Subjects in this analysis set will be used for demographic, baseline characteristic, and safety 
summaries.
11.1.1.2 PK Set
The PK set will include all subjects who received at least 1 dose of study drug and have at least 
1 measurable plasma or CSF concentration or amount of drug in urine for TAK-418.
11.1.1.3 PD Set
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 and other baseline characteristic variables (eg, age, height, weight, BMI) 
for the pooled placebo group, each TAK-418 dose level, and TAK-418 overall. The number and 
percentage of subjects in each class of the categorical demographic and other baseline 
characteristic variables (eg, sex, ethnicity, race) will be tabulated for the pooled placebo group, 
each TAK-418 dose level, and TAK-418 overall. Data from subjects who received placebo will be 
pooled across cohorts, as appropriate to each analysis. Individual subject demographic and other 
baseline characteristic data will be listed.
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11.1.3 PK Analysis
TAK-418 concentrations in plasma (including trough concentrations for the MRD cohorts) and 
CSF will be summarized by dose over each scheduled sampling time point using descriptive 
statistics. Individual plasma concentration data versus time will be presented in a data listing. CSF 
samples will be collected on a more limited schedule than plasma samples, and not all PK analyses 
will be appropriate for these data.
Descriptive statistics (arithmetic mean, SD, %CV, median, minimum, maximum, and/or 
geometric mean) will be used to summarize the plasma and CSF PK parameters for TAK-418, as 
appropriate.
An analysis of variance (ANOVA) model may be used to assess time dependency in the PK of 
plasma TAK-418 between Day 1 and Day 10. Specifically, time invariance will be assessed by 
comparing AUCτ for Day 10 to the AUC∞for Day 1, separately for each dose. The model will 
include dose level, day, and interaction of dose level by day as factors and the natural logarithmic 
AUCs as the responses. Within the framework of the ANOVA, the point estimates for the ratios of 
AUC central values and their 90% CIs between Day 10 and Day 1 also will be provided for each 
dose level.
The amount of TAK-418 excreted in urine will be summarized by dose over each scheduled 
sampling interval using descriptive statistics. Individual urine TAK-418 excretion data by 
collection interval will be presented in a data listing.
Urine PK parameters will be summarized using descriptive statistics.
11.1.4 PD Analysis
Concentrations of 
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summarized by dose using descriptive statistics for baseline, postdose, and change from baseline 
to postdose. AUEC will be calculated for each subject and summarized by dose.
The difference in 
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estimated. The distribution of this difference will be characterized. Further details will be provided 
in the SAP.
11.1.5
11.1.6 Safety Analysis
Safety summaries will be performed separately for cohort 1 (SRD cohort) and cohorts 2 to 6 (MRD 
cohorts); data for subjects who received placebo will be pooled across all cohorts, as appropriate to 
each analysis. All safety data will be presented in data listings.
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11.1.6.1 AEs
TEAEs will be summarized by placebo, TAK-418 dose level, and TAK-418 overall.
11.1.6.2 Clinical Laboratory Evaluations
Individual results of clinical laboratory tests from hematology, chemistry, or urinalysis that meet 
Takeda’s markedly abnormal criteria (to be defined in the SAP) will be listed and summarized by 
placebo, TAK-418 dose level, and TAK-418 overall. Baseline, postdose, and change from baseline 
to postdose clinical laboratory data will be summarized for placebo and TAK-418 dose levels.
11.1.6.3 Vital Signs
Individual results of vital signs that meet Takeda’s markedly abnormal criteria (to be defined in the 
SAP) will be listed and summarized by placebo, TAK-418 dose level, and TAK-418 overall. 
Baseline, postdose, and change from baseline to postdose vital sign data will be summarized for 
placebo and each TAK-418 dose level.
11.1.6.4 ECGs
Individual quantitative ECG parameters from the 12-lead safety ECGs that meet Takeda markedly 
abnormal criteria (to be defined in the SAP) will be listed and summarized by placebo, each 
TAK-418 dose level, and TAK-418 overall. Baseline, postdose, and change from baseline to 
postdose quantitative ECG parameter data will be summarized for placebo and each TAK-418 
dose level.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned. However, a blinded review of the safety, tolerability, and available 
PK data, will be conducted after completion of each cohort and prior to dose escalation in the trial.
11.3
Determination of Sample Size
The sample sizes chosen are considered sufficient for evaluation of safety, tolerability, PK, and PD 
of each cohort but are not based on statistical considerations.
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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 designee 
and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 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 trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the study drug 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
This study will be conducted in accordance with the protocol and with the consensus ethical 
principles derived from international guidelines, including the Declaration of Helsinki and 
CIOMS (Council for International Organizations of Medical Sciences) International Ethical 
Guidelines, ICH GCP guidelines, and laws and regulations applicable to clinical studies (including 
US 21 Code of Federal Regulations [CFR] and European regulation 536/2014).
The protocol, informed consent forms, investigator's brochure, and other relevant supporting 
documents (eg, advertisements, information on payments and compensation available to subjects) 
must be submitted to an IRB/IEC by the investigator. Written approval of the protocol from the 
IRB/IEC must be obtained before the study is initiated, ie, the first subject signs the study informed 
consent form. 
The study cannot be initiated until notification is received from the sponsor.
Any amendment to the protocol, except when necessary to eliminate an immediate hazard to study 
participants, requires IRB/IEC written approval before implementation.
If required by either country or regional regulations or procedures, approval from the Competent 
Regulatory Authority will be obtained before commencement of the study or implementation of an 
amendment. 
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC.

Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures.
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, 
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transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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.
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Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify the 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 
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.
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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 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 
designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information
Trial contact numbers can be found in the study manual, the communication plan, or other similar 
documents provided to the site.
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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 serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 List of Abbreviations
Aet
amount of drug excreted in urine from time 0 to time t
ALT
alanine aminotransferase
ANOVA
analysis of variance 
aPTT
activated partial thromboplastin time
ASD
autism spectrum disorder
AST
aspartate aminotransferase
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUCτ
area under the plasma concentration-time curve during a dosing interval
AUCt
area under the plasma concentration-time curve from time 0 to time t
BMI
body mass index
%CV
percent coefficient of variation
CFR
Code of Federal Regulations
CL/F
apparent clearance after extravascular administration
CLR
renal clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CSF
cerebrospinal fluid
CSF AUC24
area under the CSF concentration-time curve from time 0 to 24 hours
CSF AUC48
area under the CSF concentration-time curve from time 0 to 48 hours
CSF AUC24:plasma 
AUC24
ratio of CSF AUC24 to area under the plasma concentration-time curve from time 0 to 
24 hours (AUC24)
CSF AUC48:plasma 
AUC48
ratio of CSF AUC48 to area under the plasma concentration-time curve from time 0 to 
48 hours (AUC48)
CSF Cmax
maximum observed concentration in CSF
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
fe,t
fraction of administered dose of drug excreted in urine from time 0 to time t
FIH
first-in-human
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For non-commercial u
ce after ex
e after
e
observed
observe
l nervous 
nervou
rebrospina
brospi
area und
rea un
area 
are
ma
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:plasma
:plasma
Cmax
max
SSRS
SSRS
ECG
ECG
eCR
C
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C
se only and s
ion
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ubject to the applicable Terms of Use
ours
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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
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
KDM1
lysine-specific demethylase family 1
LFT
liver function test
LH
luteinizing hormone
LSD1
lysine-specific demethylase 1A
MRD
multiple-rising dose 
NOAEL
no-observed-adverse-event-level
PAD
pharmacologically active dose
PD
pharmacodynamic(s)
PGx
Pharmacogenomic(s)
PK
pharmacokinetic(s)
PT
prothrombin time
PTE
pretreatment event
QD
once daily
QTcF
QT interval with Fridericia correction method
Rac(AUC)
accumulation ratio based on AUCτ
Rac(Cmax)
accumulation ratio based on Cmax
SAE
serious adverse event
SAP
statistical analysis plan 
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TEAEs
treatment-emergent adverse events
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
CCI
CCI
CCI
Property of Takeda: For non-commercial us
s)
mic(s)
ic(s)
netic(s)
tic(s)
mbin time
bin tim
eatment e
atment
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QT int
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15.0
DATA HANDLING AND RECORDKEEPING
The investigator or qualified designee is responsible for recording and verifying the accuracy of 
subject data. By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature. By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate.
Detailed information regarding data management procedures for this protocol will be provided by 
the sponsor or designee.
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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.
5. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43.
6. Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr 2007;12(2):156-62.
7. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol 
1974;47:211-8.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 
31 days after the last dose of study drug. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. If a subject is found to be pregnant 
during study, study drug will be discontinued and the investigator will offer the subject the 
choice to receive unblinded treatment information.
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 31 days after last 
dose of study drug, female subjects of childbearing potential* must use a highly effective method 
of contraception with low user dependency (from the list below).
In addition, they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
*A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range 
(FSH >40 IU/L) may be used to confirm a postmenopausal state in younger women (eg, those <45 
years old) or women who are not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, <1% failure rate per year when used consistently and correctly). 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are as follows:

