Clinical trial NCT04461483
Conditions: Healthy Volunteer
Sponsor: Takeda
Start date: 2020-08-13; Completion date: 2020-11-14
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-935 with single ascending doses (Part 1) and multiple doses with titration (Part 2).

Detailed description:
The drug being tested in this study is called TAK-935 tablet. TAK-935 tablet is being tested in Japanese healthy adult men. This study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-935 with single ascending doses (Part 1) and multiple doses with titration (Part 2).

The study will enroll up to 33 participants in total (Part 1 + 2). In Part 1, participants will be randomly assigned (by chance, like flipping a coin) to one of these treatment cohorts/groups;

* Cohort 1: Single dose of TAK-935 at 200 mg or placebo (fasted)
* Cohort 2: Single dose of TAK-935 at 600 mg or placebo (fasted)
* Cohort 3: Single dose of TAK-935 at 1200 mg or placebo (fasted)

In Part 2, participants will be randomly assigned to one of these treatment groups;

\- Cohort 4: Multiple doses with titration of TAK-935 or placebo at 100 mg twice daily (BID) from Day 1 to Day 7, 200 mg BID from Day 8 to Day 14 and 300 mg BID from Day 15 to Day 21 (fasted).

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 36 days for Part 1 and 63 days for Part 2. Participants will be hospitalized for 5 days in Part 1 and 26 days in Part 2.

Arms: arm 1: Part 1, Cohort 1; TAK-935 200 mg, tablets, orally once on Days 1 in fasted state. arm 2: Part 1, Cohort 2; TAK-935 600 mg, tablets, orally once on Days 1 in fasted state. arm 3: Part 1, Cohort 3; TAK-935 1200 mg, tablets, orally once on Days 1 in fasted state. arm 4: Part 1, Cohort 1-3; TAK-935 placebo-matching tablets, orally once on Days 1 in fasted state. arm 5: Part 2, Cohort 4: TAK-935 100 mg, tablets, orally twice on Days 1-7 in fasted state with multiple doses with titration. arm 6: Part 2, Cohort 4: TAK-935 200 mg, tablets, orally twice on Days 8-14 in fasted state with multiple doses with titration. arm 7: Part 2, Cohort 4: TAK-935 300 mg, tablets, orally twice on Days 15-21 in fasted state with multiple doses with titration. arm 8: Part 2, Cohort 4: TAK-935 placebo-matching tablets, orally twice on Days 1-21 in fasted state.
Interventions: intervention 1: TAK-935 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-935 Tablets intervention 2: TAK-935 placebo-matching tablets

Protocol documents:
Prot_000.pdf: 
Title: A Randomized, Double-blind, Placebo-Controlled, Phase 1 Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of Single Ascending Dose and Multiple Doses 
with Titration of TAK-935 in Healthy Japanese Subjects 
NCT Number: NCT04461483 
Protocol Approve Date: 02-JUL-2020 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


TAKEDA PHARMACEUTICALS 
PROTOCOL 
A Randomized, Double-blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of Single Ascending Dose and Multiple Doses with 
Titration of TAK-935 in Healthy Japanese Subjects 
 
 
 
Study Identifier: 
TAK-935-1004 
 
 
 
 
Compound: 
TAK-935 
 
 
 
 
Date: 
02 July 2020 
 
 
 
 
 
 
Version/Amendment 
Number: 
Amendment 2 
 
 
 
 
 
 
 
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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TABLE OF CONTENTS
1.0
STUDY SUMMARY...........................................................................................................7
2.0
STUDY SCHEMATIC ......................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES .......................................................................12
4.0
INTRODUCTION .............................................................................................................16
4.1
Background ..................................................................................................................16
4.2
Rationale for the Proposed Study ................................................................................18
4.3
Benefit/Risk Profile .....................................................................................................18
5.0
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................20
5.1
Hypothesis....................................................................................................................20
5.2
Trial Objectives ............................................................................................................20
5.2.1
Trial Primary Objective .........................................................................................20
5.2.2
Trial Secondary Objective .....................................................................................20
5.2.3
20
5.3
Endpoints .....................................................................................................................20
5.3.1
Primary Endpoint ...................................................................................................20
5.3.2
Secondary Endpoints .............................................................................................21
5.3.3
21
6.0
TRIAL DESIGN AND DESCRIPTION ...........................................................................23
6.1
Trial Design .................................................................................................................23
6.2
Dose Escalation ............................................................................................................24
6.3
Rationale for Trial Design, Dose, and Endpoints ........................................................25
6.3.1
Rationale of Trial Design .......................................................................................25
6.3.2
Rationale for Dose .................................................................................................26
6.3.3
Rationale for Endpoints .........................................................................................27
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures .................27
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters ....................................................................................................................28
6.5
Trial Beginning and End/Completion ..........................................................................28
6.5.1
Definition of Beginning of the Trial ......................................................................28
6.5.2
Definition of End of the Trial ................................................................................28
6.5.3
Definition of Trial Discontinuation .......................................................................28
6.5.4
Criteria for Premature Termination or Suspension of the Trial .............................29
6.5.5
Definition of Trial Completion ..............................................................................29
6.5.6
Criteria for Premature Termination or Suspension of a Site ..................................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............31
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7.1
Inclusion Criteria .........................................................................................................31
7.2
Exclusion Criteria ........................................................................................................32
7.3
Excluded Medications, Supplements, Dietary Products ..............................................33
7.4
Diet, Fluid, Activity .....................................................................................................34
7.4.1
Diet and Fluid ........................................................................................................34
7.4.2
Activity ..................................................................................................................35
7.5
Documentation of Subject Failure ...............................................................................35
7.6
Criteria for Discontinuation or Withdrawal of a Subject .............................................35
7.7
Procedures for Discontinuation or Withdrawal of a Subject .......................................37
7.8
Subject Replacement ....................................................................................................37
8.0
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................38
8.1
Clinical Study Drug .....................................................................................................38
8.1.1
Clinical Study Drug Labeling ................................................................................38
8.1.2
Clinical Study Drug Inventory and Storage ...........................................................38
8.1.3
Clinical Study Drug Blinding ................................................................................38
8.1.4
Randomization Code Creation and Storage ...........................................................39
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ......................................39
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs .................................39
9.0
STUDY PROCEDURES ...................................................................................................40
9.1
Administrative Procedures ...........................................................................................40
9.1.1
Informed Consent Procedure .................................................................................40
9.1.2
Inclusion and Exclusion .........................................................................................40
9.1.3
Medical History/Demography ...............................................................................41
9.1.4
Concomitant Medications ......................................................................................41
9.2
Clinical Procedures and Assessments ..........................................................................41
9.2.1
Full Physical Exam and Eye Exam ........................................................................41
9.2.2
Height and Weight .................................................................................................41
9.2.3
BMI ........................................................................................................................41
9.2.4
41
9.2.5
42
9.2.6
42
9.2.7
Study Drug Administration ....................................................................................43
9.2.8
Columbia Suicide Severity Rating Scale (C-SSRS) ..............................................43
9.2.9
Neuropsychiatric assessment .................................................................................43
9.2.10 AE Monitoring .......................................................................................................44
9.2.11
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9.2.12 Follow-up Visit ......................................................................................................46
9.3
Biomarker, PK, and PGx, Samples ..............................................................................46
9.3.1
PK Measurements ..................................................................................................47
9.3.2
Biomarker Measurements ......................................................................................49
9.3.3
PGx Measurements ................................................................................................50
9.4
Confinement .................................................................................................................51
10.0
ADVERSE EVENTS .........................................................................................................52
10.1
Definitions and Elements of AEs .................................................................................52
10.1.1 SAEs ......................................................................................................................54
10.1.2 Adverse Events of Special Interest ........................................................................55
10.2
AE Procedures .............................................................................................................55
10.2.1 Assigning Severity/Intensity of AEs ......................................................................55
10.2.2 Assigning Causality of AEs ...................................................................................56
10.2.3 Assigning Causality of AEs to Study Procedures ..................................................56
10.2.4 Start Date ...............................................................................................................56
10.2.5 End Date.................................................................................................................56
10.2.6 Pattern of Adverse Event (Frequency) ...................................................................56
10.2.7 Action Taken With Study Treatment .....................................................................56
10.2.8 Outcome .................................................................................................................57
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs .......................................................................................................................57
10.2.10
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities..............................................................................................................60
11.0
STATISTICAL METHODS ..............................................................................................61
11.1
Statistical and Analytical Plans ....................................................................................61
11.1.1 Analysis Sets ..........................................................................................................61
11.1.2 Analysis of Demography and Other Baseline Characteristics ...............................61
11.1.3 PK Analysis ...........................................................................................................61
11.1.4
61
11.1.5 Safety Analysis ......................................................................................................62
11.2
Interim Analysis and Criteria for Early Termination ...................................................63
11.3
Determination of Sample Size .....................................................................................63
12.0
QUALITY CONTROL AND QUALITY ASSURANCE .................................................64
12.1
Study-Site Monitoring Visits .......................................................................................64
12.2
Protocol Deviations ......................................................................................................64
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..................................64
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13.0
ETHICAL ASPECTS OF THE STUDY ...........................................................................65
13.1
IRB and/or IEC Approval ............................................................................................65
13.2
Subject Information, Informed Consent, and Subject Authorization ..........................65
13.3
Subject Confidentiality ................................................................................................67
13.4
Publication, Disclosure, and Clinical Trial Registration Policy ..................................67
13.4.1 Publication and Disclosure ....................................................................................67
13.4.2 Clinical Trial Registration ......................................................................................67
13.4.3 Clinical Trial Results Disclosure ...........................................................................68
13.5
Insurance and Compensation for Injury .......................................................................68
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION ...........................................69
14.1
Administrative Information .........................................................................................69
14.1.1 Study Contact Information .....................................................................................69
14.1.2 Investigator Agreement ..........................................................................................69
14.1.3 Study-Related Responsibilities ..............................................................................69
14.1.4 List of Abbreviations .............................................................................................69
15.0
DATA HANDLING AND RECORDKEEPING ..............................................................71
15.1
CRFs (Electronic) ........................................................................................................71
15.2
Record Retention .........................................................................................................72
16.0
REFERENCES ..................................................................................................................73
17.0
APPENDICES ...................................................................................................................74
LIST OF IN-TEXT TABLES
Table 2.a
Outline of the Study Parts and Planned Dosing Cohorts .......................................11
Table 6.a
Outline of the Study Parts and Planned Dosing Cohorts .......................................23
Table 7.a
Prohibited Medications ..........................................................................................34
Table 9.a
45
Table 9.b
Primary Specimen Collections ...............................................................................47
Table 9.c
Sampling of Blood Samples for PK Analysis (Part 1) ...........................................48
Table 9.d
Sampling of Blood Samples for PK Analysis (Part 2) ...........................................48
Table 9.e
50
Table 9.f
50
Table 10.a
Takeda Medically Significant AE List ..................................................................54
LIST OF IN-TEXT FIGURES
Figure 6.a
Dose Escalation ......................................................................................................25
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LIST OF APPENDICES
.74
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Study No. TAK-935-1004
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-935
Study Identifier: TAK-935-1004
Phase: 1
Protocol Title: A Randomized, Double-blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability 
and Pharmacokinetics of Single Ascending Dose and Multiple Doses with Titration of TAK-935 in Healthy Japanese 
Subjects.
Trial Design:
This study consists of 2 parts. 
Part 1 is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics (PK) 
and 
 single ascending
doses (SAD) of TAK-935 in healthy Japanese subjects.
Part 2 is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, PK and PD of multiple 
doses (MD) with titration of TAK-935 in healthy Japanese subjects when administered daily for 21 days. The subjects 
enrolled in Part 2 will initially receive TAK-935 or placebo at 100 mg twice daily (BID) followed by escalation to 
200 mg BID, and then followed by 300 mg BID, with 7 days for each titration period.
Trial Primary Objective:
To evaluate the safety and tolerability of TAK-935 in healthy Japanese subjects when administered as single oral dose 
or multiple oral doses with titration.
Secondary Objectives:
To evaluate the pharmacokinetics of TAK-935 in healthy Japanese subjects when administered as single oral dose or 
multiple oral doses with titration.
Trial Subject Population: Healthy Japanese subjects
Planned Number of Subjects:
Part 1 (SAD): 24 subjects; 8 subjects per cohort
Part 2 (MD): 9 subjects
Planned Number of Sites:
1
Dose Levels:
<Part 1>
Cohort 1: Single dose at 200 mg(fasted)
Cohort 2: Single dose at 600 mg (fasted)
Cohort 3: Single dose at 1200 mg (fasted)
<Part 2>
Cohort 4: Multiple doses with titration at 100 mg BID 
from Day 1 to Day 7, 200 mg BID from Day 8 to Day 
14 and 300 mg BID from Day 15 to Day 21 (fasted)
Route of Administration:
Oral
Duration of Treatment:
Part 1: 1 day per each cohort
Part 2: 7 days per each dose level and 21 days for 
complete treatment
Planned Trial Duration:
<Part 1> 
Screening period: Days -28 to -3 
Check-in: Day -2 
Treatment period: Days 1 to 3
Follow-up period: Day 8
<Part 2> 
Screening period: Days -28 to -3 
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Study No. TAK-935-1004
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Check-in: Day -2
Treatment period: Days 1 to 24
Follow-up period: Day 35
Main Criteria for Inclusion:
In order to be eligible for study participation,
1.
The subject must understand the study procedures and agree to participate by providing written informed consent.
2.
The subject must be willing and able to comply with all study procedures and restrictions.
3.
The subject must be a Japanese healthy adult male or female, aged 20 to 55 years, inclusive, at the time of 
informed consent. 
4.
7KHVXEMHFWPXVWKDYHDERG\PDVVLQGH[DQGNJP2 at the Screening Visit.
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The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months prior to the first dose of study drug or first invasive procedure.
6.
The subject must be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 
 performed at the Screening Visit and prior to the first dose of study drug.
7.
The subject must meet the following birth control requirements:
•
Is a male subject who is sterile or agrees to use an appropriate method of contraception, including a condom with 
spermicidal cream or jelly, from the first dose of study drug until 90 days after the last dose of study drug. No 
restrictions are required for a vasectomized male subject provided the subject is at least 1-year postbilateral 
vasectomy procedure prior to the first dose of study drug. A male subject whose vasectomy procedure was 
performed less than 1 year prior to the first dose of study drug must follow the same restrictions as a 
nonvasectomized man. Appropriate documentation of surgical procedure should be provided.
•
Is a male subject who agrees to not donate sperm from the first dose of study drug until 90 days after the last dose 
of study drug.
•
Is a female subject of nonchildbearing potential, defined by at least 1 of the following criteria:
a.
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of spontaneous amenorrhea in females aged >45 years with serum follicle-stimulating hormone [FSH] levels 
>40 mIU/mL). Appropriate documentation of follicle-stimulating hormone levels should be required.
b.
Hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure.
c.
Had a tubal ligation with appropriate documentation of surgical procedure.
d.
Congenital conditions such as uterine aplasia etc.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject:
1.
Has a history of clinically significant endocrine, gastrointestinal (including motility disorder and intestinal 
obstruction), cardiovascular (including arrhythmia), hematological, hepatic, immunological, renal, respiratory, 
genitourinary, major neurological (including stroke and epileptic seizure), or degenerative ophthalmological
abnormalities or diseases.
2.
Has participated in another investigational trial within 4 weeks or 5 half-lives (whichever is longer) before the 
pretrial visit (Screening). The 4-week or 5 half-lives window will be derived from the date of the last trial 
procedure and/or adverse event (AE) related to the trial procedure in the previous trial to the pretrial/Screening 
Visit of the current trial.
3.
Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the sponsor.
4.
Has a history of cancer (malignancy).
5.
Has any lifetime history of a suicide attempt, or have suicidal ideation or, any suicidal behavior within 12 months, 
or who are at significant risk to commit suicide, as judged by the investigator using the Columbia Suicide Severity 
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TAK-935 
 
