Clinical trial NCT03332784
Conditions: Healthy Participants and Patients With Narcolepsy
Sponsor: Takeda
Start date: 2017-11-04; Completion date: 2018-09-04
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to investigate safety, tolerability, and pharmacokinetics of TAK-925 when a single dose of TAK-925 is administered to healthy adult participants, healthy elderly participants and patients with type 1 narcolepsy.

Detailed description:
Orexins are neuropeptides that play a role in the regulation of sleep and wakefulness. In type 1 narcolepsy, there is a loss of orexin producing neurons in the brain. The investigational drug, TAK-925, is an orexin 2 receptor agonist that is being tested in healthy adult participants, healthy elderly participants and patients with narcolepsy in order to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single intravenous administration.

The study will enroll approximately 20 healthy participants and 16 healthy elderly participants in Part 1 of the study and approximately 20 patients with narcolepsy in Part 2.

In Part 1, the study consists of 4 cohorts of 8 or 4 participants each. Participants will be randomly assigned (by chance, like flipping a coin) to one of the following treatment groups to receive TAK-925 or placebo:

\- Part 1, Cohort 1; TAK-925 (Dose Level 1, 3, 5), Cohort 2; TAK-925 (Dose Level 2, 4, 6), Cohort 3 and 4; TAK-925 (Dose Level 5)

For Cohort 1-4, healthy adult and elderly participants will be administered TAK-925 or placebo once in each cohort or dose level. The dose at the start (Cohort 1 dose level 1) is 7 mg of TAK-925 and following doses in Cohorts 1-4 will be determined based on available data from previous Cohorts/dose levels.

In Part 2 of the study, the study consists of 3 cohorts of 4 to 12 patients with narcolepsy. Patients will be randomly assigned to one of the treatment groups of Cohort 5-7 and will be administered TAK-925 or placebo once in each cohort. The dose of TAK-925 in Cohort 5-7 is TBD and will be decided based on available data from Part 1 and previous Cohorts.

\- Part 2, Cohort 5-7

This multi-center trial will be conducted in Japan. Participants will make multiple visits to the clinic. Visits in Part 1 will include a screening period (Day -28 to -2), Check-in on Day -1, Treatment period (Day 1 and 2), and follow-up visit on Day 7. In Part 2 of the study, the visits include a screening period (Day -42 to -2), Check-in on Day -1, Cross-over period (Day 1 to 4), and follow-up visit on Day 7.

Arms: arm 1: TAK-925, Intravenous single administration. Healthy adults will be enrolled in double blind manner. arm 2: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 2). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. arm 3: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 3). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. arm 4: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 4). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. arm 5: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 5). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. arm 6: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 6). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. arm 7: TAK-925 Placebo, Intravenous single administration. Healthy adults will be enrolled in double blind manner. arm 8: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 5). Healthy elderly participants will be enrolled in double blind manner. arm 9: TAK-925 Placebo, Intravenous single administration. Healthy elderly participants will be enrolled in double blind manner. arm 10: TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 5). Healthy adults will be enrolled in non-blinded manner. arm 11: TAK-925, Intravenous single administration. Dose in Cohort 5 will be based on safety and tolerability in the Part 1. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). arm 12: TAK-925, Intravenous single administration. Dose in Cohort 6 TBD based on safety, tolerability, PK data, and results of the Maintenance Wakefulness Test (MWT) from previous Cohorts. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). arm 13: TAK-925, Intravenous single administration. Dose in Cohort 7 TBD based on safety, tolerability, PK data, and results of the Maintenance of Wakefulness Test (MWT) from previous Cohorts. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). arm 14: TAK-925 Placebo, Intravenous single administration. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open).
Interventions: intervention 1: TAK-925 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-925 Intravenous Infusion intervention 2: TAK-925 Placebo Intravenous Infusion

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult and Elderly 
Volunteers and Patients with Narcolepsy 
 