Nonhormonal Methods:
–
IUD.
–
Bilateral tubal occlusion or ligation.
2. Unacceptable methods of contraception are as follows:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
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3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy and donation of ova during 
the course of the study.
4. During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed and all subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures. Such guidance should include a 
reminder of the following:
a) contraceptive requirements of the study
b) assessment of subject compliance through questions such as the following:
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late? (Even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes.”)
iv. Is there a chance you could be pregnant?
5. In addition to a negative serum hCG pregnancy test at screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), and a negative serum hCG pregnancy test prior to receiving the first dose of 
study drug on Day 1.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (ie, condom) in males with pregnant partners.

assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-418 and placebo) should be immediately discontinued.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418
Study ID TAK-418-1003
Page 84 of 84
Protocol 
20 March 2018
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the subject agrees to the primary care physician being informed, the investigator should notify 
the primary care physician that the subject was participating in a clinical study at the time she 
became pregnant and provide details of the study drug the subject received (blinded or unblinded, 
as applicable).
All pregnancies in subjects on active study drug will be followed up to final outcome, using the 
pregnancy form. Pregnancies will remain blinded to the study team. The outcome, including any 
premature termination, must be reported to the sponsor. An evaluation after the birth of the child 
will also be conducted.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in 
Healthy Subjects
NCT Number: NCT03501069
SAP Approve Date: 28 January 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-418-1003
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in 
Healthy Female Subjects
PHASE 1
Version: Final
Date: 28 January 2019
Prepared by:
Based on:
Protocol Version: Original
Protocol Date: 05 March 2018
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ultiple O
iple 
macodyna
acodyn
sion
on: : Fin
Fin
e: 28
28 Jan
J
Protoc
Proto
Pr
P
For non-co
r


TAK-418-1003
Page 2 of 25
Statistical Analysis Plan Final
28 January 2019
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418-1003
Page 3 of 25
Statistical Analysis Plan Final
28 January 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Trial Exploratory Objectives......................................................................................6
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1
Primary Endpoints .....................................................................................................8
5.2
Secondary Endpoints .................................................................................................8
5.3
Exploratory Endpoints ...............................................................................................8
5.3.1
Exploratory PK Endpoints....................................................................................8
5.3.2
Exploratory PD Endpoints....................................................................................9
5.3.3
Exploratory Biomarker Endpoints......................................................................10
5.3.4
Other Exploratory Endpoints..............................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.1.3
Definition of Study Visit Windows ....................................................................13
7.1.4
Conventions for Missing Adverse Event Dates...................................................13
7.1.5
Conventions for Missing Concomitant Medication Dates...................................13
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................15
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................15
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418-1003
Page 4 of 25
Statistical Analysis Plan Final
28 January 2019
7.9.1
Pharmacokinetic Analysis ..................................................................................15
7.9.2
Exploratory Pharmacodynamic Analysis............................................................18
7.10
Other Outcomes.......................................................................................................18
7.11
Safety Analysis........................................................................................................18
7.11.1 Adverse Events ..................................................................................................19
7.11.2 Clinical Laboratory Evaluations .........................................................................20
7.11.3 Vital Signs .........................................................................................................21
7.11.4 12-Lead ECGs ...................................................................................................21
7.11.5 Other Observations Related to Safety.................................................................21
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................21
8.0
REFERENCES..............................................................................................................22
LIST OF IN-TEXT TABLES
Table 4.a - Planned Dosing Regimens and Ethnicity of Subjects .................................................7
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................23
Appendix B
Criteria for Abnormal Changes from Baseline of Vital Signs..............................24
Appendix C
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters ......25
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418-1003
Page 5 of 25
Statistical Analysis Plan Final
28 January 2019
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
CPAP
Clinical Pharmacology Analysis Plan
CPK
creatine phosphokinase
CRF
case report form
ECG
electrocardiogram
FAS
full analysis set
GGT
-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IVRS
Interactive Voice Response System
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
PRO
patient-reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SDB
standard database
TLGs
tables, listings, and graphs
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418-1003
Page 6 of 25
Statistical Analysis Plan Final
28 January 2019
4.0
OBJECTIVES
4.1
Primary Objectives
To characterize the safety and tolerability of TAK-418 in non-Japanese and Japanese healthy 
female subjects when administered at single or multiple (once daily [QD]) oral escalating doses.
4.2
Secondary Objectives
To characterize the PK of TAK-418 in non-Japanese and Japanese healthy female subjects when 
administered at single or multiple (QD) oral escalating doses.
4.3
Trial Exploratory Objectives
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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ale subje
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TAK-418-1003
Page 7 of 25
Statistical Analysis Plan Final
28 January 2019
4.4
Study Design
This phase 1, randomized, double-blind, placebo-controlled trial is designed to evaluate the 
safety, tolerability, PK, and PD of single and multiple (QD) rising oral doses of TAK-418 
(capsule formulation) in healthy adult female subjects.
Approximately 48 subjects are planned for enrollment in 6 cohorts (n=8 per cohort). In SRD 
cohort 1, subjects will receive a single oral dose of study drug (TAK-418 or matching placebo) 
in a double-blind manner in period A. After a washout interval of at least 14 days after the dose 
of study drug and following the review of the safety, tolerability, and PK data from period A, 
subjects in cohort 1 may receive a second single dose of study drug in period B. In 
multiple-rising dose (MRD) cohorts 2 to 6, subjects will receive study drug QD for 10 days in a 
double-blind manner. In each SRD and MRD cohort, 6 subjects will be randomly assigned to 
receive TAK-418 and 2 to receive placebo. The cohorts will be enrolled in a consecutive, 
staggered, or parallel manner (see the protocol [1]).
For all SRD and MRD cohorts, blood samples will be collected for PK (TAK-418), 
 