Study No. TAK-935-1004 
Page 9 of 78 
Protocol 
02 July 2020 
 
Rating Scale (C-SSRS) or are clinically judged by the investigator to be at risk for suicide. 
6. 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. 
7. Has a positive alcohol or drug screen. 
8. Had major surgery, donated or lost whole blood prior to the start of study drug administration as any of below: 
For both male and female subjects, 
≥200 mL within 4 weeks (28 days) 
For male subjects, 
≥400 mL within 12 weeks (84 days) 
≥800 mL in total within 52 weeks (364 days) 
For female subjects, 
≥400 mL within 16 weeks (112 days) 
≥400 mL in total within 52 weeks (364 days) 
9. Had gastrointestinal surgery that could impact the absorption of study drug. 
10. Has a history of a major psychiatric disorder as diagnosed utilizing Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition criteria. 
11. Has a known hypersensitivity to any component of the formulation of TAK-935 or related compounds. 
12. Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription 
drugs or herbal remedies, beginning approximately 7 days before administration of the initial dose of study drug, 
throughout the trial (including washout intervals between trial periods), until the Follow-up Visit. 
13. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the 
Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. 
14. 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. 
15. Has a substance abuse disorder. 
16. Has a QT interval with Fridericia’s correction method (QTcF) >450 msec confirmed with one repeat testing, at the 
Screening Visit. 
17. Had abnormal Screening or Day -1 laboratory values that suggested a clinically significant underlying disease or 
subject with the following laboratory abnormalities: alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >1.5 times the upper limit of normal (ULN). 
18. Has tested positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody, HIV 
antibody/antigen, or serologic reactions for syphilis at Screening. 
19. In the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.  
Main Criteria for Evaluation and Analyses: 
The primary endpoint of the study is: 
Safety: 
• 
Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE). 
The secondary endpoints will be assessed through evaluation of the following parameters: 
PK parameters of TAK-935: 
• 
Maximum observed plasma concentration (Cmax) 
• 
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration 
(AUClast) (Part 1 only). 
• 
AUC from time 0 to time of infinity (AUC∞) (Part 1 only). 
• 
AUC from time 0 to 24 hours (AUC24) (Part 1 only). 
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TAK-935
Study No. TAK-935-1004
Page 10 of 78
Protocol
02 July 2020
•
AUC during a dosing interval (AUCĲ) at steady state (Part 2 only).
Statistical Considerations:
Safety analysis: 
Analyses will be conducted using the safety analysis set.
A TEAE is defined as an AE that occurs on or after the start of study drug administration. TEAEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) dictionary and tabulated by the system organ class 
(SOC) and the preferred term (PT). Percentage of subjects who experience at least 1 TEAE (the primary endpoint of 
the study) will be calculated within the following analyses.
•
The frequency of all TEAEs
•
The frequency of drug-related TEAEs
•
The frequency of TEAEs by intensity
•
The frequency of drug-related TEAEs by intensity
•
The frequency of TEAEs leading to study drug discontinuation
•
The frequency of serious TEAEs
PK Measures: 
Concentrations of TAK-935 and its metabolite M-I in plasma will be summarized in each of Part 1 and Part 2 by cohort 
over each scheduled sampling time using descriptive statistics. Individual plasma concentration data versus time will 
be presented in a data listing. Plasma PK parameters will be calculated using noncompartmental modeling and 
summarized by cohort and day using descriptive statistics. Dose proportionality in plasma PK parameters (Cmax and 
AUCs) will be assessed graphically for those parameters in Part 1. Additional analyses will be included if appropriate.
Sample Size Justification:
The sample sizes of 8 subjects for each of the cohorts in Part 1 and 9 subjects for Part 2 (Part 1: 6 active 2 placebo in 
each cohort, Part 2: 6 active 3 placebo as total) are considered to be sufficient for the evaluation of safety, tolerability, 
and PK of each cohort. Sample sizes were not based on statistical power considerations.
CCI
Property of Takeda: For non-commercial use 
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TAK-935 
 
Study No. TAK-935-1004 
Page 11 of 78 
Protocol 
02 July 2020 
 
2.0 
STUDY SCHEMATIC 
Table 2.a 
Outline of the Study Parts and Planned Dosing Cohorts 
Part 
Cohort 
Daily dose level 
(mg) 
Dosing regimen 
Randomization 
Part 1 
1 
200 
Single oral dose 
under fasted 
condition 
Subjects will be 
randomized to 
TAK-935 or placebo 
at a ratio of 6:2 in 
each cohort, 
double-blind. No 
stratification 
variables will be used 
for randomization. 
2 
600 
3 
1200 
Part 2 
4 
Day 1-7: 200 
(100 mg BID) 
Day 8-14: 400 
(200 mg BID) 
Day 15-21: 600 
(300 mg BID) 
Multiple oral doses 
up/titration with 
TAK-935 for 7 days 
per each dose level 
within the same 
subjects under fasted 
condition 
Subjects will be 
randomized to 
TAK-935 or placebo 
at a ratio of 6:3, 
double-blind. No 
stratification 
variables will be used 
for randomization. 
BID: twice daily 
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TAK-935
Study No. TAK-935-1004
Page 12 of 78
Protocol
02 July 2020
3.0
SCHEDULE OF STUDY PROCEDURES
Part 1
Screening Check-in
Baseline 
Treatment 
Study 
Exit 
Follow-up 
Early 
Termination 
Days
-28 to -3 
Day -2 
Day -1 
Day 1
Day 2
Day 3 
Day 8
Informed consent
x
Inclusion/exclusion criteria
x
x
x
x
(predose)
Demographics and medical 
history 
x
Medication history
x
Physical exam
x
x
x
(predose)
x
x
x
Eye exam a
x
x
x
Neuropsychiatric assessment
(MMSE and pre-determined 
questions) 
x
x
x
x
Weight, height, and BMI c
x
x
x
x
Concomitant medications d
x
x
x
x
x
x
x
x
Concurrent medical conditions
x
x
Hormone laboratory tests f
x
x
x
Hepatitis panel
x
HIV, Syphilis
x
Serum FSH (if applicable)
x
Urine drug and alcohol screen
x
x
Confinement i
x
x
x
x
x
PK blood collection j
x
x
x
x
PGx DNA collection l
x
Study drug dosing
x
C-SSRS assessment 
x
x
x
x
AE assessment m
x
x
x
x
x
x
x
x
AE: adverse event; BMI: body mass index; C-SSRS: Columbia Suicide Severity Rating Scale; ECG: electrocardiogram; FSH: 
follicle-stimulating hormone; MMSE: mini mental state examination; PGx: pharmacogenomic(s); PK: pharmacokinetic(s); TSH: 
thyroid stimulating hormone; 
a
Eye exam includes visual field evaluation, best corrected visual acuity, fundoscopy without pupillary dilation, and a slit lamp 
microscopy  
c
Height and BMI will only be collected at Screening. 
CCI
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Study No. TAK-935-1004
Page 13 of 78
Protocol
02 July 2020
d
Record all ongoing medications from Screening and throughout the study.
Hormone laboratory tests (prolactin, growth hormone, cortisol, and TSH) will be collected on Day-1 (upon rising), and 
Discharge (upon rising) or Early Termination under fasted conditions.
i
Subjects will be discharged on Day3.
j
Blood samples for pharmacokinetic analyses will be collected at predose and at 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 12, 16, 24 and 48 
hours postdose or Early Termination. 
One blood sample will be collected for PGx DNA analysis on Day 1.
m
Any event from signing of informed consent will be captured as an AE.
CCI
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applic


TAK-935
Study No. TAK-935-1004
Page 14 of 78
Protocol
02 July 2020
Part 2
Screening
Check-
in
Baseline
Dose Level 1
Dose Level 2
Dose Level 3
Study 
Exit
Follow-
up
Early 
Termination
Days
-28 to -3
Day
-2
Day
-1
Day
1
Day
2-6
Day 
7
Day
8
Day 
9-13
Day
14
Day
15
Day 
16-20
Day
21
Day 
22-23
Day
24
Day
35
Informed consent
x
Inclusion/exclusion criteria
x 
x 
x 
x
(predose)
Demographics and medical 
history
x 
Medication history
x
Physical exam
x 
x 
x
(predose)
x
(predose)
x 
x 
x 
Eye exam a
x
x
x
Neuropsychiatric 
assessment
(MMSE and pre-determined 
questions)
x 
x 
x 
x 
x 
x 
x 
Weight, height, and BMI c
x
x
x
x
Concomitant medications d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent medical 
conditions
x 
x 
Hormone laboratory tests f
x
x
x
x
x
Hepatitis panel
x
HIV, Syphilis
x
Serum FSH (if applicable)
x
Urine drug and alcohol 
screen
x 
x 
Confinement i
x
x
x
x
x
x
x
x
x
x
x
x
x
PK blood collection j
x
x
x
x
x
PGx DNA collection l
x
Study drug dosing
x
x
x
x
x
x
x
x
x
C-SSRS assessment
x
x
x
x
AE assessment m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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TAK-935
Study No. TAK-935-1004
Page 15 of 78
Protocol
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AE: adverse event; BMI: body mass index; C-SSRS: Columbia Suicide Severity Rating Scale; ECG: electrocardiogram; FSH: follicle-stimulating hormone; MMSE: mini 
mental state examination; PGx: pharmacogenomic(s); PK: pharmacokinetic(s); TSH: thyroid stimulating hormone; 
a
Eye exam includes visual field evaluation, best corrected visual acuity, fundoscopy without pupillary dilation, and a slit lamp microscopy. 
c
Height and BMI will only be collected at Screening.
d
Record all ongoing medications from Screening and throughout the study. 
f
Hormone laboratory tests (prolactin, growth hormone, cortisol, and TSH) will be collected on Day-1 (upon rising), Day 8 (upon rising), Day 15 (upon rising), and Day 
22 (upon rising) or Early Termination under fasted conditions
i
Subjects will be discharged on Day 24
j
Blood samples for pharmacokinetic analyses will be collected at pre-morning dose and at 0.25, 0.5, 1, 2, 4, 8, 10 and 12 hours after morning dose on Day 1, Day 7, 
Day 14 and Day 21  or Early Termination  
One blood sample will be collected for PGx DNA analysis on Day 1.
m
Any event from signing of informed consent will be captured as an AE.
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TAK-935 
 