NCT Number: NCT03332784 
Protocol Approve Date: 06-Mar-2018 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information 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 Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of a single dose of TAK-925 in Healthy Adult and Elderly Volunteers 
and Patients with Narcolepsy
Phase 1 Study of TAK-925 in Healthy Adult and Elderly Volunteers and Patients with 
Narcolepsy
Study Identifier:
TAK-925-1001
Compound:
TAK-925 (Research Name: TAK-925 iv)
Date:
06 March 2018
Version/Amendme
nt Number:
Amendment 2
Amendment History
Date
Amendment Number
Region
11 September 2017
First Edition
all sites
22 January 2018
Amendment 1
all sites
06 March 2018
Amendment 2
all sites
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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 ......................................................................................................8
2.0
STUDY SCHEMATIC..................................................................................................15
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................16
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit/Risk Profile .................................................................................................23
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................25
5.1
Hypothesis...............................................................................................................25
5.2
Trial Objectives .......................................................................................................25
5.2.1
Trial Primary Objectives...................................................................................25
5.2.2
Trial Secondary Objective.................................................................................25
5.2.3
Trial Exploratory Objectives.............................................................................25
5.3
Endpoints.................................................................................................................26
5.3.1
Primary Endpoints ............................................................................................26
5.3.2
Secondary Endpoint..........................................................................................26
5.3.3
Exploratory Endpoints ......................................................................................26
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................27
6.1
Trial Design.............................................................................................................27
6.2
Cohort Transition/Dose Escalation...........................................................................31
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................33
6.3.1
Rationale of Population.....................................................................................33
6.3.2
Rationale for Trial Design.................................................................................33
6.3.3
Rationale for Dose ............................................................................................34
6.3.4
Rationale for Endpoints ....................................................................................36
6.3.4.1
Safety Endpoints .......................................................................................36
6.3.4.2
PK Endpoints ............................................................................................36
6.3.4.3
PD Endpoints ............................................................................................37
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures...............37
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................38
6.5
Trial Beginning and End/Completion.......................................................................39
6.5.1
Definition of Beginning of the Trial..................................................................39
6.5.2
Definition of End of the Trial............................................................................40
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6.5.3
Definition of Trial Discontinuation ...................................................................40
6.5.4
Criteria for Premature Termination or Suspension of the Trial ..........................40
6.5.4.1
Criteria for Premature Termination or Suspension of Trial.........................40
6.5.4.2
Procedures for Premature Termination or Suspension of the Trial..............41
6.5.5
Criteria for Premature Termination or Suspension of the Trial at a Site.............41
6.5.5.1
Criteria for Premature Termination or Suspension of the Trial at a Site......41
6.5.5.2
Procedures for Premature Termination or Suspension of the Trial at a Site 41
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............42
7.1
Inclusion Criteria .....................................................................................................42
7.2
Exclusion Criteria ....................................................................................................44
7.3
Excluded Medications, Supplements, Dietary Products............................................47
7.4
Diet, Fluid, Activity.................................................................................................50
7.4.1
Diet and Fluid...................................................................................................50
7.4.2
Activity.............................................................................................................50
7.5
Record of Discontinuation or Withdrawal of a Subject before Study Drug 
Administration.........................................................................................................51
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................51
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................54
7.8
Subject Replacement................................................................................................54
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................55
8.1
Clinical Study Drug .................................................................................................55
8.1.1
Clinical Study Drug Labeling............................................................................55
8.1.2
Clinical Study Drug Inventory and Storage.......................................................55
8.1.3
Randomization Code Creation and Storage .......................................................56
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure ...................................56
8.1.5
Accountability and Destruction of Sponsor-Supplied Drugs..............................57
9.0
STUDY PROCEDURES...............................................................................................58
9.1
Administrative Procedures.......................................................................................58
9.1.1
Informed Consent Procedure.............................................................................58
9.1.1.1
Assignment of Subject Identification Number ...........................................58
9.1.1.2
Study Drug Assignment.............................................................................58
9.1.2
Inclusion and Exclusion....................................................................................60
9.1.3
Medical History/Demography...........................................................................60
9.1.4
Concomitant Medications .................................................................................61
9.1.5
Epworth Sleepiness Scale (ESS) .......................................................................61
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9.1.6
HLA-DQB1 *06:02 Typing Gene Analysis.......................................................61
9.2
Clinical Procedures and Assessments.......................................................................61
9.2.1
Full Physical Exam...........................................................................................61
9.2.2
Height and Weight............................................................................................61
9.2.3
BMI..................................................................................................................62
9.2.4
Columbia Suicide Severity Rating Scale (C-SSRS)...........................................62
9.2.5
Vital Signs........................................................................................................62
9.2.6
12-Lead ECG....................................................................................................62
9.2.7
Study Drug Administration ...............................................................................63
9.2.8
AE Monitoring..................................................................................................63
9.2.9
Laboratory Procedures and Assessments...........................................................63
9.2.9.1
Clinical Laboratory Tests ..........................................................................63
9.3
PK, PD, and PGx, Samples ......................................................................................65
9.3.1
PK Measurements.............................................................................................65
9.3.1.1
Plasma Samples for PK Measurements......................................................67
9.3.1.2