and 
. For MRD cohort 3 only, serial lumbar CSF samples will 
be collected through an indwelling temporary catheter for 48 hours after the last dose of study 
drug for PK (TAK-418) and 
. Urine samples will be collected 
from selected non-Japanese MRD cohorts.
The planned TAK-418 dosing regimens and ethnicity of subjects are presented in Table 4.a. 
Non-Japanese subjects will be enrolled in cohorts 1 to 4 and Japanese subjects in cohorts 5 and 6. 
Planned doses range from 20 to 160 mg, but the actual doses administered after cohort 1 
(period A) and cohort 2 will be based on emerging safety, tolerability, and PK data available 
from the previous doses.
The trial may be conducted at multiple phase 1 units to support both CSF collection and 
recruitment of Japanese subjects.
Due to the early termination of the study, cohort 6 was not run. For cohorts 4 and 5, 4 subjects, 
instead of 8 were recruited. The actual doses for cohorts 3 and 4 are
mg and 
mg, 
respectively.
Table 4.a - Planned Dosing Regimens and Ethnicity of Subjects
Cohort
Ethnicity
Planned TAK-418
Dosing Regimen
Comments
1 (period A)
Non-Japanese
single dose
Cohort 1 (period A) may receive a second single dose 
(period B).
1 (period B)
single dose
2
D (10 days)
Cohort 2 may run in parallel with cohort 1 (period A or 
period B).
3
D (10 days)
Serial CSF samples will be collected.
4
D (10 days)
5
Japanese
D (10 days)
Cohort 5 may run in parallel with cohort 1, 2, or 3.
6
D (10 days)
CCI
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CCI
CCI
CCI
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TAK-418-1003
Page 8 of 25
Statistical Analysis Plan Final
28 January 2019
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
For All Cohorts
∀
Number and percentage of subjects with at least 1 TEAE.
∀
Number and percentage of subjects with at least 1 serious adverse event (SAE).
∀
Number and percentage of subjects who meet the markedly abnormal criteria for clinical 
laboratory values at least once postdose.
∀
Number and percentage of subjects who meet the markedly abnormal criteria for vital signs 
at least once postdose.
∀
Number and percentage of subjects who meet the markedly abnormal criteria for safety 
12-lead ECG parameters at least once postdose.
5.2
Secondary Endpoints
For SRD Cohort 1 (Periods A and B)
∀
AUC∞after a single dose of TAK-418.
For MRD Cohorts 2 to 6
∀
Area under the plasma concentration-time curve during a dosing interval (AUCτ) on Day 1 
and after the final dose following multiple (QD) dosing of TAK-418.
For All Cohorts
∀
Cmax.
∀
Time of first occurrence of Cmax (tmax).
5.3
Exploratory Endpoints
5.3.1
Exploratory PK Endpoints
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Page 9 of 25
Statistical Analysis Plan Final
28 January 2019
5.3.2
Exploratory PD Endpoints
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
3.2.2
Ex
E
keda: For non-commercial use only and subject to the applicable Terms of
rty of T
CI


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Page 10 of 25
Statistical Analysis Plan Final
28 January 2019
5.3.3
Exploratory Biomarker Endpoints
5.3.4
Other Exploratory Endpoints
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le Ter
and subject to the applica
For non-commercial use only