Study ID TAK-935-1004 
Page 16 of 78 
Protocol 
02 July 2020 
 
 
4.0 
INTRODUCTION 
4.1 
Background 
Around 50 million people worldwide suffer from epilepsy, and nearly 80% of these are in 
developing countries [1]. Annual new cases run between 40 and 70 per 100,000 in the general 
population in developed nations, and in undeveloped nations, the figure is often close to twice that 
due to the higher risk of experiencing conditions that lead to permanent brain damage [1]. Epilepsy 
is a prevalent disease (0.4% to 0.8%) with the highest incidence rates in early childhood and in the 
elderly [2]. With nearly one-third of patients having symptoms refractory to available medications 
[2], the National Institute of Neurological Diseases and Stroke has identified “an urgent need for 
novel chemical entities… that will provide a greater likelihood of complete control of seizures in 
patients who are currently treatment-resistant [3]”. 
All currently available medications for epilepsy are anticonvulsant rather than antiepileptogenic or 
disease-modifying [4]. Their mechanism of action involves the modulation of ion channels, 
receptors, or neurotransmitter metabolism, with none primarily targeting astrocyte function. There 
is a significant need and opportunity to develop drugs that not only influence the seizure threshold 
but also mitigate the neurobiological changes that occur in epileptogenesis. 
TAK-935 is the first potent, selective, and central nervous system (CNS)-penetrant inhibitor of the 
cholesterol 24-hydroxylase (CH24H) to have entered clinical development. CH24H converts brain 
cholesterol to 24S-hydroxycholesterol (24HC). This cholesterol metabolite, 24HC, leaves the 
brain via lipoproteins and is excreted in bile. Aberrant cholesterol metabolism is implicated in 
epilepsy disorders/syndromes. CH24H, which is expressed by the CYP46A1 gene, is a 
brain-specific enzyme responsible for cholesterol catabolism [5-7]. Deletion of the CH24H gene in 
knock out mice is compatible with normal life and does not significantly decrease or increase the 
total brain cholesterol, as catabolism appears tightly linked with synthesis. Therefore, when 
CH24H is deleted, an adaptation occurs reducing ~40% of de novo cholesterol synthesis [6]. While 
the enzyme is predominantly expressed in neurons in a normal state, nonclinical and human 
postmortem studies have shown that neurodegeneration and brain insults lead to induction of 
CH24H expression in astrocytes and microglia [8,9]. 
Under normal conditions, extracellular glutamate is sequestered by glutamate transporters on 
neighboring astrocytes that require adequate cholesterol levels to efficiently maintain lipid raft 
structures in the astrocyte plasma membrane. Upon CNS injury, CH24H is induced in reactive 
astrocytes and microglia. This leads to disruption in astrocytic glutamate homeostasis and a large 
increase in extracellular glutamate levels. As the CH24H enzyme converts cholesterol essential for 
the integrity of plasma membrane lipid rafts to 24HC, the circulating levels of 24HC increase and 
may further contribute to underlying pathophysiological processes. Excessive extracellular 
glutamate and 24HC levels are thought to play major roles in excitotoxicity either through a 
sustained activation of the N-methyl-D-aspartate receptor channel or as a positive allosteric 
modulator of the receptor. The processes may be equally important in contributing to the enhanced 
glutamatergic activity observed in epilepsy disorders. TAK-935 target engagement has been 
confirmed in the human brain with a proprietary positron emission tomography ligand. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-935
Study ID TAK-935-1004
Page 17 of 78
Protocol
02 July 2020
There have been reports that some eye diseases (such as glaucoma and cataract) may be associated 
with cholesterol metabolism. Subjects in the study will have ophthalmological evaluations. 
To date, TAK-935 has been studied in 4 phase 1 studies in healthy adult subjects and in a phase 2a 
study in adult subjects with developmental and epileptic encephalopathies (DEEs) in the United 
States. Overall, 108 healthy subjects have been enrolled in phase 1 studies, of which 86 subjects 
have received active treatment with TAK-935. Safety results from these studies showed that 
TAK-935 up to a single dose of 1350 mg (Study TAK-935-101) and multiple doses up to 400 mg 
once daily (QD) for 14 days (Study TAK-935-1002) is generally safe and well tolerated. However, 
multiple doses of 300 mg twice daily (BID) and 600 mg QD for 10 days, both without up-titration, 
did not appear to be well tolerated due to the emergence of neurologic and psychiatric adverse 
events (AEs) in healthy subjects in the Study TAK-935-1002. Two subjects discontinued study 
drug due to a treatment-emergent adverse event (TEAE) of acute psychosis (Cohort 4: TAK-935 
600 mg QD) and a TEAE of confusional state (Cohort 3: TAK-935 300 mg BID). The former 
acute psychosis event was reported on Study Day 10, for a 
-year-old male, and was considered 
of severe intensity, lasting through Day 14; the investigator considered the TEAE to be related to 
study treatment. The latter, a confusional state TEAE, was reported for a 
-year-old subject on 
Study Day 9, lasting through Day 11; the event was of mild intensity and also considered related to 
study drug. As a result of these events, dosing for all subjects in Cohorts 3 and 4 was stopped after 
Day 10. For the subsequent Cohort 5, the dose of TAK-935 was reduced to 400 mg QD, and 
additional safety monitoring measures as well as stopping rules were implemented. All subjects in 
the 400 mg QD Cohort 5 completed the 14-day dosing as planned. 
Subsequently in 18 subjects with DEEs (Study TAK-935-2001), TAK-935 was titrated to the 
target dose of 300 mg BID over 30 days followed by maintenance period up for a total duration of 
85-91 days and was generally well tolerated, although fully reversible psychiatric AEs were 
observed; consisting of insomnia, agitation, communication disorder, irritability, and listlessness.
After single-dose oral administration of TAK-935 from 15 to 1350 mg as solution under fasted 
conditions in healthy Western subjects, TAK-935 Cmax was reached rapidly at 0.25 to 0.52 hours 
postdose (median tmax). Mean TAK-935 t1/2z ranged from 0.82 to 7.16 hours. Exposure to 
TAK-935 increased in a greater than dose-proportional manner over the 15 to 1350 mg dose range. 
Over the 90-fold dose range of 15 to 1350 mg, mean TAK-935 Cmax and AUC increased by 183- 
and 581-fold, respectively. 
Following multiple doses (10 to 14 days) of TAK-935 100 mg QD, 300 mg QD, 300 mg BID, 
400 mg QD, and 600 mg QD (without up-titration) as solution under fasted conditions, TAK-935 
Cmax was reached rapidly at 0.33 to 0.5 hours across the dose range studied. Mean TAK-935 t1/2z
was similar between Days 1 and 14, ranging from 3.49 to 4.83 hours across the 100 to 600 mg dose 
range. Over the 4-fold dose range of 100 to 400 mg QD after multiple-dose administration, mean 
TAK-935 Cmax and AUCĲ on Day 14 increased 6.08- and 6.12-fold, respectively. Doses of 100 or 
400 mg QD for 14 days did not show apparent exposure accumulation on Day 14 when compared 
with Day 1, while 300 mg QD for 14 days showed about 1.74- and 1.42-fold increase of Cmax and 
AUCĲ on Day 14, respectively. 
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Study ID TAK-935-1004
Page 20 of 78
Protocol
02 July 2020
5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed on the basis of the following hypotheses. 
x
Safety results from overseas phase 1 studies showed that TAK-935 up to a single dose of 
1350 mg (Study TAK-935-101) and multiple doses up to 400 mg QD for 14 days (Study 
TAK-935-1002) is generally safe and well tolerated.
x
In 18 subjects with DEEs, TAK-935 was titrated to the target dose of 300 mg BID over 30 days 
followed by maintenance period up for a total duration of 85-91 days and was generally well 
tolerated, although fully reversible psychiatric AEs were observed (Study TAK-935-2001). 
x
5.2
Trial Objectives
5.2.1
Trial Primary Objective
x
The primary objective of the study is to evaluate the safety and tolerability of TAK-935 in 
healthy Japanese subjects when administered as single oral dose or multiple oral doses with 
titration.
5.2.2
Trial Secondary Objective
x
The secondary objective of the study is to evaluate the PK of TAK-935 in healthy Japanese 
subjects when administered as single oral dose or multiple oral doses with titration.
5.3
Endpoints
5.3.1
Primary Endpoint
The primary endpoint of the study includes: 
Safety endpoint: 
x
Percentage of subjects who experience at least 1 TEAE
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TAK-935
Study ID TAK-935-1004
Page 21 of 78
Protocol
02 July 2020
5.3.2
Secondary Endpoints
Secondary endpoints include:
Pharmacokinetic endpoints: 
x
Maximum observed plasma concentration (Cmax).
x
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast) (Part 1 only). 
x
AUC from time 0 to time of infinity (AUC) (Part 1 only).
x
AUC from time 0 to 24 hours (AUC24) (Part 1 only). 
x
AUC during a dosing interval (AUCĲ) at steady state (Part 2 only).
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Study ID TAK-935-1004
Page 22 of 78
Protocol
02 July 2020
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Study ID TAK-935-1004
Page 23 of 78
Protocol
02 July 2020
6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This study consists of 2 parts, which is a randomized, double-blind, placebo-controlled study to 
assess safety, tolerability, and PK 
 of TAK-935 when administered via oral administration 
in healthy Japanese subjects.
Part 1 is a SAD study, consisting of 3 cohorts containing 8 subjects each. On Day 1 of each dose 
level, a single dose of TAK-935 or placebo will be administered, and safety, PK 
 will be 
evaluated. 
Part 2 is a MD with titration study within the same subjects. TAK-935 or placebo will be 
administered to the 9 subjects at the dose of 100 mg BID from Day 1 to Day 7, then 200 mg BID 
from Day 8 to Day 14, and finally 300 mg BID from Day 15 to Day 21, and safety, PK 
 will 
be confirmed. The planned dose levels of TAK-935 to be evaluated are outlined in Table 6.a. 
Table 6.a 
Outline of the Study Parts and Planned Dosing Cohorts
Part
Cohort
Daily dose level 
(mg)
Dosing regimen
Randomization
Part 1
1
200
Single oral dose 
under fasted 
condition
Subjects will be 
randomized to 
TAK-935 or placebo 
at a ratio of 6:2 in 
each cohort, 
double-blind. No 
stratification 
variables will be used 
for randomization.
2
600
3
1200
Part 2
4
Day 1-7: 200 
(100 mg BID)
Day 8-14: 400 
(200 mg BID)
Day 15-21: 600 
(300 mg BID)
Multiple oral doses 
up/titration with 
TAK-935 for 7 days 
per each dose level 
within the same 
subjects under fasted 
condition
Subjects will be 
randomized to 
TAK-935 or placebo 
at a ratio of 6:3, 
double-blind. No 
stratification 
variables will be used 
for randomization.
BID: twice daily
Study Population 
Study Population: Healthy Japanese subjects. 
Planned Number of Subjects 
Part 1 (SAD): Total of 24 subjects 
x
Cohort 1: 8 subjects 
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TAK-935 
 