Urine samples for PK Measurements.........................................................68
9.3.1.3
CSF for PK Measurements ........................................................................68
9.3.1.4
Bioanalytical Methods...............................................................................69
9.3.2
PD Measurements.............................................................................................69
9.3.2.1
Maintenance of Wakefulness Test (MWT) ................................................69
9.3.2.2
.69
9.3.2.3
.70
9.3.2.4
.70
9.3.2.5
.70
9.3.3
PGx Measurements...........................................................................................71
9.3.3.1
Blood Sample for DNA PGx Measurements..............................................71
9.3.3.2
Blood Sample for RNA PGx Measurements..............................................71
9.3.4
Confinement .....................................................................................................71
10.0
ADVERSE EVENTS ....................................................................................................72
10.1
Definitions and Elements of AEs .............................................................................72
10.1.1 SAEs ................................................................................................................74
10.2
AE Procedures.........................................................................................................75
10.2.1 Assigning Severity/Intensity of AEs..................................................................75
10.2.2 Assigning Causality of AEs ..............................................................................75
10.2.3 Assigning Causality of AEs to Study Procedures ..............................................76
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10.2.4 Start Date..........................................................................................................76
10.2.5 End Date...........................................................................................................76
10.2.6 Pattern of Adverse Event (Number) ..................................................................76
10.2.7 Action Taken With Study Treatment.................................................................76
10.2.8 Outcome ...........................................................................................................76
10.2.9 Collection and Reporting of AEs, SAEs and Abnormal LFTs............................77
10.2.9.1 Collection Period.......................................................................................77
10.2.9.2 Reporting AEs...........................................................................................77
10.2.9.3 Reporting SAEs.........................................................................................78
10.2.9.4 The Adverse Event Related 
................................................78
10.2.9.5 Reporting of Abnormal LFTs ....................................................................79
10.2.10 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities....79
11.0
STATISTICAL METHODS..........................................................................................80
11.1
Statistical and Analytical Plans ................................................................................80
11.1.1 Analysis Sets ....................................................................................................80
11.1.1.1 Safety Analysis Set....................................................................................80
11.1.1.2 PK Analysis Set ........................................................................................80
11.1.1.3 PD Analysis Set ........................................................................................80
11.1.2 Analysis of Demography and Other Baseline Characteristics ............................80
11.1.3 PK Analysis......................................................................................................80
11.1.4 PD Analysis......................................................................................................81
11.1.5 Safety Analysis.................................................................................................81
11.1.5.1 AEs ...........................................................................................................82
11.1.5.2 Clinical Laboratory Evaluation..................................................................82
11.1.5.3 Vital Signs, Weight ...................................................................................82
11.1.5.4 Other Safety Parameters ............................................................................82
11.2
The Conversion Method of Data, and Handling of Lack of Data ..............................83
11.3
Committees Set Up for This Study...........................................................................83
11.4
Interim Data Review and Criteria for Premature Termination...................................83
11.5
Determination of Sample Size..................................................................................83
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................85
12.1
Study-Site Monitoring Visits ...................................................................................85
12.2
Protocol Deviations..................................................................................................85
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................85
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................86
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13.1
IRB and/or IEC Approval ........................................................................................86
13.2
Subject Information, Informed Consent, and Subject Authorization .........................86
13.3
Subject Confidentiality ............................................................................................87
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................88
13.4.1 Publication and Disclosure................................................................................88
13.4.2 Clinical Trial Registration.................................................................................88
13.4.3 Clinical Trial Results Disclosure.......................................................................88
13.5
Insurance and Compensation for Injury....................................................................88
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................89
14.1
Administrative Information......................................................................................89
14.1.1 Study Contact Information................................................................................89
14.1.2 Investigator Agreement.....................................................................................89
14.1.3 Study-Related Responsibilities..........................................................................89
14.1.4 List of Abbreviations ........................................................................................89
15.0
DATA HANDLING AND RECORDKEEPING............................................................92
15.1
eCRFs......................................................................................................................92
15.2
Record Retention .....................................................................................................93
16.0
REFERENCES..............................................................................................................94
17.0
APPENDICES...............................................................................................................96
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Cohorts..........................................................................................30
Table 7.a
Excluded Medications, Supplements, and Dietary Products (Part 1)...................48
Table 7.b
Excluded Medications and Dietary Products (Part 2)..........................................49
Table 9.a
Primary Sample Collections...............................................................................65
Table 9.b
Collection of Blood Samples for Pharmacokinetic Analysis (Part 1)...................67
Table 9.c
Collection of Blood Samples for Pharmacokinetic Analysis (Part 2)...................68
Table 9.d
Collection of Urine Samples for Pharmacokinetic Analysis................................68
Table 9.e.
Collection of CSF Samples for Pharmacokinetic Analysis..................................69
Table 10.a
Takeda Medically Significant AE List................................................................75
LIST OF IN-TEXT FIGURES
Figure 2.a
Summary of the Study Design............................................................................15
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Figure 6.a
Overview of the Trial Schedules ........................................................................31
Figure 9.a
Summary of Cohorts 1 and 2..............................................................................59
Figure 9.b
Summary of Cohort 3 and Cohort R1 (Healthy Elderly Supplement Cohort)......59
Figure 9.c
Summary of Cohorts S1-S4 (Healthy Adult Supplement Cohorts)......................59
Figure 9.d
Summary of Cohorts 5-7....................................................................................59