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Page 11 of 25
Statistical Analysis Plan Final
28 January 2019
6.0
DETERMINATION OF SAMPLE SIZE
The sample sizes chosen are considered sufficient for evaluation of safety, tolerability, PK, and 
PD of each cohort but are not based on statistical considerations.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418-1003
Page 12 of 25
Statistical Analysis Plan Final
28 January 2019
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percentage of subjects (N[%]) for each category, where applicable. Missing values 
will be categorized separately where deemed appropriate and necessary. 
Baseline values are defined as the last observed values before the first dose of study drug, unless 
otherwise stated; baseline values for Cohort 1 are defined as the last observed values before the 
first dose of study drug in each period.
In general, the presentation of decimal points will follow the following rules as appropriate: 
minimum and maximum values will be presented using the same number of decimal places as 
the recorded data. Arithmetic means, geometric means, and medians will be presented to 1 more 
decimal place than the recorded data, and SDs will be presented to 2 more decimal places than 
the recorded data. The confidence interval (CI) for a parameter estimate will be presented using 
the same number of decimal places as the parameter estimate. Percentage will be presented to 1 
decimal place (eg, 80.1%). All p-values will be rounded to 3 decimal places prior to assessment 
of statistical significance.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
As applicable, summaries for the study will be presented by pooled placebo, each TAK-418 dose 
level, TAK-418 overall and overall total for SRD and MRD parts. Data from Cohort 1 will be 
summarized separately by treatment regimen.
All statistical analyses will be performed using the SAS System® Version 9.4 or higher.
7.1.1
Study Definitions
There are no study-specific definitions.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) dosing page. Other study days are defined relative to Study Day 1, with 
Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. Study days prior to the 
first dose of study drug will be calculated as: {date of assessment/event – date of first dose of 
study drug}. Study days on or after the first dose of study drug will be calculated as: {date of 
assessment/event – date of first dose of study drug + 1}.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-418-1003
Page 13 of 25
Statistical Analysis Plan Final
28 January 2019
7.1.3
Definition of Study Visit Windows
All data will be categorized on the basis of the scheduled visit at which they are collected. These 
visit designators are predefined values that appear as part of the visit tab in the electronic case 
report form (eCRF). 
7.1.4
Conventions for Missing Adverse Event Dates
Incomplete adverse event (AE) start dates will be imputed to determine the relationship between 
the start date and the informed consent date, as well as the start date and the first dose date of the 
double-blind study medication. Incomplete AE dates will be presented as they are in the listings.
The following methods will be used to impute incomplete start dates of AEs:
∀
If only the month and year of the start date are available and the month and year are different 
than the month and year of the first dose of double-blind study medication or the stop date is 
prior to the first dose of study medication, then the first day of the month will be used for the 
start date. If only the month and year of the start date are available and the month and year 
are the same as the month and year of the first dose of double-blind study medication and the 
stop date is not prior to the date of first dose, then the date of first dose will be used for the 
start date.
∀
If only the year of the start date is available and the year is different than the year of the first 
dose of double-blind study medication or the stop date is prior to the first dose of study 
medication, then January 1st will be used for start date. If only the year of the start date is 
available and the year is the same as the year of the first dose of double-blind study 
medication and the stop date is not prior to the date of first dose, then the date of first dose 
will be used for start date.
7.1.5
Conventions for Missing Concomitant Medication Dates
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data.
∀
Safety Set: The safety set will include all subjects who were enrolled and received at least 1 
dose of study drug. Subjects in this analysis set will be used for demographic, baseline 
characteristic, and safety summaries.
∀
Pharmacokinetic (PK) Set: The PK set will include all subjects who received at least 1 dose 
of study drug and have at least 1 measurable plasma or CSF concentration or amount of drug 
in urine for TAK-418.
∀
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-418-1003
Page 14 of 25
Statistical Analysis Plan Final
28 January 2019
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in 
the PK and PD analyses; however, data for all subjects will be presented in the data listings.
7.3
Disposition of Subjects
Disposition of all screened failure subjects will be summarized according to the primary reason 
for screen failure. Additionally, disposition information for screen failures will be listed. 
Disposition of all randomized subjects will be summarized by pooled placebo, each TAK-418 
dose level, TAK-418 overall and overall for SRD and MRD parts. The categories will include:

Subjects who were randomized but not treated, if applicable.

Subjects who completed the study.