Study ID TAK-935-1004 
Page 24 of 78 
Protocol 
02 July 2020 
 
 
• Cohort 2: 8 subjects 
• Cohort 3: 8 subjects 
Part 2 (MD): Total of 9 subjects 
• Cohort 4: 9 subjects (dose up/titration within the same subjects) 
Key Study Procedure Overview 
<Part 1> 
After the screening visit, eligible participants will check-in on Day-2. On Day 1, eligible 
participants will be randomized 6:2 to TAK-935 or placebo in each dose group in double-blinded 
fashion. No stratification variables will be used for randomization. On the same day, study drug 
will be administered by oral administration of single dosing of TAK-935 to each cohort at each 
dose level. The subjects will be discharged on Day 3. Intensive PK sampling will be performed 
from Day 1 to Day 3. A schedule of the events in this part is shown in Section 3.0. 
<Part 2> 
After the screening visit, eligible participants will check-in on Day-2. On Day 1, eligible 
participants will be randomized 6:3 to TAK-935 or placebo in double-blinded fashion. No 
stratification variables will be used for randomization. Study drug will be administered every day 
by oral administration of multiple dosing with up-titration of TAK-935 to 9 subjects firstly at 
100 mg BID from Day 1 to Day 7, then at 200 mg BID from Day 8 to Day 14, and finally at 
300 mg BID from Day 15 to Day 21, successively. The subjects will be discharged on Day 24. 
Intensive PK sampling will be performed on Day 1, Day 7, Day 14 and Day 21. A schedule of the 
events in this part is shown in Section 3.0. 
6.2 
Dose Escalation 
<Part 1> 
Blinded safety and PK will be evaluated at the end of treatment for each cohort and prior to dose 
escalation. 
For each dose level administered/completed cohort, the principal investigator and the sponsor will 
carefully review the available safety, tolerability, and blinded PK data and determine whether 
dosing should stop or continue in this study. 
If the Cmax and/or the AUC is expected to be much greater than the maximum exposure at 
maximum dose evaluated in precedent clinical studies, the dose level in the subsequent cohort may 
be lower than the planned dose. 
All AEs reported during the Treatment Period, both within and across cohorts, up to the time of 
discharge on Day 3, will be evaluated to assess the need for subject and/or study termination in 
accordance with the pre-specified criteria for discontinuation/termination (Section 6.5.4.1). 
Following assessment of the AE data and pre-defined criteria for study termination, dose 
escalation may be interrupted/stopped and the blind broken for further analysis. 
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If agreement regarding a dose escalation decision cannot be reached between the principal 
investigator and the sponsor, the study will be stopped. 
<Part 2> 
Part 2 (Cohort 4) will be initiated after the evaluation of blinded safety and PK at 600 mg single 
dose in Part 1 (Cohort 2). 
All AEs reported during the Treatment Period up to the time of discharge on Day 24 will be 
evaluated to assess the need for subject and/or study termination in accordance with the 
pre-specified criteria for discontinuation/termination (Section 6.5.4.1).
Figure 6.a shows the dose escalation scheme. 
Figure 6.a 
Dose Escalation 
Part 1 (Single dose)
Part 2 (Multiple dose)
Cohort 1 a—o
Cohort 2 a—o
Cohort 3 a
Cohort 4 b
TAK-935 200 mg or 
placebo
TAK-935 600 mg or 
placebo
TAK-935 1200 mg or 
placebo
TAK-935 100 mg BID or 
placebo, then TAK-935
200 mg BID or placebo, and 
finally TAK-935 300 mg 
BID or placebo with 
up-titration within the same 
subjects
a
The subsequent cohort should be run after the evaluation of blinded safety and PK in the prior cohort and 
confirmed that the prior cohort is well tolerated. 
b
Cohort 4 will be initiated after the evaluation of blinded safety and PK in Cohort 2.
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design
The subjects of this study will be healthy Japanese adult subjects who do not have any significant 
diseases including cardiovascular or cerebrovascular diseases. This population will allow 
evaluation of the safety, tolerability, PK, 
 profile of TAK-935 in healthy subjects after 
single and repeated daily oral administration. Results of this study of Japanese healthy subjects 
will support further development of TAK-935 for the treatment of DEEs.
This study consists of 2 parts, which is a randomized, double-blind, placebo-controlled study to 
assess safety, tolerability, and PK 
 of TAK-935 when administered via oral administration 
in healthy Japanese subjects. Part 1 is a SAD study, consisting of 3 cohorts containing 8 subjects 
each, with each cohort randomized 6:2 (active vs. placebo). Part 2 is a MD with titration study 
containing 9 subjects randomized 6:3 (active vs. placebo). These parts are intended to support the 
design of and dosing regimen selection for subsequent studies with TAK-935 in patients with 
DEEs.
Study safety assessments are selected based on data from nonclinical and clinical studies with 
TAK-935. In nonclinical studies in rats, cataracts were observed after TAK-935 administration. 
Therefore, eye examination will be conducted accompanied with physical examination in this 
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study. Based on the potential risk of TAK-935 on neurologic and psychiatric effects which were 
observed in clinical studies, neuropsychiatric assessment will be conducted during the study. 
6.3.2 Rationale for Dose 
To date, 86 subjects have received active treatment with TAK-935 and safety results from Phase 1 
studies conducted previously showed that TAK-935 up to a single dose of 1350 mg (Study 
TAK-935-101) and multiple doses up to 400 mg QD for 14 days (Study TAK-935-1002) is 
generally safe and well tolerated. However, multiple initial doses of 300 mg BID and 600 mg QD, 
without up-titration, did not appear to be well tolerated due to the emergence of neurologic AEs in 
healthy subjects. Subsequently in 18 subjects with DEEs (Study TAK-935-2001), TAK-935 was 
titrated to the target dose of 300 mg BID over 30 days followed by maintenance period up for a 
total duration of 85-91 days and was generally well tolerated, although fully reversible psychiatric 
AEs were observed. In the current on-going Phase 2a study in adult subjects with complex regional 
pain syndrome, the up-titration scheme from TAK-935 100 to 300 mg BID over 21 days (7 days 
per each dose level) was selected based on population PK/PD simulations showing that the target 
dose of 600 mg/day is associated with a greater probability of demonstrating effectiveness in the 
majority of subjects, while maintaining an acceptable tolerability profile in this target patient 
population. The same dosing regimen, based on subject’s body weight is also used in the ongoing 
Phase 2 studies with pediatric epileptic syndromes such as Dravet Syndrome, Lennox-Gastaut 
syndrome, Duplication 15q syndrome, and Cyclin-dependent kinase-like 5 deficiency syndrome. 
Consequently, 200 mg is selected as starting dose and 1200 mg as highest dose for Part 1 and 
similar titration regimen, ie, TAK-935 100 to 300 mg BID was selected for Part 2. The highest 
dose level in Part 1 (ie, 1200 mg) allows the evaluation of QT intervals at supratherapeutic 
exposure and may be adjusted on the basis of review of the emerging safety and PK data available 
at that point. Only doses lower than or equal to 1200 mg will be assessed. 
The relative bioavailability BA of TAK-935 tablets vs solution was evaluated in Study 
TAK-935-1005. Following administration TAK-935 300 mg (as three 100 mg tablets) vs 
TAK-935 300 mg solution in the fasted state, median TAK-935 tmax was 0.53 and 0.35 hours, 
respectively. The geometric mean Cmax, AUClast, and AUC∞ was 995 ng/mL, 1260 h*ng/mL, and 
1294 h*ng/mL, respectively, following administration of the tablet, and 1577 ng/mL, 
1481 h*ng/mL, and 1440 h*ng/mL, respectively, following administration of the solution. The 
ratio (tablet vs solution) TAK-935 Cmax was 0.63 (90% CI, 0.41-0.97), AUClast was 0.85 (90% CI, 
0.71-1.02), and AUC∞ was 0.84 (90% CI, 0.68-1.05). 
Under the fasting conditions, oral administration of the TAK-935 tablet formulation had a Cmax 
37% lower than that observed with the solution, but only a minor decrease (15%-16%) in total 
exposure when TAK-935 was administered as a tablet relative to the solution. 
Food decreased TAK-935 Cmax by 60% but had little impact on the total TAK-935 exposure of the 
tablet formulation, as AUClast and AUC∞ decreased by only 11%. Therefore, fasted condition is 
selected for both single and multiple dose part. 
This study is also intended to support inclusion of Japanese subjects in future late phase clinical 
studies. 
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6.3.3
Rationale for Endpoints 
6.3.3.1
Safety Endpoints 
Since this is the first study in Japanese subjects, the standard safety endpoints for early clinical will 
be included. 
There have been reports that some eye diseases (such as glaucoma and cataract) may be associated 
with cholesterol metabolism. Subjects in the study will have ophthalmological evaluations.
6.3.3.2
Pharmacokinetic Endpoints 
To characterize the PK of TAK-935 and its metabolites M-I in Japanese subjects, the 
pharmacokinetic parameters will be estimated as data permit. See Section 9.3.1 for more details.
6.3.3.3
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this trial, the blood samplings for PK and PD evaluation are the critical procedures. 
x
At any postdose time point, the blood sampling for PK evaluation need to be performed as 
close to the exact nominal time point/scheduled time as possible.
x
All other procedures should be performed as close as possible either before or after the 
scheduled times.
x
x
The order of priority of which procedure can be changed during the study with joint agreement 
of the investigator and the sponsor. 
x
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
x
Safety evaluation will be performed within the specified time frame as close as possible.
x
Blood sampling for PK evaluation should occur before the nominal time of standard meal, if 
scheduled together.
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• If the times for meals and the study procedures are conflicted, meals should be taken basically 
after all of the study procedures are completed. 
6.4 
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters 
The maximum daily dose may not exceed that currently outlined in Section 6.3.2. In other words, 
the highest dose level in Cohort 3 of Part 1 (ie, 1200 mg) may be adjusted on the basis of review of 
the emerging safety and PK data available at that point. Only doses lower than or equal to 1200 mg 
will be assessed. No modification will be made except for the dose level of Cohort 3. 
It is understood that the current study may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the study 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. Above alterations will also be reflected in future protocol 
amendment as needed to avoid possible confusion at the site. 
6.5 
Trial Beginning and End/Completion 
6.5.1 Definition of Beginning of the Trial 
The overall study begins when the first subject signs the study informed consent form. 
6.5.2 Definition of End of the Trial 
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit, discontinues from the study, or is lost to follow-up 
(ie, the investigator is unable to contact the subject). 
6.5.3 Definition of Trial Discontinuation 
Study discontinuation because of nonsafety reasons, such as the following: 
• A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical study 
using the study treatment(s) results in the study being stopped for a nonsafety-related reason. 
• Data from drug(s) of the same class, or methodology(ies) used in this study become available 
and results in the study being stopped for a nonsafety-related reason. 
• The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment. 
Study discontinuation because of safety reasons: 
• Early study termination because of unanticipated concerns of safety to the study subjects 
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s) 
of the same class, or methodology(ies) used in this study. 
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6.5.4 Criteria for Premature Termination or Suspension of the Trial 
6.5.4.1 Criteria for Premature Termination or Suspension of the Trial 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
• Study-specific criteria for terminating the study (eg, study meets predefined rule for futility or 
benefit, study meets predefined stopping rules within or between cohorts per Section 6.2). 
• One or more subjects in any single cohort develop acute psychosis. 
• Two or more subjects in any single cohort or across more than one cohort experience any of the 
Takeda Medically Significant AE List (as outlined in Table 10.a).* 
• Two or more subjects in any single cohort or across more than 1 cohort experience alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations >5×upper limit of 
normal (ULN) in the absence of a concomitant bilirubin increase (see below).* 
• One or more subjects in any single cohort or across more than 1 cohort experience ALT and/or 
AST elevations >3×ULN in the presence of a total bilirubin increase >2×ULN or an 
international normalized ratio (INR) >1.5 without findings of cholestasis or other alternate 
etiology to explain the elevations (ie, “Hy’s Law cases”). 
• Two or more subjects in any single cohort or across more than 1 cohort experience ALT and/or 
AST elevations >3×ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).* 
* Please note that the study may be terminated early prior to full attainment of these criteria (eg, if 
just 1 subject experiences 1 of these events) if warranted by safety data from the other subjects 
dosed in the study to date. 
6.5.4.2 Procedures for Premature Termination or Suspension of the Trial 
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
study, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by the study site during the course of termination or study 
suspension. 
6.5.5 Definition of Trial Completion 
The overall study is to be considered as completed as per the same definition as in Section 6.5.2. 
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6.5.6 Criteria for Premature Termination or Suspension of a Site 
6.5.6.1 Criteria for Premature Termination or Suspension of a Site  
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, or is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.5.6.2 Procedures for Premature Termination or Suspension of a Site 
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
participation of a study site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by the study site during the course of 
termination or study suspension. 
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. The subject must understand the study procedures and agree to participate by providing written 
informed consent. 
2. The subject must be willing and able to comply with all study procedures and restrictions. 
3. The subject must be a Japanese healthy adult male or female, aged 20 to 55 years, inclusive, at 
the time of informed consent.
4. The subject must have a body mass index (BMI) DQGNJP2 at the Screening Visit.
5. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing 
products (eg, nicotine patch) for at least 6 months prior to the first dose of study drug or first 
invasive procedure.
6. The subject must be judged to be in good health by the investigator, based on clinical 
evaluations including laboratory safety tests, medical history, physical 
 performed at the Screening Visit and prior to 
the first dose of study drug. 
7. The subject must meet the following birth control requirements:
x
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicidal cream or jelly, from the first dose of study drug until 
90 days after the last dose of study drug. No restrictions are required for a vasectomized 
male subject provided the subject is at least 1-year postbilateral vasectomy procedure prior 
to the first dose of study drug. A male subject whose vasectomy procedure was performed 
less than 1 year prior to the first dose of study drug must follow the same restrictions as a 
nonvasectomized man. Appropriate documentation of surgical procedure should be 
provided. 
x
Is a male subject who agrees to not donate sperm from the first dose of study drug until 90 
days after the last dose of study drug. 
x
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a. Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
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serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate 
documentation of follicle-stimulating hormone levels should be required. 
b. Hysterectomy and/or bilateral oophorectomy with appropriate documentation of 
surgical procedure. 
c. Had a tubal ligation with appropriate documentation of surgical procedure. 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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d. Congenital conditions such as uterine aplasia etc. 
7.2 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has a history of clinically significant endocrine, gastrointestinal (including motility disorder 
and intestinal obstruction), cardiovascular (including arrhythmia), hematological, hepatic, 
immunological, renal, respiratory, genitourinary, major neurological (including stroke, 
epileptic seizure), or degenerative ophthalmological abnormalities or diseases 
2. Has participated in another investigational trial within 4 weeks or 5 half-lives (whichever is 
longer) before the pretrial visit (Screening). The 4-week or 5 half-lives 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 pretrial/Screening Visit of the current trial. 
3. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the sponsor. 
4. Has a history of cancer (malignancy). 
5. Has any lifetime history of a suicide attempt, or have suicidal ideation or, any suicidal behavior 
within 12 months, or who are at significant risk to commit suicide, as judged by the 
investigator using the C-SSRS or is clinically judged by the investigator to be at risk for 
suicide. 
6. 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. 
7. Has a positive alcohol or drug screen. 
8. Had major surgery, donated or lost whole blood prior to the start of study drug administration 
as any of below: 
For both male and female subjects, 
≥200 mL within 4 weeks (28 days) 
For male subjects, 
≥400 mL within 12 weeks (84 days) 
≥800 mL in total within 52 weeks (364 days) 
For female subjects, 
≥400 mL within 16 weeks (112 days) 
≥400 mL in total within 52 weeks (364 days) 
9. Had gastrointestinal surgery that could impact the absorption of study drug. 
10. Has a history of a major psychiatric disorder as diagnosed utilizing Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition criteria. 
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11. Has a known hypersensitivity to any component of the formulation of TAK-935 or related 
compounds. 
12. Is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before 
administration of the initial dose of study drug, throughout the trial (including washout 
intervals between trial periods), until the Follow-up Visit. 
13. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 
1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs 
throughout the study. 
14. 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. 
15. Has a substance abuse disorder. 
16. Has a QTcF >450 msec confirmed with one repeat testing, at the Screening Visit. 
17. Had abnormal Screening or Day -1 laboratory values that suggested a clinically significant 
underlying disease or subject with the following laboratory abnormalities: ALT and/or AST 
>1.5 time ULN. 
18. Has tested positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) 
antibody, HIV antibody/antigen, or serologic reactions for syphilis at Screening. 
19. In the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for 
any other reason. 
7.3 
Excluded Medications, Supplements, Dietary Products 
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until subject is discharged from the unit. 
Subjects must be instructed not to take any medications including over-the-counter (OTC) 
products, until the study is completed, without first consulting with the investigator. 
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Table 7.a 
Prohibited Medications 
28 days prior to Check-in  
(Day -2) 
7 days prior to Check-in  
(Day -2) 
72 hours prior to Check-in  
(Day -2) 
Prescription medications (including 
perampanel and oral contraceptives) 
OTC medications a 
Products containing caffeine or 
xanthine 
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin) 
Vitamin supplements 
Poppy seeds 
Immunization/Vaccines b 
Foods or beverages containing 
grapefruit or grapefruit juice, star 
fruit or star fruit juice, Seville-type 
(sour) oranges and marmalade, apple 
juice, orange juice, pineapple juice, 
vegetables from the mustard green 
family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled 
meats 
Green tea 
Nicotine-containing products 
Alcohol containing products 
 
Intake of known OTC 
inhibitors/inducers of CYPs 3A4/5, 
2C9, 2C19, 2D6, 1A2, 2B6, 2E1, and 
2A6 c 
 