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-925
Study Identifier: TAK-925-1001
Phase: 1
Protocol Title: A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of a single dose of TAK-925 in Healthy Adult and Elderly Volunteers and Patients with 
Narcolepsy
Trial Design:
This study consists of two parts: Part 1 and Part 2.
Part 1 is an alternating panel, randomized, double-blind, placebo-controlled, crossover study to assess the single rising 
dose safety, tolerability and pharmacokinetics (PK) of a single rising dose of TAK-925 in healthy adult and elderly
volunteers. In Part 1, the safety, tolerability and the PK including the concentration in the cerebrospinal fluid (CSF) at
a single dose of TAK-925 in healthy adult volunteers will be also evaluated in an open cohort.
Part 2 is a sequential panel, randomized, double-blind (unblended for the sponsor), placebo-controlled, 2-period 
crossover study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of one or more 
dose levels of TAK-925 vs. placebo in patients with type 1 narcolepsy.
(1)
Part 1
Part 1 of the study will enroll 16 healthy adults into two separate cohorts of 8 subjects each, Cohort 1 and Cohort 2. In 
Cohort 3, 8 healthy elderly will be enrolled. In Cohorts 1 and 2 consisting of 8 subjects each, 6 subjects will receive 
TAK-925 and 2 subjects will receive placebo, assigned randomly in each dosing period (each period is composed of a 
single dose level), and 2 subjects each in Cohorts 1 and 2 will be randomly assigned to Groups A to H. To assess the 
safety, tolerability, and PK of TAK-925 including concentration of TAK-925 in CSF, 4 healthy adults will be enrolled 
as Cohort 4.
Administration of the study drug in Cohorts 1 and 2 will be performed alternately, with at least a 3-day interval 
between the cohorts and with a 7-day interval as well as more than 5 times the terminal half-life (t1/2) of TAK-925
within the same cohort. Each subject will be given the study drug a maximum of three times.
The summary of the study design including the starting dose and the target plasma concentrations of TAK-925 for 
each panel are shown in Figure 2.a.
Once the safety and tolerability in healthy adults has been confirmed, a dose level that is not higher than that 
investigated in healthy adults will be evaluated in the healthy elderly in Cohort 3.
Additionally, the concentration of TAK-925 in the CSF will be evaluated in healthy adults in Cohort 4.
TAK-925 will be administered as an intravenous (IV) infusion over a 9 hour period.
The first dose level cohort (Cohort 1, Dose Level 1) is designed to obtain the safety and tolerability information when 
a single dose of TAK-925 is administered as well as to obtain the information on the pharmacokinetic parameters that 
will determine the dosing regimen (infusion rate) and doses in the subsequent periods in Part 1. For example, if the 
time to achieve a steady state at a constant intravenous infusion rate is too long, and if the initial dose is safe and well 
tolerated, the infusion rate for the first 2 hours may be accelerated to achieve a steady state earlier in the subsequent
periods. In Cohort 1 Dose Level 1, a small number of subjects will be given the study drug first as a sentinel group. 
One subject each in the sentinel group (two subjects) will receive either TAK-925 or placebo first prior to the 
remaining six subjects and those remaining 6 subjects will be dosed at least two hours after the sentinel group was 
dosed. In Cohort 3, Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort (in the event that a 
cohort is added) following Cohort 2 Dose Level 2, all subjects should not receive TAK-925 simultaneously. (such that 
4 subjects will be dosed at first time, and if there are no safety issues, then the remaining 4 subjects will be dosed about 
1 hour later.)
Doses following Cohort 1 Dose Level 1 will be determined depending on the safety, tolerability and available PK data 
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obtained from the previous doses. After evaluating the safety, tolerability and PK in Cohort 1 Dose Level 1, dosing in 
Cohort 2 Dose Level 2 will be commenced. After evaluating the safety, tolerability and PK in Cohort 2 Dose Level 2, 
dosing in Cohort 1 Dose Level 3 will be commenced. After evaluating the safety, tolerability and available PK data in 
Cohort 1 Dose Level 3, Cohort 2 Dose Level 4 will be commenced. In a similar fashion, Cohort 1 Dose Level 5 and
Cohort 2 Dose Level 6 will be commenced. Not all the Cohorts should be run, and the dose may be higher or lower
than or the same to that of prior cohort dose levels, or an intermediate dose between two prior doses.
In the event that further investigation on the safety, tolerability and PK is needed after completion of Cohort 2 Dose 
Level 6, Healthy Adult Supplement Cohorts that will include 8 healthy adults per cohort (up to maximum of 4
additional cohorts that include 32 healthy adults) may be commenced without amendment of the protocol. The cohort 
names of S1 to S4 will be assigned for the Healthy Adult Supplement Cohorts. Six subjects will be randomly assigned
to the TAK-925 group and 2 subjects to the placebo group, to evaluate the safety, tolerability and PK. In the Healthy 
Adult Supplement Cohort, the dose may be higher or lower than or the same to that of the prior cohort dose levels, or 
an intermediate dose between two prior doses.
In Cohort 3, 8 healthy elderly will be enrolled. Of these 8 subjects, six will be randomly assigned to the TAK-925 
group and 2 to the placebo group. This cohort will be initiated after started with the dose of which the safety and 
tolerability has been established in healthy adults. In the event that further investigation on the safety, tolerability and 
PK is needed after completion of Cohort 3, a maximum of 1 additional cohort for Healthy Elderly Supplement Cohort
that enrolls 8 healthy elderly per cohort will be commenced without amendment of the protocol. The cohort name of 
R1 will be assigned for the Healthy Elderly Supplement Cohort. Six subjects will be randomly assigned to the 
TAK-925 group and 2 subjects to the placebo group, to evaluate the safety, tolerability and PK. InHealthy Elderly 
Supplement Cohort, the dose may be higher or lower than or the same to that of prior cohort dose levels, or an 
intermediate dose between two prior doses.
In Cohort 4, 4 healthy adults will be enrolled to evaluate the safety, tolerability and the CSF concentration of TAK-925 
measured at one time point and the plasma concentration of TAK-925. In Cohort 4, subjects, study sites and the 
sponsor will not be blinded. This cohort will be initiated after the safety and tolerability of the dose to be evaluated in 
Cohort 4 has been established in healthy adults.
Cohort 3, Healthy Elderly Supplement Cohort and Cohort 4 may be started at the discretion of the sponsor, 
considering the status of Cohorts 1, 2 and Healthy Adult Supplement Cohort.
(2)
Part 2
In Part 2, patients with type 1 narcolepsy will be enrolled in three cohorts: Cohorts 5 to 7. Part 2 is a 2-period crossover 
study to assess the safety, tolerability, PK and PD effects of a single dose of TAK-925. Part 2 may begin prior to the 
completion of Part 1. However, the dose to be used in Cohort 5 should be lower thanthe dose used in Part 1 as well as
be lower than 1/3 of the maximum dose of TAK-925 of which the safety and tolerability has been already confirmed. 
If Cohort 3 is not completed prior to starting Part 2, subjects aged 56 years or older should not be enrolled in Cohorts 
5, 6 and 7 until Cohort 3 is completed. The outline of the study design is shown in Figure 2.a.
In Cohorts 5 and 6, 4 subjects each will be enrolled, and TAK-925 or placebo will be intravenously infused for 9 hours 
on Day 1 and Day 3. Of 4 subjects in each cohort, 2 subjects each will be randomly assigned to one of the defined 
sequences (Groups I to L, TAK-925 may be given at one dose level in each cohort). In Cohort 7, a maximum of 12 
patients with type 1 narcolepsy will be enrolled. Of a maximum of 12 patients, 6 each will be randomly assigned to 
Group M or Group N. The dose level to be used in Cohort 5 will be determined based on the safety, tolerability and PK
data obtained from Part 1. After the safety, tolerability, PD effects (Maintenance Wakefulness Test : MWT) in Cohort 
5 and available PK data have been investigated, dosing in Cohort 6 will be started using another 4 new subjects. The 
same trial design as Cohort 5 will be used in Cohort 6. The dose to be used in Cohort 6 will be discussed by the
sponsor's unblinded team. The sponsor's unblinded team must not directly be involved in the execution of the study at 
a study site or directly contact the site. This team will review unblinded data on the safety, tolerability and PD effects
(MWT) and available PK of TAK-925, and recommend a dose based on those data. The dose level to be used in 
Cohort 6 may be higher or lower than the one used in Cohort 5. Cohort 7 will be composed of up to 12 subjects. The 
dose and the number of subjects to be used in Cohort 7 will be recommended by the sponsor’s unblinded team on the 
basis of safety, tolerability, PD effects (MWT) obtained from Cohorts 5 and 6 and available PK data of TAK-925. The 
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TAK-925
Study ID. TAK-925-1001
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06 March, 2018
CONFIDENTIAL
dose may be higher or lower than the doses used in Cohorts 5 and 6, or intermediate dose between these cohorts.
Primary Objectives:

To evaluate the safety and tolerability of TAK-925 when a single dose of TAK-925 is administered to healthy adult 
and elderly volunteers and patients with type 1 narcolepsy.

To evaluate the PK of TAK-925 when a single dose of TAK-925 is administered to healthy adult and elderly 
volunteers and patients with type 1 narcolepsy.
Secondary Objectives:

To evaluate PD effects (mainly, sleep latency in the MWT) of TAK-925 when a single dose of TAK-925 is 
administered to patients with type 1 narcolepsy.
Trial Subject Population:
Healthy adult and elderly volunteers and patients with type 1 narcolepsy
Planned Numberof Subjects:
(1)
Part 1

Cohort 1: 8 subjects (cumulative total of 24 subjects)

Cohort 2: 8 subjects (cumulative total of 24 subjects)

Cohort 3: 8 subjects

Cohort 4: 4 subjects
In the event that a cohort is added, a maximum of 5 cohorts (40 additional 
subjects) can be enrolled.
(2)
Part 2

Cohort 5: 4 patients (cumulative total of 8 subjects)

Cohort 6: 4 patients (cumulative total of 8 subjects)

Cohort 7: A maximum of 12 patients
(up to a cumulative total of 24 subjects)
Planned Number of Study Sites:
(1)
Part 1
1 study site
(2)
Part 2
2 study sites
Total: 3 study sites
Dose Levels:

Dosage
(1)
Part 1
A single dose of TAK-925 will be administered intravenously for 9 hours on 
Day 1.
(2)
Part 2
A single dose of TAK-925 or placebo will be administered intravenously for
9 hours on Day 1 or Day 3 alternately.
If placebo is given on Day 1, TAK-925 is to be given on Day 3. If TAK-925 
is given on Day 1, placebo is to be given on Day 3.

Administration
In Part 1, the starting dose (Cohort 1 Dose Level 1) of TAK-925 will be 7 mg.
From Cohort 2 Dose Level 2 through Cohort 5 in Part 2, the dose will be 
determined based on the safety, tolerability and pharmacokinetic data 
obtained from the prior cohorts. In Cohorts 6 and 7 in Part 2, the dose will be 
determined based on the safety, tolerability, PD effects (MWT) obtained in 
Part 1 and the previous cohort and available pharmacokinetic data so far.
Route of Administration:
IV
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TAK-925
Study ID. TAK-925-1001
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CONFIDENTIAL
Duration of Treatment:
(1)
Part 1
A single administration on Day 1 for each cohort
(2)
Part 2
A single administration on Day 1 and Day 3 for each cohort (TAK-925 will 
be given only once)
Planned Trial Duration:
(1)
Part 1
Screening period (Cohort 1 Dose 
Level 1, Cohort 2 Dose Level 2,
Cohorts 3 and 4, Healthy Adult 
Supplement Cohort and Healthy 
Elderly Supplement Cohort)
Days -28 to -2
Hospital admission day: Day -1
Treatment period: Day 1 and 2
Follow-up period: Day 7
(2)
Part 2
Screening period: Days -42 to -2
Hospital admission day: Day -1
Crossover period: Day 1 to 4
Follow-up Period: Day 7
Main Criteria for Inclusion:
All Subjects

Sex: Male and/or female

A male subject who is nonsterilized and sexually active and has a female partner of childbearing potential agrees to 
use adequate contraception from the signing of informed consent to 12 weeks (84 days) after the last dose of study 
drug. The female partner of a male subject should also be advised to use adequate contraception (See Appendix B).
Healthy Adults (Cohort 1, 2, 4 and Healthy Adult Supplement Cohort)

A subject who is a healthy adult, aged between 20 and 55 years, at the time of signing the informed consent form.

A subject weighing at least 50 kg and has a body mass index (BMI) of 18.5 to 30 kg/m2 at Screening.
The Healthy Elderly (Cohort 3 and Healthy Elderly Supplement Cohort)

A subject who is a healthy elderly aged between 65 and 80 years at the time of signing the consent form.

A subject weighing at least 40 kg and has a BMI of 18.5 to 30 kg/m2 at Screening.
Patients with type 1 narcolepsy (Cohorts 5-7)

A patient aged between18 and 80 years at the time of signing the consent form.

A patient weighing at least 40 kg at Screening.

Patients with type 1 narcolepsy: Those diagnosed with type 1 narcolepsy, as defined by the International 
Classification of Sleep Disorders, Third Edition (ICSD-3)

A patient who is positive for HLA-DQB1*06:02

Epworth Sleepiness Scale (ESS) score on Day -1 is ≥10

A female patient of childbearing potential who is sexually active and has a nonsterilized male partner agrees to 
routinely use an adequate contraception from the time of signing the consent form throughout the study.
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Study ID. TAK-925-1001
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Main Criteria for Exclusion:
All Subjects

Creatinine clearance (Ccr) of ≤50 mL/min at Screening or on hospital admission (Day -1)

Blood pressure (BP) of ≥140 mmHg(systolic) or ≥ 90 mmHg(diastolic) at Screening, Day -1 or before study drug 
administration on Day 1, confirmed by repeated measurements of BP after resting in a supine position for 
approximately 10 or 30 minutes.

A subject who has a risk of suicide according to the investigator's judgment based on the assessment of the 
Columbia Suicide Severity Rating Scale (C-SSRS) or has made a suicide attempt within 6 months before the start 
of study drug administration.

A subject who has a current or past history of epilepsy, convulsion, tremor or related symptoms.

A subject who has a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, arteriovenous 
malformation.

A subject who has known coronary artery disease, and a history of myocardial infarction (MI), angina, cardiac 
rhythm abnormality or heart failure.
Healthy Adult and The Healthy Elderly (Cohorts 1-4, Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort)

A subject unwilling to stop smoking during the study period.

A female subjects of childbearing potential who is sexually active (premenopausal and nonsterilized).

A subject who has clinically significant sleep disorders (including sleep apnea syndrome and insomnia).
Healthy Adults (Cohort 4 only)

A subject whose CSF was collected within 14 days prior to hospitalization (Day -1).