Subjects who prematurely discontinued the study.
Primary reasons for discontinuing study drug and/or visits, as recorded on the eCRF, will be 
summarized. 
Disposition information for randomized subjects will be listed. A listing of inclusion/exclusion 
criteria not met will be provided for randomized subjects who did not meet at least one inclusion 
criterion.
Significant protocol deviations will be listed and summarized. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for subjects in the Safety Set. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous demographic and other baseline characteristic variables (eg, age, height, weight, 
BMI) for the pooled placebo group, each TAK-418 dose level, and TAK-418 overall. The 
number and percentage of subjects in each class of the categorical demographic and other 
baseline characteristic variables (eg, sex, ethnicity, race) will be tabulated for the pooled placebo 
group, each TAK-418 dose level, and TAK-418 overall. Data from subjects who received 
placebo will be pooled across cohorts, as appropriate to each analysis. Individual subject 
demographic and other baseline characteristic data will be listed.
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant conditions or 
diseases that are present or ongoing at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 19 or higher) coding system.
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TAK-418-1003
Page 15 of 25
Statistical Analysis Plan Final
28 January 2019
Medical history and concurrent medical conditions will be listed by site and subject number. The 
listing will contain subject identifier, treatment, system organ class (SOC), preferred term (PT), 
whether there was any medical history or concurrent condition, and, if yes, a detail of the 
medical history or concurrent condition.
There will be no inferential analysis of medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medications are recorded on 
the eCRF and include any medications, other than study drug, taken at any time from signing of 
informed consent through the end of the study.
All medication history and concomitant medications will be listed by site and subject number. 
The listings will contain subject identifier, treatment, World Health Organization Drug 
Dictionary (WHODrug) preferred medication name, dose, unit, frequency, route, start date, stop 
date, whether the medication was ongoing, and reason for use. No inferential statistics will be 
presented. 
Medication history and concomitant medications will be coded using the WHODrug Version 01 
March 2016 or higher.
7.7
Study Drug Exposure and Compliance
Each subject will be given a single dose for each period in SRD and multiple doses in MRD as 
per the study design. Since all doses of study medication will be administered during 
confinement, study drug compliance will not be summarized. Dosing administration as well as 
study drug concentration data will be provided by subject and visit in the listings. 
There will be no inferential analysis of study drug exposure.
7.8
Efficacy Analysis
Not applicable
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
All PK summaries and analyses will be based on the PK Set. The PK parameters of TAK-418 
will be determined from the concentration-time data for all evaluable subjects. Actual sampling 
times, rather than scheduled sampling times, will be used in computations involving sampling 
times, except where otherwise noted. Nominal time intervals will be used for computations of
urine PK parameters.
PK blood, urine and CSF samples for TAK-418 concentrations will be collected as specified in 
the protocol. Plasma, urine, and CSF concentrations of TAK-418 free base will be measured by a 
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Statistical Analysis Plan Final
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validated high-performance liquid chromatography with tandem mass spectrometry assay. Free 
base TAK-418 concentrations are used for all PK summaries and analyses. 
TAK-418 concentrations in plasma (including trough concentrations for the MRD cohorts) and 
CSF will be summarized by dose over each scheduled sampling time point using descriptive 
statistics. The amount of TAK-418 excreted in urine will be summarized by dose over each 
scheduled sampling interval using descriptive statistics. Plasma concentrations will be 
summarized separately for the SRD and MRD portions of the study. Subjects randomized to 
placebo will not be include in these summaries but will be listed. Individual plasma 
concentrations versus time, CSF concentration versus time and individual urine TAK-418 
excretion by collection interval and individual will be listed separately.
Plasma or urine concentrations that are below the limit of quantification (< BLQ) will be treated 
as zero in the summarization of concentration values and derivation of PK parameters
The following PK parameters will be calculated from plasma concentrations of TAK-418:
For SRD cohort 1 (periods A and B) after a single dose on Day 1

AUC∞

Cmax

tmax

AUCt

t1/2z

CL/F

Vz/F
For MRD cohorts 2 to 6 on Day 1

AUC

AUC∞

Cmax

tmax
For MRD cohorts 2 to 6 at steady state (after the final dose)

AUC

Cmax

tmax

AUCt

t1/2z 

CL/F 

Vz/F 
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Statistical Analysis Plan Final
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
Rac(AUC)

Rac(Cmax)
Descriptive statistics (N, arithmetic mean, SD, %CV, median, minimum, and maximum) will be 
used to summarize the plasma PK parameters for TAK-418 by cohort, day and period (period A 
vs period B). In addition, geometric mean will be computed for Cmax and AUCs. Individual 
plasma PK parameters will be listed.
The following PK parameters will be calculated from urine concentrations of TAK-418:
For selected MRD cohorts after a single dose on Day 1 and at steady state (after the final dose)

Aet 

fe,t 

CLR
Descriptive statistics (N, arithmetic mean, SD, %CV, median, minimum, and maximum) will be 
used to summarize the urine PK parameters for TAK-418 by cohort and day. Individual urine PK 
parameters will be listed.
The following PK parameters will be calculated from CSF concentrations of TAK-418:
For MRD cohort 3 only at steady state (after the final dose)