 
CYP: cytochrome P-450; OTC: over-the-counter. 
a 
Occasional use of acetaminophen (≤1 g/day) or other medication as approved by the sponsor on a case-by-case 
basis is allowed except on Day 1 for Part 1 and Days 1, 7, 14 and 21 for Part 2. 
b 
Inclusive of but not limited to flu vaccinations. 
c 
Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine. 
7.4 
Diet, Fluid, Activity  
7.4.1 Diet and Fluid 
During the confinement period, subjects will be given a menu for the dosing period that includes 
3 meals, however the breakfast will not be provided on Day 1 in Part 1. The meals served on the 
days of dosing should be identical for each cohort in the study. In addition, meals served on PK 
assessment days (Day 1 for Part 1and Day 1, 7, 14 and 21 for Part 2) should be identical. Subjects 
should remain fasted until 4 hours (Part 1) or 2 hours (Part 2) after dosing after which point 
breakfast will be served except on Day 1 in Part 1. Evening meals will be provided after dosing. 
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. 
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. 
On the dosing days, TAK-935 or placebo will be administered with 150 mL of water. The morning 
dose should occur after a fast of at least 10 hour (Part 1) or 8 hours (Part 2). In Part 1 Cohort 3, in 
which 1200 mg of study drug will be administered, subjects can ingest up to 150 mL of water as 
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needed (ie, subjects in this cohort are not required to ingest the full 150 mL of water). Subjects will 
continue to fast for an additional 4 hours (Part 1) or 2 hours (Part 2) after dosing. Subjects may 
consume water ad libitum with the exception of 1 hour before and 1 hour after drug administration. 
7.4.2 Activity 
Subjects will remain upright (seated, standing, or ambulatory) for 4 hours following the dose 
administration, except as necessitated by the occurrence of an AE or study procedures. Subjects 
will refrain from strenuous and/or unaccustomed exercise throughout the entire course of the study, 
from 72 hours prior to check-in through Study Exit/Early Termination. 
Blood donation within at least 12 weeks (84 days) for male subjects and 16 weeks (112 days) for 
female subjects after the last laboratory test is prohibited. 
7.5 
Documentation of Subject Failure 
The investigator must account for all subjects who sign informed consent. If a subject discontinues 
the study before the first study drug administration, the investigator should complete the electronic 
case report form (eCRF). 
The primary reason for subject failure is to be recorded in the eCRF using the following categories: 
• Death 
• AE 
• Screening failure (failed inclusion criteria or did meet exclusion criteria) <specify the reasons> 
• Protocol deviation 
• Lost to follow up 
• Withdrawal by subject <specify the reasons> 
• Study terminated by the Sponsor 
• Sample size sufficient 
• Other <specify the reasons> 
Any subject identification number, once assigned to a subject, should not be reused if the assigned 
subject discontinues the study prior to the first study drug administration. 
7.6 
Criteria for Discontinuation or Withdrawal of a Subject 
The study drug will be immediately discontinued if a condition meets any following criteria during 
the treatment. The primary reason for discontinuation or withdrawal of the subject from the study 
or study medication should be recorded in the eCRF using the following categories: 
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1. Death 
The subject died on study. 
Note: If the subject dies on study, the event will be considered as a serious adverse event (SAE). 
Refer to Section 10.2.9.3 for reporting procedures. 
2. AE. 
The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE. 
The study drug will be immediately discontinued if a condition meets any following criteria 
during the treatment, and appropriate follow-up will be performed (clinical laboratory tests 
will be repeatedly performed until the clinical laboratory test profiles have normalized or 
returned to baseline, refer to Section 9.2.11): 
• Liver Function Test (LFT) Abnormalities 
- 
ALT or AST >8×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%) 
• Prolonged QT/QTcF intervals 
If at least one remarkable prolonged QT interval was observed on 12-lead ECG (eg, 
absolute value of QTcF intervals >500 msec or an increase >60 msec from baseline), and 
the investigator considered inappropriate to continue the study. 
3. Protocol deviation. 
The discovery after the start of the first study drug administration that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health. 
4. Lost to follow-up. 
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented in the subject’s source documentation. 
5. Withdrawal by subject. 
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). 
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6. Study terminated by the Sponsor 
The Sponsor terminates the study. 
7. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.6. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
7.8 
Subject Replacement 
If a subject has not received the study drug owing to any reason occurring before the study drug 
administration, a reserve subject will be allowed to participate in the study. 
For Part 2, if a subject discontinues or withdraws from the study after initiation of the study drug, 
the subject may be replaced at the discretion of the investigator and sponsor. 
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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Clinical Study Drug 
Study drug refers to TAK-935 100 mg tablet and matching placebo. 
[Compound] 
Code name: TAK-935 
Dosage forms: 
TAK-935 100 mg tablets and matching placebo tablets are used in this study. The TAK-935 tablets 
and placebo tablets are yellow-red film-coated tablets for oral administration. A film coating is 
applied to protect against the photosensitivity exhibited by the uncoated tablets. 
Manufacturing: 
TAK-935 100 mg tablets and matching placebo tablets are manufactured by SPERA Pharma Inc. 
Osaka, Japan. 
8.1.1 Clinical Study Drug Labeling 
Study drug will be delivered to the study site in an unblinded manner. A clinical label is affixed to 
study drug containers in accordance with local regulatory requirements. 
8.1.2 Clinical Study Drug Inventory and Storage 
TAK-935 100 mg tablets and matching placebo tablets must be stored per the label at 1°C to 30°C. 
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and must remain in the original container until dispensed. The temperature 
excursion information can be found in the pharmacy manual or in the referenced compounding 
manual when applicable. Receipt and dispensing of study drug must be recorded by authorized 
personnel at the study site. 
8.1.3 Clinical Study Drug Blinding 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. The 
study drug will be provided as TAK-935 100 mg tablets and matching placebo tablets to the study 
site and unblinded randomization personnel designated by the study site will retain the blind 
according to the randomization schedule and procedure, by affixing a label with a medication 
identification number on each dispensing container containing TAK-935 100 mg tablet(s) or 
matching placebo tablet(s); this should be done in the room where the other site personnel or the 
sponsor employees are kept out. The randomization personnel at the study site will manage and 
prepare blinded doses throughout the study. 
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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 study drug blindness will be maintained through a randomization schedule and randomization 
procedure held by the randomization personnel at the study site and by the sponsor or designee. 
Randomization code/disclosure envelopes or lists (emergency key code) will be provided to the 
study site. The study drug blind shall not be broken by the investigator unless information 
concerning the study drug is necessary for the medical treatment of the subject. The sponsor or 
designee must be notified as soon as possible if the blind is broken. 
8.1.6 Accountability and Destruction of Sponsor-Supplied Drugs 
The head of the site or its delegate(s), such as the investigator or pharmacist, is responsible for 
keeping accurate records of the study drug received from the sponsor or designee, the amount 
dispensed to and returned by the subjects, and the amount remaining at the end of the study. For all 
study sites, the sponsor personnel or designee will provide appropriate documentation that must be 
completed for study drug accountability, return, and destruction. 
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9.0 
STUDY PROCEDURES 
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the schedule of study procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, per the 
discretion of the investigator. 
9.1 
Administrative Procedures 
9.1.1 Informed Consent Procedure 
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2. 
9.1.1.1 Assignment of Subject Identification Number 
A unique 7-digit subject identification number will be assigned to each subject at the time that 
informed consent is explained; this subject identification number will be used throughout the 
study. 
9.1.1.2 Study Drug Assignment 
Each subject will be assigned a medication identification number to receive treatment in 
accordance with the randomization schedule. The medication identification number will be a 
4-digit number, starting with the following numbers: 
Cohort 1: 1101, Cohort 2: 1201, Cohort 3: 1301, Cohort 4: 2001 
The assigned medication identification number will be used to identify the samples for PK/PD by 
the study site and the only number to identity a subject during blood sampling for PK/PD. The 
number will always be shown on the sample vials, which are sent to the laboratory to evaluate 
PK/PD. The laboratory will report the results using this number. The number will only be used for 
the purpose described in this section and cannot be replaced with the 7-digit subject identification 
number, which is assigned at the time of informed consent procedure and used in all other 
procedures during the clinical study period to identify a subject. In case of subject replacement 
before the study drug administration, the medication identification number for the withdrawn 
subject will be re-used by the replacing subject. For Part 2, if a subject is replaced after initiation of 
the study drug administration, an unused medication identification number will be used by the 
replacing subject. 
9.1.2 Inclusion and Exclusion  
Each subject will be assessed before randomization, according to the eligibility criteria provided in 
Section 7.0. 
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9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, height, weight, caffeine 
use, alcohol use, and smoking status of the subject.
Medical history to be obtained will include determining whether the subject has any clinically 
significant conditions or diseases that resolved within 1 year prior to the signing of informed 
consent. Ongoing conditions will be considered concurrent medical conditions. Medication history 
information to be obtained will include any medication relevant to eligibility criteria and safety 
evaluations stopped at or within 4 weeks (28 days) prior to the signing of informed consent. 
9.1.4
Concomitant Medications
Qualified site personnel will review subject prior and concomitant medication use. Medications 
are defined as prescription and OTC drugs, vaccines, supplements, nutraceuticals, and oral herbal 
preparations. Subjects will be asked whether they have taken any medications other than the study 
drug (during a period from the signing of informed consent through the end of the study), and all 
medications including vitamins, OTC drugs and Chinese herbal medicines used by a subject must 
be recorded in each subject’s eCRF. The nonproprietary name, route of administration, dates of 
initial and final administrations and reasons for use must also be recorded in the eCRF.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam and Eye Exam 
Qualified site personnel will conduct full physical examinations. And qualified site personnel will 
conduct an eye exam including visual field evaluation, best corrected visual acuity,fundoscopy 
without pupillary dilation, and a slit lamp microscopy. 
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed. 
Height will be measured in centimeters (cm) and the measured value will be rounded off to the 
nearest whole number. Weight will be measured in kilograms (kg) and the measured value will be 
rounded off to 1 decimal place.
9.2.3
BMI
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
The measured value should be rounded off to 1 decimal place. The inclusion criteria for BMI will 
be defined based on the values after rounding. 
9.2.4
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9.2.5
9.2.6
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9.2.7
Study Drug Administration
<Part 1>
Subjects will receive a single dose of TAK-935 or placebo of 200 mg, 600 mg, or 1200 mg with 
150 mL of water, after fasting for at least 10 hours and will remain fasted until 4 hours after dosing.
In Cohort 3, in which 1200 mg of study drug will be administered, subjects can ingest up to 
150 mL of water as needed (ie, subjects in this cohort are not required to ingest the full 150 mL of 
water).
<Part 2>
Subjects will receive multiple oral doses of TAK-935 or placebo escalating from 100 mg BID, 
200 mg BID, and then to 300 mg BID with 150 mL of water for 7 days per each dose level. For the 
morning dose, subjects are kept fasted for at least 8 hours before administration and up to 2 hours 
after administration. The evening dose will be administered at any time between 8 hours and 
12 hours after the morning dose, but prior to the evening meal except for Days 1, 7, 14, and 21. On 
Days 1, 7, 14, and 21, the evening dose will be administered 12 hours after the morning dose and 
prior to the evening meal.
9.2.8
Columbia Suicide Severity Rating Scale (C-SSRS)
Suicidal risk will be assessed using the C-SSRS at the times stipulated in the Schedule of Study 
Procedures (Screening, Day-2 and Day 3 [Part 1] or Screening, Day-2 and Day 24 [Part 2]). Two 
versions of the C-SSRS will be used in this trial: the screening/baseline C-SSRS Lifetime and the 
Since-Last-Visit C-SSRS. Any suicidal ideation or suicidal behavior during the trial periods 
detected by C-SSRS will be recorded as AEs by the investigator. The investigator will ensure that 
any suicidal ideation or behavior is medically addressed, including assessment and treatment by 
qualified medical personnel.
9.2.9
Neuropsychiatric assessment
Mini mental state examination (MMSE) and pre-determined questions are a set of cognitive 
function test for screening delirium and psychosis. The investigator, sub-investigator, or study 
coordinator will evaluate the cognitive functions of subjects using MMSE. The details of the 
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pre-determined questions are listed in Appendix D. These are recommended to screen and monitor 
for both delirium and psychosis. 
9.2.10 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. 
9.2.11 CCI
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9.2.12 Follow-up Visit
The Follow-up Visit will occur by direct visit on Day 8 (Part 1) or Day 35 (Part 2) and will be for 
the purpose of assessing AE and inquiring about concomitant medications since completing the 
trial.
9.3
Biomarker, PK, and PGx, Samples
Samples for PK, biomarker, PD, and pharmacogenomic analysis will be collected at the time 
points stipulated in the schedule of procedures (Section 3.0). Please refer to the laboratory manual 
for information on the collection, processing, and shipment of samples to the central laboratory. 
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The decision as to which collected samples will be assayed for evaluation of PK and biomarkers 
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.
Primary specimen collection parameters are provided in Table 9.b. 
Table 9.b 
Primary Specimen Collections
9.3.1
PK Measurements
The PK parameters of TAK-935 
 will be determined from the 
concentration-time profiles for all evaluable subjects. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times.
The following PK parameters will be calculated from plasma concentrations of TAK-935
 
 unless otherwise specified:
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In the case when the subject prematurely discontinues the study between the first and the last 
scheduled PK sample blood draw, final blood samples to be used for PK analysis are sampled from 
subjects during hospitalization. The exact date and time of each sample should be recorded. 
On the other hand, in the case of premature discontinuation during the period of follow-up after 
discharge, blood samples for PK analysis are not collected from the subjects who came to 
outpatient medical examination.
9.3.2
Biomarker Measurements
9.3.2.1
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9.3.3
PGx Measurements
9.3.3.1
Blood Sample for DNA PGx Measurements 
Sampling of whole blood for pharmacogenomic analysis is optional in this study and will only be 
performed for subjects who provide consent to participate in this assessment.
Pharmacogenomics (PGx) is the study of variations of DNA characteristics as related to drug 
response. There is increasing evidence that an individual’s genetic background may affect the PK
(absorption, distribution, metabolism, and excretion), PD (pharmacologic effects), and/or clinical 
effects (efficacy and/or safety) of a drug.
Pharmacogenomic research in this study may be conducted to understand how individual genetic 
variation in subjects impacts their response to study drug treatment. This information may also be 
used, for example, to develop a better understanding of the safety and efficacy of TAK-935 and 
other study drugs, to increase understanding of the disease/condition being studied and other 
related conditions, to gain a better understanding of the drug pharmacology, and to generate 
information needed for research, development, and regulatory approval of tests to predict response 
to TAK-935. 
Whole blood samples for DNA isolation will be collected from each consented subject in the 
study. 
Since pharmacogenomics is an evolving science, many genes and their functions are not yet fully 
understood. Future data may suggest a role of these genes in drug response, which may lead to 
additional hypothesis-generating exploratory research and diagnostic development on stored 
samples.
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9.3.3.2 Biological Sample Retention and Destruction 
In this study, blood samples for pharmacogenomic analysis will be collected as described in 
Section 9.3.3.1. Genetic material will be initially stored at a vendor or comparable laboratory, 
under contract to the sponsor, with validated procedures in place, and then preserved and retained 
at a long-term storage vendor, or a comparable laboratory, with validated procedures in place, for 
up to but not longer than 15 years from the end of the study when the clinical study report is signed, 
or if less, the maximum period permitted under applicable law or until consent is withdrawn. 
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the study 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 study but using a code 
that is different from the code attached to the health information and other clinical test results 
collected in the study. 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 pharmacogenomic 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 
Confinement 
<Part 1> 
Subjects will be admitted to a hospital during a period from Day -2 to Day 3 and discharged from 
the hospital if no clinically significant abnormalities were found at the physical examination and 
tests on Day 3, and confirmed by the investigator. 
<Part 2> 
Subjects will be admitted to a hospital during a period from Day -2 to Day 24 and discharged from 
the hospital if no clinically significant abnormalities were found at the physical examination and 
tests on Day 24, and confirmed by the investigator. 
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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 or the study participation. 
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 during 
participating the study, whether or not it is considered related to the drug or the study procedure. 
An untoward finding generally may: 
x
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.) 
x
Necessitate therapeutic intervention.
x
Require an invasive diagnostic procedure. 
x
Require discontinuation or a change in dose of study medication or a concomitant medication.
x
Be considered unfavorable by the investigator for any reason. 
Diagnoses versus signs and symptoms: 
x
Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or 
) 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). 
Pre-existing conditions:
x
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. The first 
evaluation (eg, laboratory test
X-ray, etc) after obtaining the consent should NOT be 
recorded as an AE unless related to a study procedure. However, if the subject experiences a 
worsening or complication of such a concurrent medical history condition, the worsening or 
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complication should be recorded appropriately as an AE (worsening or complication occurs 
after informed consent is signed). Investigators should ensure that the event term recorded 
captures the change in the condition (eg, “worsening of…”). 
• If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”). 
• If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study 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 medication, the event should be captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
• An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor. 
• All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE eCRF(s) according to 
Section 10.0. 
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• SAEs of overdose should be reported according to the procedure outlined in Section 10.2.9. 
• In the event of drug overdose, the subject should be treated symptomatically. 
10.1.1 SAEs 
An SAE is defined as any untoward medical occurrence on subjects who signed the informed 
consent forms as follows: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• 
The term “life threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• 
May require intervention to prevent items 1 through 5 above. 
• 
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• 
Includes any event or synonym described in the Takeda Medically Significant AE 
List (Table 10.a). 
Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory 
distress syndrome 
Hepatic necrosis 
Acute liver failure 
Torsade de pointes / ventricular fibrillation/ 
ventricular tachycardia 
Anaphylactic shock 
Acute renal failure 
Malignant hypertension 
Pulmonary hypertension 
Convulsive seizures (including convulsion and 
epilepsy) 
Pulmonary fibrosis (including interstitial pneumonia) 
Agranulocytosis 
Neuroleptic malignant syndrome/ malignant hyperthermia 
Aplastic anemia 
Spontaneous abortion/ stillbirth and fetal death 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Confirmed or suspected transmission of infectious agent by a 
medicinal product 
 