A subject who has known hypersensitivity to anesthetics or medications used for CSF collection or lumbar 
puncture.

A subject who has clinically significant vertebral deformities (scoliosis or kyphosis), which, in the opinion of the 
investigator, may interfere with lumbar puncture.

A subject who has a clinically significant back pain and/or back injury.

A subject who has a local infection at the puncture site.

A subject who has thrombocytopenia or bleeding tendencies noted before the beginning of study procedures.

A subject who has signs and symptoms of radiculopathy including in leg pain and paresthesia.

A subject who has focal neurological deficit that might suggest an increase in intracranial pressure.

A subject who has abnormal findings on ophthalmological examination/fundoscopy suggestive of raised 
intracranial pressure (eg, optic disc swelling/papilledema, uncontrolled hypertensive retinopathy).

A subject who suffers from moderate to severe headaches requiring analgesics.
Patients with type 1 narcolepsy (Cohorts 5-7)

A patient unwilling to quit smoking 40 minutes before the scheduled MWT and one hour before sleeping.

A patient who has sleep disorder(s) associated with excessive sleepiness (including sleep apnea syndrome) other 
than narcolepsy.

Excessive caffeine consumption (>400 mg/day) within seven days before hospital admission (Day -1).

Use of drugs with stimulating or sedating properties, anti-parkinson drugs or anti-convulsant drugs within 7 days 
before the start of study drug administration or 5 times the half life of each drug. For selective serotonin reuptake 
inhibitors (SSRIs) and tricyclic antidepressants, there should be a washout period (at least 5 times the elimination 
half-life of each drug or for 7 days, whichever is longer) prior to the start of study drug administration, and the 
administration should be discontinued with gradual dose reductions.
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TAK-925
Study ID. TAK-925-1001
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CONFIDENTIAL
Main Criteria for Evaluation and Analyses:
The primary endpoints

Safety and tolerability: adverse events, vital signs, body weight, 12-lead electrocardiogram (ECG) and clinical 
laboratory tests (hematology, serum chemistry and urinalysis)

Pharmacokinetics: Plasma concentrations and pharmacokinetic parameters, urine pharmacokinetic parameters of 
TAK-925, and CSF concentrations and pharmacokinetic parameters of TAK-925 and its metabolites (
 