CSF tmax

CSF Cmax

CSF AUC24

CSF AUC48

CSF AUC24:plasma AUC24

CSF AUC48:plasma AUC48
Descriptive statistics (N, arithmetic mean, SD, %CV, median, minimum, maximum, and/or 
geometric mean) will be used to summarize the CSF PK parameters for TAK-418 by cohort, as 
appropriate. Individual CSF PK parameters will be listed.
Specific or additional PK parameters may be added as appropriate per the Clinical Pharmacology 
Analysis Plan (CPAP).
For the MRD part, an analysis of variance (ANOVA) model may be used to assess time 
dependency in the PK of plasma TAK-418 between Day 1 and Day 10. Specifically, time 
invariance will be assessed by comparing AUCτ for Day 10 to the AUC∞for Day 1, separately 
for each dose. The model will include dose level, day, and interaction of dose level by day as 
fixed factors and the natural logarithmic AUCs as the responses. Using the ANOVA model, the 
point estimates for the ratios of AUC central values and their 90% CIs between Day 10 and Day 
1 will also be provided for each dose level.
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Statistical Analysis Plan Final
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For non-Japanese MRD cohorts, dose proportionality for Cmax and AUCs will be tested using a 
power model. The power fit will be assumed as described by the following equation:
ln( 	
	
) =  +  ln() + 
where  is the intercept and  is the slope with random error ε. Dose proportionality will be 
declared if the 90% confidence interval (CI) for  lies entirely within the critical region,
1 + ln(0.80)
ln(
)
, 1 + ln(1.25)
ln(
)  
where 
 is the ratio of the highest and the lowest dose in the study. [3]
7.9.2
Exploratory Pharmacodynamic Analysis
7.10
Other Outcomes
7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory parameters, vital sign results, 12-lead ECG 
results, and other safety parameters. The Safety Set will be used for all summaries of safety 
CCI
CCI
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l be
be
n,
er Outc
Out
r non-commercial use only and subject to t
ty of Takeda: F


TAK-418-1003
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Statistical Analysis Plan Final
28 January 2019
parameters. These summaries will be presented by pooled placebo, each TAK-418 dose level, 
and TAK-418 overall, where appropriate, for the SRD and MRD portions of the study. Data for 
subjects who received placebo will be pooled across all cohorts, as appropriate to each analysis. 
All safety data will be presented in data listings.
7.11.1 Adverse Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation.
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
A TEAE is defined as any sign, symptom, syndrome, or new illness, regardless the relationship 
to study drug, which occurs on or after the administration of the study drug and no more than 30 
days after receiving the last dose of study drug (onset data-last date of dose +1 ≤ 30). A TEAE 
may also be a pretreatment AE or a concurrent medical condition diagnosed prior to the date of 
first dose of study drug that increases in severity after the start of dosing. Any event with 
partially or completely missing onset date information will be considered treatment emergent 
unless the available information indicates that the onset occurred outside the window (onset data-
last date of dose +1 ≤ 30).
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA, version 19 or higher). 
TEAEs are recorded in the eCRF as being related or not related to study drug and study 
procedure. TEAEs that are recorded as related to study drug and/or study procedure will be 
summarized separately. TEAEs will also be presented by intensity/severity (mild, moderate, and 
severe). Serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to 
death will also be summarized using SOC and PT.
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
TEAEs will be presented by pooled placebo, each TAK-418 dose level and TAK-418 overall. 
The tables will include the number and percentage (N[%]) of subjects. The following summary 
tables will be generated: 
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TAK-418-1003
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Statistical Analysis Plan Final
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
Overviews of TEAEs, including number of subjects and events.

TEAEs by SOC and PT, including number of subjects and events.

Subject mappings for TEAEs by SOC and PT.

TEAEs by PT.

Serious TEAEs by SOC and PT.

Relationship of TEAEs to study drug by SOC and PT.

Drug related TEAEs by SOC and PT.

Drug related TEAEs by PT.

Intensity of TEAEs by SOC and PT.

Intensity of drug related TEAEs by SOC and PT.