Confirmed or suspected endotoxin shock 
 
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AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the following manner (see Sections 10.2.9.3). 
10.1.2 Adverse Events of Special Interest 
An AE of special interest (serious or nonserious) is one of scientific and medical concern specific 
to the compound or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor may be appropriate. Such events may require further investigation in 
order to characterize and understand them. The reporting of specific AEs of special interest is 
described in the following sections. 
10.1.2.1 Psychiatric Effects: Psychosis 
During the phase 1 multiple repetitive dose study, episodes of confusion, euphoria, and psychosis 
were seen at the highest dose of 600 mg/day. However, in that study subjects were not titrated. 
Psychiatric AEs will be monitored closely. 
10.1.2.2 Convulsions 
During nonclinical studies, convulsions were seen in the rat at extremely high doses. Convulsions 
will be considered an AE of special interest and subjects will be carefully monitored for any signs 
of convulsive activity. 
10.1.2.3 Cataracts 
During nonclinical studies, incipient posterior cortical, subcapsular lenticular cataracts of 
moderate grade were seen in 1 male rat at 300 mg/kg/day and 1 female rat at 100 mg/kg/day. 
Cataracts will be considered an AE of special interest and subjects will be carefully monitored for 
any signs of ocular abnormalities. 
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 medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments. 
10.2.3 Assigning Causality of AEs to Study Procedures 
The causality of each AE to study procedures will be assessed. 
The causality should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the causality should be assessed as 
Not Related. 
10.2.4 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator. 
10.2.5 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. 
10.2.6 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. 
10.2.7 Action Taken With Study Treatment 
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 
• Unknown – only to be used if it has not been possible to determine what action has been taken. 
• Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE. 
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10.2.8 Outcome 
• Recovered/resolved – subject returned to first assessment status with respect to the AE. 
• Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to the baseline value; the subject died from a cause other than 
the particular AE with the condition remaining “recovering/resolving.” 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
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. 
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs 
10.2.9.1 Collection Period 
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent and continue until the follow-up visit. For subjects 
who discontinue prior to the administration of study medication, AEs will be followed until the 
subject discontinues study participation. 
10.2.9.2 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 study drug 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 
study drug, related or unrelated to the study procedure, need not be followed-up for the purposes of 
the protocol. 
All subjects experiencing AEs, after the first administration of the study medication, whether 
considered associated with the use of the study medication or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
Baseline or until there is a satisfactory explanation for the changes observed. All AEs will be 
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documented in the AE page of the eCRF, whether or not the investigator concludes that the event is 
related to the drug treatment. The following information will be documented for each event: 
• Event term. 
• Start and end date and time. 
• Pattern of AE (frequency). 
• Severity/Intensity. 
• Investigators’ opinion of the causal relationship between the event and administration of study 
drug. 
• Investigators’ opinion of the causal relationship between the event and the study procedure(s) 
(The details of study procedure(s) that may cause the event should also be provided). 
• Action taken with trial drug. 
• Outcome of event. 
• Seriousness. 
• Timing of occurrence (after administration of the study drug) 
10.2.9.3 Reporting SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below: 
An SAE should be reported by the investigator to the Sponsor (see Protocol Annex 1) within 1 
business day of the first onset or notification of the SAE, along with any relevant information. The 
principal investigator should submit a detailed SAE Form to the Sponsor within 10 calendar days. 
The information should be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation. 
SAE Follow-Up 
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form copy or provide other written documentation 
and submit it to the Sponsor immediately. Copies of any relevant data from the hospital notes (eg, 
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laboratory tests, discharge summary, postmortem results) should be sent to the Sponsor, if 
requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.9.4 Reporting AEs of Special Interest 
If the subject experiences psychosis, convulsions, or cataracts during the treatment period or the 
safety follow-up period as described in Section 10.1.2, the event should be reported on a specific 
form within 1 business day of the investigator’s awareness. Any relevant supporting 
documentation (ie, additional diagnostic testing, consultation reports) must be submitted to the 
sponsor. 
If a convulsion occurs during the study, the investigator should document the following 
information: 
x
A complete description of the convulsion event. This description should include precise details 
of any eyewitness accounts that might be available. Particular attention should be paid to 
phenomena such as loss of consciousness (rapid or sudden), brief tonic posturing followed by 
more prolonged clonic contractions, loss of bowel/bladder control, tongue biting, or aura. 
Include the sequence of events and the time-course of notable signs and symptoms (eg, 
duration of the aura, if present, duration of the convulsion itself, and any postictal symptoms 
such as confusion or amnesia). 
x
The date and time of the last dose of the study medication. 
x
Full drug accountability information, including the number of study medication tablets that the 
subject took. Evaluate for the possibility that the subject took an incorrect dosage of 
medication within a few days of the convulsion. 
x
Was the tablet taken intact or was it crushed, chewed, etc.? 
x
The presence of any of the following at the time of the convulsion: eating disorders, changes in 
diet, and/or fever and dehydration.
x
Any previous history of convulsions (including an early history of febrile seizures), 
accompanied by a description of the frequency and intensity. Evaluate for the possibility that 
partial convulsions may have occurred in the past but were not recognized as such. 
x
Any predisposing factors such as previous head trauma not recognized previously. 
x
Any family history of convulsions. 
x
Any alcohol consumption by the subject within the week preceding the event. 
x
The use of all concomitant medications, including sedatives/hypnotics (eg, benzodiazepines, 
barbiturates). Collect dosing information along with product names. 
x
Any concurrent use of illicit drugs. 
CCI
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• A urine sample for illicit drug use and a blood alcohol level should be obtained as soon as 
possible after the convulsion has occurred. 
• Document any electrolyte abnormalities or other signs of systemic illness not otherwise 
evident. Other pertinent laboratory values that should be recorded include the subject’s 
electrolyte panel results, blood urea nitrogen, creatinine, complete blood count with 
differential, and blood glucose level. 
AEs of special interest have to be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor. 
10.2.9.5 Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. 
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 10.2.9.3. The investigator must contact the trial clinician or its delegates or designee 
(contact information may be found in Annex 1) for discussion of the relevant subject details and 
possible alternative etiologies, such as acute viral hepatitis A or B or other acute liver disease. 
Follow-up laboratory tests as described in Section 9.2.11 must also be performed. 
10.2.10Safety 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/head of the study 
site 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 to the regulatory authorities as 
expedited report 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 study drug or that would be sufficient to consider changes in the study drug 
administration or in the overall conduct of the trial. The study 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 database lock. This 
document will provide further details regarding the definitions of analysis variables, and analysis 
methodologies to address all study objectives.
A blinded data review will be conducted before database lock. This review will assess the accuracy 
and completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
11.1.1 Analysis Sets
11.1.1.1 Safety Analysis Set
The safety analysis set will be defined as all subjects who received at least 1 dose of study drug. 
11.1.1.2 PK Analysis Set 
The PK analysis set will be defined as all subjects who received at least 1 dose of study drug and 
had at least 1 estimable PK parameter.
11.1.1.3
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized for each of Part 1 and Part 2 
using the safety analysis set.
11.1.3 PK Analysis
The following analyses will be conducted using the PK analysis set. 
Concentrations of TAK-935 and its metabolite M-I in plasma will be summarized in each of Part 1 
and Part 2 by cohort over each scheduled sampling time using descriptive statistics. Individual 
plasma concentration data versus time will be presented in a data listing. Plasma PK parameters 
will be calculated using noncompartmental modeling and summarized by cohort and day using 
descriptive statistics. Dose proportionality in plasma PK parameters (Cmax and AUCs) will be 
assessed graphically for those parameters in Part 1. Additional analyses will be included if 
appropriate. 
11.1.4
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11.1.5 Safety Analysis 
A summary will be provided for Part 1 and Part 2 separately. In Part 1, subjects from different 
cohorts who received placebo will be pooled together to form one placebo group. Analyses will be 
conducted using the safety analysis set.
11.1.5.1 AEs
A TEAE is defined as an AE that occurs on or after the start of study drug administration. TEAEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary and 
tabulated by the system organ class (SOC) and the preferred term (PT). Percentage of subjects who 
experience at least 1 TEAE (the primary endpoint of the study) will be calculated within the 
following analyses.
x
The frequency of all TEAEs 
x
The frequency of drug-related TEAEs
x
The frequency of TEAEs by intensity 
x
The frequency of drug-related TEAEs by intensity 
x
The frequency of TEAEs leading to study drug discontinuation 
x
The frequency of serious TEAEs 
11.1.5.4
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11.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned. Section 6.2 describes the blinded safety and PK reviews 
which will take place after completion of each cohort and prior to the next dose escalation stage in 
the study. 
11.3
Determination of Sample Size
The sample sizes of 8 subjects for each of the cohorts in Part 1 and 9 subjects for Part 2 (Part 1: 6 
active 2 placebo in each cohort, Part 2: 6 active 3 placebo as total) are considered to be sufficient 
for the evaluation of safety, tolerability, and PK of each cohort. Sample sizes were not based on 
statistical power 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 its 
designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, trial drug, subject medical records, informed consent documentation, and 
review of 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 medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, U.S. Food and Drug Administration [FDA], Medicines and 
Healthcare products Regulatory Agency [MHRA], Pharmaceuticals and Medical Devices Agency 
[PMDA]). 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 Conference on Harminsation (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 investigator responsibilities. 
13.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. 
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor. 
13.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
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applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor 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 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, MHRA, PMDA), 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. 
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, the sponsor will, at a minimum register all 
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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 facility names and city, country, and recruiting status will be 
registered and available for public viewing.  
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  
The sponsor will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
13.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee. 
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
A contact information list (Protocol Annex 1) will be provided to each study site separately.
14.1.2
Investigator Agreement
An agreement will be provided to each study site separately. 
14.1.3
Study-Related Responsibilities
A contact information list (Protocol Annex 1) will be provided to each study site separately.
14.1.4 List of Abbreviations
Term
Definition
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUEC
area under the effect-time curve
BID
twice daily
BMI
body mass index
BP
blood pressure
CH24H
cholesterol 24-hydroxylase
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
CNS
central nerve system
C-QTc
concentration-QTc
C-SSRS
Columbia Suicide Severity Rating Scale
DEE
developmental epileptic encephalopathies
eCRF
electronic case report form
Emax
maximum drug-induced effect
Et
observed effect at time t
FDA
U.S. Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HR
heart rate
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ely.
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Study ID TAK-935-1004 
Page 70 of 78 
Protocol 
02 July 2020 
 
 
Term 
Definition 
ICH 
International Conference on Harminsation of Technical Requirements for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LFT 
liver function test 
MD 
multiple doses 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MMSE 
mini mental state examination 
MR 
metabolic ratio 
OTC 
over the counter 
PD 
pharmacodynamics 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
preferred Term 
QD 
once daily 
QTcF 
QT interval with Frederica correction method 
Rac 
accumulation ratio 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2z 
terminal disposition phase half-life 
TEAE 
treatment-emergent adverse event 
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 
24HC 
24S-hydroxycholesterol 
 
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary. 
15.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent. 
The Sponsor or its designee will supply investigative sites with access to eCRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. 
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded in the eCRF: 
x
PD results
x
PGx results
x
Laboratory results
x
x
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must e-sign. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor. 
CCI
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Property of Takeda: For
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15.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and Sponsor. 
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents. 
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16.0 
REFERENCES 
1. World Health Organization. Epilepsy Fact Sheet N°999. Published October 2012. Accessed 13 
December 2013. Available at: http://www.who.int/mediacentre/factsheets/fs999/en/. 
2. Centers for Disease Control and Prevention. Targeting epilepsy: Improving the lives of people 
with one of the nation’s most common neurological conditions at a glance 2011. Updated 06 
June 2011. Accessed 16 January 2014. Available at: 
http://www.cdc.gov/chronicdisease/resources/publications/AAG/epilepsy.htm. 
3. National Institute of Neurological Disorders and Stroke. Epilepsy research benchmarks 
progress report 2007 – 2012. National Institute of Neurological Disorders and Stroke. Updated 
23 December 2013. Accessed 16 January 2014. Available at: 
http://www.ninds.nih.gov/research/epilepsyweb/benchmarks_2007-2012progress.pdf. 
4. McNamara JO. Pharmacotherapy of the epilepsies. In: Brunton LL, editor. Goodman & 
Gilman’s the pharmacological basis of therapeutics. 11th ed. New York, NY: McGraw-Hill; 
2006; Chapter 19, p. 501-26. 
5. Xie C, Lund EG, Turley SD, Russell DW, Dietschy JM. Quantitation of two pathways for 
cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J Lipid 
Res 2003;44(9):1780-9. 
6. Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW. Knockout of the cholesterol 
24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J 
Biol Chem 2003;278(25):22980-8. 
7. Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T. Cholesterol 24-hydroxylase: an 
enzyme of cholesterol turnover in the brain. Annu Rev Biochem 2009;78:1017-40. 
8. Cartagena CM, Ahmed F, Burns MP, Pajoohesh-Ganji A, Pak DT, Faden AI, et al. Cortical 
injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J Neurotrauma 
2008;25(9):1087-98. 
9. Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, et al. On the 
turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the 
cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 2001;314(1-2):45-8. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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17.0
APPENDICES
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CCI
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a: For non-commercial use only and subject to the applicable Terms of U


Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

SAP_001.pdf: 
Title: A Randomized, Double-blind, Placebo-Controlled, Phase 1 Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of Single Ascending Dose and Multiple Doses 
with Titration of TAK-935 in Healthy Japanese Subjects 
NCT Number: NCT04461483 
Statistical analysis plan Approve Date: 20-NOV-2020 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-935-1004 
A Randomized, Double-blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of Single Ascending Dose and Multiple Doses with 
Titration of TAK-935 in Healthy Japanese Subjects.
PHASE 1
Version: Second 
Date: 20 Nov 2020 
Prepared by:
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 02 July 2020  
PPD
Property of Takeda: For n
Protoco
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ommercial use only and subject to the applicable Terms of Use
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to Ev
and Mu
and M
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Second 
econd
20 Nov
Nov 2
Pro
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Statistical Analysis Plan Second  
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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


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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......................................................................................................................7
4.1
Primary Objectives.........................................................................................................7
4.2
Secondary Objectives.....................................................................................................7
4.3
.7
4.4
Study Design ..................................................................................................................7
5.0
ANALYSIS ENDPOINTS...................................................................................................9
5.1
Primary Endpoints .........................................................................................................9
5.2
Secondary Endpoints .....................................................................................................9
5.3
9
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 Visit Windows .......................................................................13
7.2
Analysis Sets ................................................................................................................13
7.3
Disposition of Subjects ................................................................................................14
7.3.1
Study Information ..................................................................................................14
7.3.2
Screen Failures .......................................................................................................14
7.3.3
Subject Eligibility ..................................................................................................14
7.3.4
Disposition of Subjects ..........................................................................................15
7.3.5
Study Completion Status........................................................................................15
7.3.6
Protocol Deviations and Analysis Sets ..................................................................16
7.4
Demographic and Other Baseline Characteristics .......................................................17
7.5
Medical History and Concurrent Medical Conditions .................................................17
7.6
Medication History and Concomitant Medications .....................................................18
7.7
Study Drug Exposure and Compliance ........................................................................18
7.8
Efficacy Analysis .........................................................................................................19
7.8.1
Primary Efficacy Endpoint(s) ................................................................................19
7.8.2
Secondary Efficacy Endpoint(s) ............................................................................19
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7.8.3
Additional Efficacy Endpoint(s) ............................................................................19
7.8.4
Statistical/Analytical Issues ...................................................................................19
7.9
Pharmacokinetic/
 Analysis .............................................................20
7.9.1
Pharmacokinetic Analysis ......................................................................................20
7.9.2
24
7.10
Other Outcomes ...........................................................................................................28
7.11
Safety Analysis ............................................................................................................29
7.11.1 Adverse Events ......................................................................................................29
7.11.2
32
7.11.3
 and Weight ..........................................................................................34
7.11.4
35
7.11.5 Other Observations Related to Safety ....................................................................36
7.12
Interim Analysis ...........................................................................................................36
7.13
Changes in the Statistical Analysis Plan ......................................................................36
8.0
REFERENCES ..................................................................................................................43
LIST OF IN-TEXT TABLES
Table 4.a
Outline of the Study Parts and Planned Dosing Cohorts .........................................7
Table 7.a
Percent Change from Time-Matched Baseline for Part 1 ......................................13
Table 7.b
Percent Change from Time-Matched Baseline for Part 2 ......................................13
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUEC
area under the effect-time curve
BID
twice daily
BMI
body mass index
BP
blood pressure
CH24H
cholesterol 24-hydroxylase
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed plasma concentration
CNS
central nerve system
C-QTc
concentration-QTc
CRF
case report form
C-SSRS
Columbia Suicide Severity Rating Scale
DEE
developmental epileptic encephalopathies
eCRF
electronic case report form
Emax
maximum drug-induced effect
Et
observed effect at time t
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL
high density lipoprotein
HR
heart rate
ICH
International Conference on Harminsation of Technical Requirements for Human 
Use 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
LFT
liver function test
MD
multiple doses
CCI
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administr
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MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MMSE
mini mental state examination
MR
metabolic ratio
OTC
over the counter
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency
PT
preferred term
PT/INR
prothrombin time / international normalized ratio
QD
once daily
QTcF
QT interval with Frederica correction method
Rac
accumulation ratio
RBC
red blood cells
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
Tmax
time of first occurrence of Cmax
TSH
thyroid stimulating hormone
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after 
extravascular administration
WBC
white blood cells
24HC
24S-hydroxycholesterol
CCI
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4.0
OBJECTIVES
4.1
Primary Objectives
•
The primary objective of the study is to evaluate the safety and tolerability of TAK-935 in 
healthy Japanese subjects when administered as single oral dose or multiple oral doses with 
titration.
4.2
Secondary Objectives
•
The secondary objective of the study is to evaluate the PK of TAK-935 in healthy Japanese 
subjects when administered as single oral dose or multiple oral doses with titration.
4.3
4.4
Study Design
This study consists of 2 parts, which is a randomized, double-blind, placebo-controlled study to 
assess safety, tolerability, and PK and PD of TAK-935 when administered via oral 
administration in healthy Japanese subjects.
Part 1 is a SAD study, consisting of 3 cohorts containing 8 subjects each. On Day 1 of each dose 
level, a single dose of TAK-935 or placebo will be administered, and safety, PK and PD will be 
evaluated. 
Part 2 is a MD with titration study within the same subjects. TAK-935 or placebo will be 
administered to the 9 subjects at the dose of 100 mg BID from Day 1 to Day 7, then 200 mg BID 
from Day 8 to Day 14, and finally 300 mg BID from Day 15 to Day 21, and safety, PK and PD 
will be confirmed. The planned dose levels of TAK-935 to be evaluated are outlined in Table 4.a
Table 4.a 
Outline of the Study Parts and Planned Dosing Cohorts
Part
Cohort
Daily dose level 
(mg)
Dosing regimen
Randomization
Part 1
1
200
Single oral dose 
under fasted 
condition
Subjects will be 
randomized to TAK-
935 or placebo at a 
ratio of 6:2 in each 
cohort, double-blind. 
No stratification 
variables will be 
used for 
2
600
3
1200
CCI
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-935 or p
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randomization. 
Part 2 
4 
Day 1-7: 200 
(100 mg BID) 
Day 8-14: 400 
(200 mg BID) 
Day 15-21: 600 
(300 mg BID) 
Multiple oral doses 
up/titration with 
TAK-935 for 7 days 
per each dose level 
within the same 
subjects under fasted 
condition 
Subjects will be 
randomized to TAK-
935 or placebo at a 
ratio of 6:3, double-
blind. No 
stratification 
variables will be 
used for 
randomization. 
BID: twice daily 
 
Study Population 
Study Population: Healthy Japanese subjects. 
Planned Number of Subjects 
Part 1 (SAD): Total of 24 subjects 
• Cohort 1: 8 subjects 
• Cohort 2: 8 subjects 
• Cohort 3: 8 subjects 
Part 2 (MD): Total of 9 subjects 
• Cohort 4: 9 subjects (dose up/titration within the same subjects) 
Key Study Procedure Overview 
<Part 1> 
After the screening visit, eligible participants will check-in on Day-2. On Day 1, eligible 
participants will be randomized 6:2 to TAK-935 or placebo in each dose group in a double-
blinded fashion. No stratification variables will be used for randomization. On the same day, 
study drug will be administered by oral administration of a single dose to each subject at each 
dose level. The subjects will be discharged on Day 3. Intensive PK sampling will be performed 
from Day 1 to Day 3. 
<Part 2> 
After the screening visit, eligible participants will check-in on Day-2. On Day 1, eligible 
participants will be randomized 6:3 to TAK-935 or placebo in a double-blinded fashion. No 
stratification variables will be used for randomization. Study drug will be administered every day 
by oral administration of multiple dosing. The 3 subjects receiving placebo will receive placebo 
throughout the study. The other 6 subjects will receive TAK-935 with up-titration firstly at 
100 mg BID from Day 1 to Day 7, then at 200 mg BID from Day 8 to Day 14, and finally at 
300 mg BID from Day 15 to Day 21, successively. The subjects will be discharged on Day 24. 
Intensive PK sampling will be performed on Day 1, Day 7, Day 14 and Day 21.  
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint of the study includes: 
Safety endpoint: 
•
Percentage of subjects who experience at least 1 TEAE
5.2
Secondary Endpoints
Secondary endpoints include:  
Pharmacokinetic endpoints: 
•
Maximum observed plasma concentration (Cmax).
•
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast) (Part 1 only).
•
AUC from time 0 to time of infinity (AUCinf) (Part 1 only).
•
AUC from time 0 to 24 hours (AUC24) (Part 1 only).
•
AUC during a dosing interval (AUCtau) at steady state (Part 2 only).
5.3
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
me 0 to ti
me 0 to 
art 1 only
t 1 on
1 only).
only)
at steady
steady
ty of Takeda: For non-commercial u


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CCI
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For non-commercial use only and subject to the applicable Terms of


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Statistical Analysis Plan Second  
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6.0 
DETERMINATION OF SAMPLE SIZE 
The sample sizes of 8 subjects for each of the cohorts in Part 1 and 9 subjects for Part 2 (Part 1: 6 
active 2 placebo in each cohort, Part 2: 6 active 3 placebo as total) are considered to be sufficient 
for the evaluation of safety, tolerability, and PK of each cohort. Sample sizes were not based on 
statistical power considerations. 
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7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
Date First Subject Signed Informed Consent Form 
Date of Last Subject’s Last Visit/Contact 
MedDRA Version 
SAS Version Used for Creating the Datasets 
Analytical Method(s): 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
7.3.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis Variable(s): 
Age (years) 
Gender 
[Male, Female] 
Analytical Method(s): 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided. 
7.3.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
Eligibility Status 
[Eligible for Randomization, Not Eligible for Randomization] 
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Primary Reason for Subject Not Being Eligible 
[Adverse Event, Death, Lost to Follow-up, Protocol Deviation, Sample Size 
Sufficient, Screen Failure, Study Terminated by Sponsor, Withdrawal by Subject, 
Other] 
Analytical Method(s): 
(1) Eligibility for Randomization 
Frequency distributions will be provided. When calculating percentages for the 
primary reasons for subject not being eligible, the total number of ineligible subjects 
will be used as the denominator. 
7.3.4 Disposition of Subjects 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Study Completion Status 
[Completed All Planned Study Visits, Did Not Complete All Planned Study 
Visits] 
Reason for Discontinuation of Study Visits 
[Adverse Event, Death, Lost to Follow-up, Protocol Deviation, Study Terminated 
by Sponsor, Withdrawal by Subject, Other] 
Analytical Method(s): 
(1) Disposition of Subjects 
Frequency distributions will be provided by dose and overall for each of Part 1 and 
Part 2. When calculating percentages for the reasons for discontinuation, the total 
number of subjects who did not complete all planned study visits will be used as the 
denominator. 
7.3.5 Study Completion Status 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Study Completion Status 
[Completed Study, Prematurely Discontinued Study] 
Reason for Discontinuation of Study 
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[Adverse Event, Death, Lost to Follow-up, Protocol Deviation, Study Terminated 
by Sponsor, Withdrawal by Subject, Other] 
Categories:  
 
Duration of Study after Baseline (days) 
 
 
[0, 1<= - <=7, 8<= - <=14, 15<= - <=23, 24<= - <=Max] 
Analytical Method: 
(1) Study Completion Status 
Frequency distribution will be provided for each category of duration of study period 
by dose and overall. This table will only be provided for Part 2. 
7.3.6 Protocol Deviations and Analysis Sets 
7.3.6.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Significant Protocol Deviation 
[Entry Criteria, Concomitant Medication, Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria, Major GCP Violations] 
Analytical Method(s): 
(1) Protocol Deviations 
Frequency distribution will be provided by dose and overall for each deviation 
category for each of Part 1 and Part 2. A subject who has several deviations will be 
counted once in each appropriate category. A subject who has several deviations that 
can be classified into the same category will be counted only once. 
7.3.6.2 Analysis Sets 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Handling of Subjects 
[Categories are based on the specifications in Subject Evaluability List] 
Analysis Sets 
Safety Analysis Set 
[Included] 
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Pharmacokinetic Analysis Set 
[Included] 
Analytical Method(s): 
(1) Subjects Excluded from Analysis Sets
(2) Analysis Sets
Frequency distributions will be provided by dose for each of Part 1 and Part 2. For 
(1), a subject who has several reasons for exclusion will be counted once in each 
appropriate category. A subject who has several reasons for exclusion that can be 
classified into the same category will be counted only once. 
7.4
Demographic and Other Baseline Characteristics
Analysis Set:
Safety Analysis Set
Analysis Variable(s): 
Age (years) 
 
Gender 
[Male, Female]
Height (cm)  
Weight (kg)  
BMI (kg/m2)  
Smoking Classification
[Never, Current, Former] 
Alcohol Classification 
[Daily, A Few Times Per Week, A Few Times Per Month, No] 
Caffeine Classification
[Yes, No]
Analytical Method(s): 
(1) Summary of Demographics and Baseline Characteristics
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by dose and overall for each of Part 1 and Part 
2. 
7.5
Medical History and Concurrent Medical Conditions
Not applicable. 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
nd Part 
nd Part
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clusion t
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(1)
(1) S


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7.6 
Medication History and Concomitant Medications 
Not applicable. 
7.7 
Study Drug Exposure and Compliance 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Number of Times the Study Drug was Taken 
 
[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14<= - <=Max] 
Analytical Method(s): 
(1) Study Drug Exposure 
This table will only be provided for Part 2. Frequency distributions will be provided 
by dose for each dose level of Part 2 (i.e., Period 1 (100 mg BID), Period 2 (200 mg 
BID), and Period 3 (300 mg BID)). 
 