).
The secondary endpoint

The average sleep latency in the Maintenance Wakefulness Test (MWT)
Statistical Considerations:
Safety:
For Cohorts 1-2 and Healthy Adult Supplement Cohort, Cohort 3 and Healthy Elderly Supplement Cohort, Cohort 4,
Part 2, the following analyses will be performed for each dose level using the safety analysis set.
A treatment emergent adverse event (TEAE) is defined as an AE that occurs on or after the start of study drug. TEAEs 
are tabulated by the number of all TEAEs, the drug-related TEAEs, the intensity of all TEAEs, the intensity of 
drug-related TEAEs, the TEAEs leading to study drug discontinuation, and the number of serious TEAEs. TEAEs will 
be coded into the System Organ Class (SOC) and the Preferred Term (PT) using the Medical Dictionary for 
Regulatory Activities (MedDRA).
For continuous variables, the observed values and the changes from baseline will be summarized for each scheduled 
sampling time using descriptive statistics. For categorical variables, shift tables showing the number of subjects in 
each category at baseline and each post- baseline scheduled sampling time will be provided.
PK:
For Cohorts 1-2 and Healthy Adult Supplement Cohort, Cohort 3 and Healthy Elderly Supplement Cohort, Cohort 4,
Part 2, the following analyses will be performed for each dose level using the PK analysis set.
Plasma and CSF concentrations of TAK-925 and its metabolites (
) will be summarized for each 
scheduled sampling time using descriptive statistics.
Plasma, urine and CSF pharmacokinetic parameters of TAK-925 and its metabolites (
) will be 
summarized using descriptive statistics.
PD:
The following analysis will be conducted using the PD analysis set.
For the average sleep latency in MWT in Part 2, descriptive statistics for the observed values will be provided by dose
level. An analysis of variance (ANOVA) for crossover design with the observed value as a response, the dose level, 
the group and the period as factors will be conducted. The differences in the least square means between each dose 
level of TAK-925 and the placebo (each dose level of TAK-925 – the placebo) and the two-sided confidence intervals 
will be provided. Bayesian posterior probabilities that the mean differences are greater than the value (specified in the 
SAP) will be provided based on the Bayesian posterior distributions for the mean differences between each dose level 
of TAK-925 and the placebo (each dose level of TAK-925 – the placebo).
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TAK-925
Study ID. TAK-925-1001
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Sample Size Justification:
For Cohorts 1 to 3 in Part 1, 8 subjects (6 in TAK-925 group, 2 in placebo group) will be enrolled in each Cohort to 
evaluate the safety, tolerability and PK of TAK-925 when a single dose of TAK-925 is administered to healthy adults 
and the healthy elderly. If further investigation on the safety, tolerability and PK in healthy adults is needed after 
completion of Cohorts 1-2, a maximum of 4 additional cohorts (a total of 32 healthy adult subjects; 8 subjects [6 in 
TAK-925 group, 2 in placebo group] per cohort) may be enrolled. If further investigation on the safety, tolerability and 
PK in healthy elderly is needed after completion of Cohort 3, a maximum of 1 additional cohort (a total of 8 healthy 
elderly subjects [6 in TAK-925 group, 2 in placebo group] per cohort) may be enrolled.
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, tolerability, PK of TAK-925 including the 
concentration of TAK-925 in the CSF when a single dose of TAK-925 is administered intravenously to healthy adults.
For Part 2, 4 patients each in Cohorts 5 and 6 and a maximum of 12 patients in Cohort 7 will be enrolled to evaluate the
safety, tolerability, PK and PD effects of TAK-925 when a single dose of TAK-925 is administered intravenously to 
patients with type 1 narcolepsy. These sample sizes are not based on any effect size or obtained by the MWT statistical 
evidence.
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TAK-925
Study ID. TAK-925-1001
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2.0
STUDY SCHEMATIC
Figure 2.a
Summary of the Study Design
<Part 1>
1.
Cohorts 1 and 2 (Healthy Adults) and Cohorts S1-S4 (Healthy Adult Supplement Cohorts)
Dose Level
Cohort
1
2
3
4
5
6
7-10
1
7 mg
28 mg
112 mg
2
14 mg
56 mg
134.4 mg
S1-4
TBD
TBD=To be determined
1)
Cohorts 1 and 2 will be implemented as alternating panel design during a maximum of 3 dosing periods.
2)
The doses of Dose Levels 7-10 are planned as follows. However based on the available the safety, tolerability and PK data, 
there is a possibility that the dose may be appropriately increased or decreased within the range not exceeding 420 mg. Dose
Level 7: 180 mg, Dose Level 8: 240 mg, Dose Level 9: 320 mg, Dose Level 10: 420 mg.
3)
See Figure 9.a for randomization scheme for Dose Levels 1-6.
4)
In the event that further investigation on the safety, tolerability and PK is needed after completion of Cohorts 1 and 2, a 
maximum of 4 additional cohorts that include 32 healthy adults can be implemented without amendment of the protocol.
5)
Double-blind. Each Cohort consists of 8 subjects. Of 8 subjects, 6 will receive TAK-925 and 2 will receive placebo.
2.
Cohort 3 (The healthy elderly) and Cohort R1 (The Healthy Elderly Supplement Cohort)
Cohort 3/Cohort R1
112 mg/TAK-925 TBD
Placebo
1)
Double-blind. Each Cohort consists of 8 subjects. Of 8 subjects, 6 will receive TAK-925 and 2 will receive placebo.
3.
Cohort 4 (Healthy adults)
Cohort 4
112 mg
1)
Unblinded. Cohort 4 consists of 4 subjects.
<Part 2>
4.
Cohorts 5-7 (Patients with narcolepsy)
Cohort 5
Cohort 6
Period 1
Period 2
cohort transition
Period 1
Period 2
TAK-925 TBD
Placebo
→
TAK-925 TBD
Placebo
Placebo
TAK-925 TBD
Placebo
TAK-925 TBD
Cohort 7
cohort transition
Period 1
Period 2
→
TAK-925 TBD
Placebo
Placebo
TAK-925 TBD
1)
Double-blind (the sponsor is unblinded), 2x2 crossover study.
2)
See Figure 9.d for randomization scheme.
3)
Cohorts 5 and 6 consist of 4 subjects each. 2 subjects each in a group will be randomized to each sequence. On Days 1 and 3, 
TAK-925 or placebo will be administered intravenously to these subjects for 9 hours.
Cohort 7 consists of a maximum of 12 subjects, and 6 subjects each at maximum in a group will receive TAK-925 or placebo
intravenously for 9 hours  on Days 1 and 3, TAK-925 or placebo will be administered intravenously to these subjects for 9 
hours.
4)
Each Cohort will be investigated in different patients.
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TAK-925
Study ID. TAK-925-1001
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3.0
SCHEDULE OF STUDY PROCEDURES 
Part1(Cohorts 1-4, Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort)
Screening 
Day -28 to Day-2 (a)
Day -1
Predose
Day 1
Day1
Day 2/Early
Termination
Follow-Up 
Visit (b)
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X (a)
Medical History/Demographics
X
X
Prior and Concomitant Medication
---------------------------------------- Continuous Monitoring --------------------------------------
Clinical Procedures/Assessments
Physical Examination
X
X
X
X
Height
X
Weight
X
X
X
X
BMI
X
Vital Signs (pulse rate, SBP and DBP) (c)
X
X
X
X
X
X
Vital Signs (respiratory rate, body temperature) (d)
X
X
X
X
12-Lead Electrocardiogram (e)
X
X
X
X
C-SSRS
X
X
TAK-925/Placebo Administration
X
Adverse Events
---------------------------------------- Continuous Monitoring --------------------------------------
Laboratory test/Assessments