Pretreatment Adverse Events (PTE) by SOC and PT.
Data listings will be provided for PTEs, AEs, TEAEs leading to study drug discontinuation, 
SAEs, and AEs that resulted in death.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. Refer to Appendix B for 
scheduled clinical laboratory test measurements.
The central laboratory will perform laboratory tests, including hematology, urinalysis, chemistry 
and other tests. 
For hematology, urinalysis and chemistry tests, descriptive statistics (N, mean, median, SD, 
minimum and maximum) will be summarized for baseline, post-baseline, and change from 
baseline values by treatment regimen and study visit for both SRD and MRD using the Safety 
Set. Only the scheduled measurements will be included in the summary. 
Individual results for hematology and chemistry laboratory tests will be evaluated against the 
Takeda predefined laboratory markedly abnormal value (MAV) criteria (see Appendix A) using 
the result and criteria in SI units. All subjects with results that meet the MAV criteria will be 
presented in a data listing. The number and percentage of subjects with at least one post dose 
markedly abnormal laboratory test result will also be summarized. The mapping of the subjects 
who meet the MAV criteria after dosing will be listed as a table. All postdose observations, 
including scheduled and unscheduled measurements will be included in the MAV summaries. 
Listings of all clinical safety laboratory data will be provided and will be presented. Laboratory 
data outside of the normal reference range will be indicated in the listings. In addition, MAVs 
will be flagged. The listing will include site number, subject identifier, age (at informed consent), 
gender, treatment group, study visit, and sample collection date. Semen analysis parameters will 
be listed separately.
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7.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Summaries will be presented by pooled placebo and each TAK-418 
dose level for SRD and MRD parts.
Individual results of vital signs that meet Takeda’s markedly abnormal criteria (see Appendix B) 
will be summarized and provided in the data listings. If a subject has a MAV for a particular vital 
sign parameter, all visits for that subject for that parameter will be listed. The number and 
percentage of subjects with at least 1 postdose MAV signs measurement will be summarized by 
pooled placebo, each TAK-418 dose level and TAK-418 overall. The mapping of the subjects 
who meet the MAV criteria will be listed as a table. All observations, including ones at 
unscheduled visits, will be included in the MAV evaluation and summaries.
All vital sign results for all subjects in the Safety Set will be listed by subject in the data listings 
and markedly abnormal values will be flagged.
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to the protocol. The ECG 
parameters include heart rate, PR-interval, QRS-interval, QT-interval, QTcF interval, and the 
interpretation of the ECG profile by the principal investigator. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters will 
be presented for baseline, each post-baseline visit, and changes from Baseline in quantitative 
ECG parameters to each post-baseline visit. Only the scheduled measurements will be included 
in the summary. No inferential statistics will be presented.
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria (see Appendix C) will be summarized and provided in the 
data listings. Shift tables will be generated to show the investigator’s ECG interpretations at each 
postdose collection by the interpretation at Baseline.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5 Other Observations Related to Safety
Physical examination, neurological examination and fundoscopic examination findings will be 
presented in the data listings. 
Columbia-Suicide Severity Rating Scale results will be presented in the data listings.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
Dose proportionality for Cmax and AUCs will be assessed for non-Japanese MRD cohorts.
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Statistical Analysis Plan Final
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8.0
REFERENCES
1. A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-418 in 
Healthy Female Subjects, Millennium Pharmaceuticals, Inc, Original Protocol, Trial No. 
TAK-418-1003, dated 20 March, 2018.
2. World Health Organization. WHO Laboratory Manual for the Examination and Processing of 
Human Semen. 5th ed. Cooper TG, editor. Geneva, Switzerland: World Health Organization; 
2010.
3. Brian P. Simith, etc. (2000), Confidence Interval Criteria for Assessment of Dose 
Proportionality, Pharmaceutical Research; Vol 17, No. 10, pp 1278-1283.
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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 × LLN
>1.5 × ULN
Platelet count
Conventional
<75 × 103/L
>600 × 103/L
SI
<75 × 109/L
>600 × 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Alkaline Phosphatase
Both
--
>3 × ULN
ALT
Both
--
>3 × ULN
AST
Both
--
>3 × ULN
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Calcium
Conventional
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
Carbon dioxide (Bicarbonate)
Conventional
<8.0 mEq/L
--
SI
<8.0 mmol/L
--
Chloride
Both
<75 
>126
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 mol/L
Glucose
Conventional
<50 mg/dL
>350 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Gamma-glutamyl transferase
Both
--
>3 ×  ULN
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Total protein
Both
<0.8 ×  LLN
>1.2 ×  ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, LLN=lower limit of normal, ULN=upper limit of 
normal.
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Statistical Analysis Plan Final
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Appendix B
Criteria for Abnormal Changes from Baseline of Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
<35.6
>37.7
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Appendix C
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters
Parameter
Unit
Lower Criteria
Upper Criteria
HR
bpm
<50 
>120 
QT-interval
msec
≤50
≥460 
QTcF-interval
msec
≤50
≥500 OR
≥30 change from baseline and
≥450 
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