 
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7.8 
Efficacy Analysis 
Not applicable 
7.8.1 Primary Efficacy Endpoint(s) 
Not applicable. 
7.8.2 Secondary Efficacy Endpoint(s) 
Not applicable. 
7.8.3 Additional Efficacy Endpoint(s) 
Not applicable. 
7.8.4 Statistical/Analytical Issues 
7.8.4.1 Adjustments for Covariates 
Not applicable. 
7.8.4.2 Handling of Dropouts or Missing Data 
For plasma concentrations and laboratory test results, values below the lower limit of 
quantification will be treated as zero when calculating the descriptive statistics. For laboratory 
test results, values above the upper limit of quantification will be treated as the upper limit value 
when calculating the descriptive statistics. 
7.8.4.3 Multicenter Studies 
Not applicable. 
7.8.4.4 Multiple Comparison/Multiplicity 
Not applicable. 
7.8.4.5 Use of an “Efficacy Subset” of Subjects 
Not applicable. 
7.8.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable. 
7.8.4.7 Examination of Subgroups 
Not applicable. 
 
 
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7.9
Pharmacokinetic/
7.9.1
Pharmacokinetic Analysis
7.9.1.1
Plasma Concentrations 
Part 1
Analysis Set:
Pharmacokinetic Analysis Set
Analysis Variable(s): 
Plasma Concentrations of TAK-935 Analyte (TAK-935, 
)
Visit: 
Predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 12, 16, 24 and 48 Hours Postdose
Analytical Method(s): 
The following summaries will be provided by dose. Subjects who were administered 
placebo will be excluded from the analysis.
(1) Summary of Plasma Concentrations by Visit
Descriptive statistics and CV will be provided by visit.
(2) Case Plots of Plasma Concentrations
Plots over time for each subject will be provided. Visit will be plotted on the 
horizontal axis and the analysis variable will be plotted on the vertical axis. In 
addition to plots with the vertical axis as a normal scale, plots with the vertical 
axis as a common logarithmic scale will also be provided.
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted. Visit will be plotted on the 
horizontal axis and each of the analysis variables will be plotted on the vertical 
axis. The vertical axis will be a normal scale. 
(4) Mean Plot of Plasma Concentrations 
Mean will be plotted. Visit will be plotted on the horizontal axis and each of the 
analysis variables will be plotted on the vertical axis. The vertical axis will be a 
common logarithmic scale.
Part 2
Analysis Set:
Pharmacokinetic Analysis Set
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
)
48 Hours
8 Hou
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Analysis Variable(s): 
Plasma Concentrations of TAK-935 Analyte (TAK-935, 
)
Visit: 
Predose, 0.25, 0.5, 1, 2, 4, 8, 10 and 12 Hours Postdose on Day 1, Day 7, Day 14 and Day 
21
Analytical Method(s): 
The following summaries will be provided. Subjects who were administered placebo will 
be excluded from the analysis.
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics and CV will be provided by visit.
(2) Case Plots of Plasma Concentrations
Plots over time for each subject will be provided. Visit will be plotted on the 
horizontal axis and the analysis variable will be plotted on the vertical axis. In 
addition to plots with the vertical axis as a normal scale, plots with the vertical 
axis as a common logarithmic scale will also be provided.
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted. A separate plot will also be 
provided for each analysis variable for each day. Visit will be plotted on the 
horizontal axis and each of the analysis variables will be plotted on the 
vertical axis. The vertical axis will be a normal scale. 
(4) Mean Plot of Plasma Concentrations 
Mean will be plotted. A separate plot will also be provided for each analysis 
variable for each day. Visit will be plotted on the horizontal axis and each of 
the analysis variables will be plotted on the vertical axis. The vertical axis will 
be a common logarithmic scale.
7.9.1.2
Pharmacokinetic Parameters
Part 1
Analysis Set:
Pharmacokinetic Analysis Set
Analysis Variable(s): 
Pharmacokinetic parameters of TAK-935: 
Cmax, Tmax, AUClast, AUCinf, AUC24, T1/2z, Lambda z, CL/F, Vz/F 
Pharmacokinetic parameters of 
CCI
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Cmax, Tmax, AUClast, AUCinf, AUC24, T1/2z, Lambda z, MR 
Analytical Method(s): 
The following summaries will be provided by dose. Subjects who were administered 
placebo will be excluded from the analysis.
(1) Summary of Pharmacokinetic Parameters
For Cmax, AUClast, AUCinf, and AUC24, descriptive statistics, geometric mean, 
CV, and geometric CV will be provided. For Tmax, descriptive statistics will be 
provided. For all other variables, descriptive statistics and CV will be provided. 
(2) Summary of Pharmacokinetic Parameters Normalized by Dose 
For Cmax, AUClast, and AUCinf that have been normalized by dose, descriptive 
statistics, geometric mean, CV, and geometric CV will be provided. 
Part 2
Analysis Set:
Pharmacokinetic Analysis Set
Analysis Variable(s): 
Pharmacokinetic parameters of TAK-935: 
Cmax, Tmax, AUClast, AUCtau, T1/2z, Lambda z, CL/F, Vz/F, Rac(AUC), Rac(Cmax)
Pharmacokinetic parameters of 
Cmax, Tmax, AUClast, AUCtau, T1/2z, Lambda z, Rac(AUC), Rac(Cmax), MR 
Visit:
Rac(AUC), Rac(Cmax): Day 7
For all other parameters: Day 1, Day 7, Day 14, Day 21 
Analytical Method(s): 
The following summaries will be provided. Subjects who were administered placebo will 
be excluded from the analysis.
(1) Summary of Pharmacokinetic Parameters
For Cmax, AUClast, and AUCtau, descriptive statistics, geometric mean, CV, and 
geometric CV will be provided. For Tmax, descriptive statistics will be provided. For 
all other variables, descriptive statistics and CV will be provided.
(2) Summary of Pharmacokinetic Parameters Normalized by Dose 
For Cmax, AUClast, and AUCtau that have been normalized by dose, descriptive 
statistics, geometric mean, CV, and geometric CV will be provided. 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
metric m
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-935:
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CCI
CCI


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7.9.1.3
Assessment of Dose Proportionality in Pharmacokinetic Parameters
Part 1
Analysis Set:
Pharmacokinetic Analysis Set
Analysis Variable(s): 
Pharmacokinetic parameters of TAK-935 and 
 
Cmax, AUClast, AUCinf, AUC24
Analytical Method(s): 
The following summaries will be provided. Subjects who were administered placebo will 
be excluded from the analysis.
(1) Scatter Plot for Pharmacokinetic Parameters and Dose
Scatter plots will be provided with dose plotted on the horizontal axis and each of the 
analysis variables plotted on the vertical axis.
(2) Regression Analysis of Pharmacokinetic Parameters on Dose
A power regression analysis will be performed for each analysis variable using the 
power model: 
y = a * (dose)b * e, 
where y is the analysis variable, a and b are the regression parameters, and e is the 
error term of the power equation.
Parameter estimates for a and b, and their two-sided 90% confidence intervals will be 
provided. 
Part 2 
Analysis Set:
Pharmacokinetic Analysis Set
Analysis Variable(s): 
Pharmacokinetic parameters of TAK-935 and 
 
Cmax, AUClast, AUCtau
Visit:
Day 7, Day 14, Day 21 
CCI
CCI
Property of Takeda: 
a
For non-commercial use only and subject to the applicable Terms of Use
erere adm
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Analytical Method(s): 
The following summaries will be provided. Subjects who were administered placebo will 
be excluded from the analysis.
(1) Scatter Plot for Pharmacokinetic Parameters and Visit
Scatter plots will be provided with visit plotted on the horizontal axis and each of the 
analysis variables plotted on the vertical axis.
7.9.2
CCI
CCI
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each of 
each o
rty of Takeda: For non-commercial use only and subject to the


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CCI
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erty of Takeda: For non-commercial use only and subject to the applicable Terms of U


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7.9.2.2
CCI
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perty of Takeda: For non-commercial use only and subject to the applicable Terms


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7.9.2.3
CCI
CCI
CCI
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erty of Takeda: For non-commercial use only and subject to the applicable Te


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7.10
Other Outcomes
Not applicable. 
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Terms


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7.11 
Safety Analysis 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
Intensity 
[Mild, Moderate, Severe] 
Analytical Method(s): 
The following summaries will be provided by dose for each of Part 1 and Part 2. 
(1) Overview of Treatment-Emergent Adverse Events 
1) All Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
2) Relationship of Treatment-Emergent Adverse Events to study drug (number of 
events, number and percentage of subjects) 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
4) Treatment-Emergent Adverse Events leading to study drug discontinuation 
(number of events, number and percentage of subjects) 
5) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
6) Relationship of serious Treatment-Emergent Adverse Events to study drug 
(number of events, number and percentage of subjects) 
7) Serious Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of subjects) 
8) Treatment-Emergent Adverse Events resulting in death (number of events, 
number and percentage of subjects) 
TEAEs will be counted according to the rules below. Percentages will be based on the 
number of subjects in the safety analysis set. The primary endpoint of this study is the 
percentage of subjects who experience at least 1 TEAE. 
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Number of subjects 
• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., Related and Not Related) 
will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity. 
• Summaries other than 2), 3), and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated 
7.11.1.2 Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Time of Onset 
[Period 1 (100 mg BID), Period 2 (200 mg BID),  
Period 3 (300 mg BID)] 
Analytical Method(s): 
The following summaries will be provided using frequency distribution by dose for each 
of Part 1 and Part 2. Summary table for (10) will only be provided for Part 2. 
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. 
SOC will be sorted alphabetically and PT will be sorted in decreasing frequency for 
tables provided by SOC and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by System Organ Class only or PT only. 
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(2) Treatment-Emergent Adverse Events by System Organ Class 
(3) Treatment-Emergent Adverse Events by Preferred Term 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
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(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class, and Preferred Term 
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
(8) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
(9) Treatment-Emergent Adverse Events of Special Interest by System Organ Class and 
Preferred Term 
(10) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Over Time 
The frequency distribution will be provided according to the rules below. Percentages 
will be based on the number of subjects in the safety analysis set. 
Number of subjects 
• Summary tables other than (5), (6), and (10) 
A subject with multiple occurrences of TEAE within a SOC will be counted only once 
in that SOC. A subject with multiple occurrences of TEAE within a PT will be 
counted only once in that PT. 
• Summary tables for (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted 
only once for the TEAE with the maximum intensity. 
• Summary tables for (10) 
A subject with a TEAE that occurs in more than one interval is counted in all the 
intervals that the TEAE occurs. For each time interval, a subject with multiple 
occurrences of TEAE within a SOC or a PT will be counted only once in that SOC or 
PT. 
When calculating percentages for each time interval, the number of subjects at risk 
(i.e., subjects who either have an exposure or have an occurrence of TEAE, during or 
after the corresponding time interval) will be used as the denominator. The number of 
subjects whose onset of any one of the TEAEs is within the time interval will be used 
as the numerator. 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
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Analysis Variable(s): 
PTE
Analytical Method(s): 
The following summaries will be provided using frequency distributions for each of Part 
1 and Part 2. 
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of PTE within a PT will be counted only 
once in that PT. 
7.11.2 CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
of Part 
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CCI
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rty of Takeda: For non-commercial use only and subject to the applicable Terms of U


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7.11.3
and Weight
Analysis Set:
Safety Analysis Set
Analysis Variable(s): 
Weight 
Visit: 
<Weight> 
Part 1: Day -2, Day 3 
CCI
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
bject to the applicable Terms
-commercial
f Takeda: Fo


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Part 2: Day -2, Day 24 
(Value from Day -2 will be used as the baseline) 
Analytical Method(s): 
The following summaries will be provided by dose for each of Part 1 and Part 2.
(1) Summary of 
 and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline (each post-
baseline visit - baseline) will be provided by visit. 
7.11.4
CCI
CCI
CCI
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(each
each po
y of Takeda: For non-commercial use only and subject to th


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7.11.5 Other Observations Related to Safety
Not applicable 
7.12
Interim Analysis
Not applicable. 
7.13
Changes in the Statistical Analysis Plan 
From the SAP Initial version, the following parts were updated. 
Before the change 
7.9.1 Pharmacokinetic Analysis
Section 7.9.1.1 Plasma Concentrations
Part 2
Analytical Method(s): 
The following summaries will be provided. Subjects who were administered placebo will 
be excluded from the analysis.
(1) Summary of Plasma Concentrations by Visit
Descriptive statistics and CV will be provided by visit.
(2) Case Plots of Plasma Concentrations
Plots over time for each subject will be provided. Visit will be plotted on the 
horizontal axis and the analysis variable will be plotted on the vertical axis. In 
addition to plots with the vertical axis as a normal scale, plots with the vertical 
axis as a common logarithmic scale will also be provided. 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted. Visit will be plotted on the 
horizontal axis and each of the analysis variables will be plotted on the 
vertical axis. The vertical axis will be a normal scale. 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
updated
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(4) Mean Plot of Plasma Concentrations 
Mean will be plotted. Visit will be plotted on the horizontal axis and each of 
the analysis variables will be plotted on the vertical axis. The vertical axis will 
be a common logarithmic scale.
After the change 
7.9.1 Pharmacokinetic Analysis
Section 7.9.1.1 Plasma Concentrations
Part 2
Analytical Method(s): 
The following summaries will be provided. Subjects who were administered placebo will 
be excluded from the analysis.
(1) Summary of Plasma Concentrations by Visit
Descriptive statistics and CV will be provided by visit. 
(2) Case Plots of Plasma Concentrations
Plots over time for each subject will be provided. Visit will be plotted on the 
horizontal axis and the analysis variable will be plotted on the vertical axis. In 
addition to plots with the vertical axis as a normal scale, plots with the vertical 
axis as a common logarithmic scale will also be provided.
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted. A separate plot will also be 
provided for each analysis variable for each day. Visit will be plotted on the 
horizontal axis and each of the analysis variables will be plotted on the 
vertical axis. The vertical axis will be a normal scale. 
(4) Mean Plot of Plasma Concentrations
Mean will be plotted. A separate plot will also be provided for each analysis 
variable for each day. Visit will be plotted on the horizontal axis and each of 
the analysis variables will be plotted on the vertical axis. The vertical axis will 
be a common logarithmic scale.
Reason for the change 
To meet another department request.
CCI
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CCI
CC


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8.0 
REFERENCES 
Not applicable. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use