Hematology
X
X
X
X
Urinalysis
X
X
X
X
Serum Chemistry
X
X
X
X
Urine Drug Screen, Cotinine Testing, Alcohol Testing
X
Hepatitis Screen, HIV Antigen-Antibody Detection Assay, Syphilis 
Serum Reaction Test
X
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TAK-925
Study ID. TAK-925-1001
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Screening 
Day -28 to Day-2 (a)
Day -1
Predose
Day 1
Day1
Day 2/Early
Termination
Follow-Up 
Visit (b)
Blood Collection for Retained Samples and Pharmacogenomic 
Research
X (a)
Pharmacokinetic Evaluations
Blood Sample Collection for Pharmacokinetic Evaluations of 
TAK-925 and its Metabolites (
) (f)
X
X
X
Urine Sample Collection for Pharmacokinetic Evaluations of 
TAK-925 and its Metabolites (
) (g)
X
X
X
CSF Sample Collection for Pharmacokinetic Evaluations of 
TAK-925 and its Metabolites (
) (h)
X
Other
Hospitalization
X (i)
X
X
X
Abbreviations: BMI=body mass index, C-SSRS=The Columbia Suicide Severity Rating Scale, HIV=human immunodeficiency virus, CSF= cerebrospinal fluid
(a) This will be performed once only in each subject during the study period. Blood samples for pharmacogenomic research will be collected after the start of study 
drug administration.
(b) Follow-up visit will occur on Day 7 (±2).
(c) Vital signs (pulse rate, SBP and DBP) will be measured:
Screening period
Day -1: Measurements will be performed at 15:00 and 19:00, totally 2 times. (No Measurement in Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort)
Day1: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 hours after the start of infusion
On Day -1 and Day 1 in Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort, measurement will be performed at following the same 
time point.
Day -1: -24, -23.75, -23.5, -23.25, -23, -22.5, -22, -21.5, -21, -20.5, -20, -19, -18, -17, -16, -15, -14, -13 and -12 hours after the start of infusion.
Day 1: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours after the start of infusion.
On Day 1, Measurement ats 24 hours after the start of infusion will also be performed.
Follow-Up visit.
Orthostatic BP (1 and 5 minutes after standing up) will also be measured after the above vital signs were measured 1, 2 and 4 hours after the start of infusion
(only on Day 1). Each BP will be measured after lying on a bed with the head of the bed up to 30 degrees and taking a rest for 5 minutes, using the same arm.
BP will be measured predose, at every 15 minutes for the first one hour, then at every 30 minutes for 1 to 4 hours and then at every 1 hour for 4 to 12 hours after 
the start of infusion, and at 24 hours thereafter. In Cohort 4, BP will be basically measured after lying on a bed with the head of the bed up to 30 degrees,
however BP can be measured with the bed flat except for the case of lumbar puncture for CSF sampling. In the event that blood sampling for PK are scheduled 
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Study ID. TAK-925-1001
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CONFIDENTIAL
at the same time as BP measurement, the blood sampling for PK should be performed first.
(d) Vital signs (respiratory rate, body temperature) will be measured during the screening period, 1 hour predose on Day 1, and 5 hours after the start of infusion on 
Day 1 and on Day 2.
(e) 12-Lead ECG will be measured during the screening period, on Day -1 and between 2 and 9 hours after the start of infusion on Day 1 and on Day 2.
(f) Blood samples for TAK-925 PK analysis will be collected: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 9 hours after the start of infusion, and 0.17, 0.33, 0.5, 0.75, 1, 
1.5, 2, 3, 4, 6, 10 and 15 hours after the end of infusion. However, Dose Levels 1 and 2 of Cohorts 1 and 2 will be excluded at 10 hours after the end of infusion.
(g) Urine samples for TAK-925 PK analysis will be collected: Predose (spot urine), 0-9 hours after the start of infusion, and 0-3, 3-6, 6-15 hours after the end of 
infusion.
(h) In Cohort 4 only, CSF samples for PK analysis of TAK-925 and its metabolites will be collected: 6 hours after the start of infusion
(i)
Hospitalization from Day -2 may be allowed for Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort as needed.
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Study ID. TAK-925-1001
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Part 2
Screening 
Day -42 to 
Day-2
Day -1
Predose
Day 1
Day 1
Day 2
Predose
Day 3
Day 3
Day 4/
Early
Termination
Follow-Up 
Visit (a)
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria (b)
X
X
X(c)
Medical History/Demographics
X
X
HLA DQB1 *06:02 Typing (d)
X
Washout of Prior Medications (e)
X
Prior and Concomitant Medication
--------------------------------------- Continuous Monitoring -------------------------------------
Clinical Procedures/Assessments
Physical Examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
BMI
X
Vital Signs (pulse rate, SBP and DBP) (f)
X
X
X
X
X
X
X
X
X
Vital Signs (respiratory rate, body temperature) (g)
X
X
X
X
X
X
X
12-Lead Electrocardiogram (h)
X
X
X
X
X
X
C-SSRS
X
X
TAK-925/Placebo Administration
X
X
MWT (Maintenance of Wakefulness Test) (i)
X
X
X
Adverse Events
-------------------------------------- Continuous Monitoring -------------------------------------
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Screening 
Day -42 to 
Day-2
Day -1
Predose
Day 1
Day 1
Day 2
Predose
Day 3
Day 3
Day 4/
Early
Termination
Follow-Up 
Visit (a)
Laboratory test/Assessments
Hematology
X
X
X (m)
X
X (m)
X
Urinalysis
X
X
X (m)
X
X (m)
X
Serum Chemistry
X
X
X (m)
X
X (m)
X
Urine Drug Screen
X
Hepatitis Screen, HIV Antigen-Antibody Detection 
Assay, Syphilis Serum Reaction Test
X
Blood Collection for Retained Samples and 
Pharmacogenomic Research
X (n)
Pregnancy Test (o)
X
Pharmacokinetic Evaluations
Blood Sample Collection for Pharmacokinetic 
Evaluations of TAK-925 and its Metabolites (
) (p)
X
X
X
X
X
X
Other
Hospitalization
X
X
X
X
X
X
X
Abbreviations: 
, 
, C-SSRS=The Columbia Suicide Severity Rating Scale; HIV=Human 
immunodeficiency virus, CSF= Cerebrospinal fluid
(a) Follow-up visit will occur on Day 7 (±2).
(b) To confirm thatthe subject meets the inclusion criteria or does not meet the exclusion criteria, the 
 or the multiple sleep latency test 
(MSLT) (including the number of sleep-onset REM periods [SOREMPs]) can be performed as a study procedure (s) at the screening visit, if necessary.
(c) Day 1 only
(d) This genotyping will be performed only for subjects of whom the presence or absence of HLA-DQB1*06:02 cannot be identified by his/her medical records.
(e) Washout of prior medications may require for about 7 days of hospital stay. The need for hospital stay and its duration can be determined by the investigators.
(f) Vital signs (pulse rate, systolic and diastolic BP) will be measured:
Screening period
Day -1: Measurements will be performed at 15:00 and 19:00, totally 2 times.
Day 1 and Day 3: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours after the start of the infusion.
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Study ID. TAK-925-1001
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Day 2 and Day 4: 24 hours after the start of infusion
Follow-up visit.
At 1 hour after the start of infusion, orthostatic BP (at 1 and 5 minutes after standing up) will also be measured after the above vital signs were measured. Each 
BP will be measured after lying on a bed with the head of the bed up to 30 degrees and taking a rest for 5 minutes, using the same arm. BP will be measured
predose and at every 15 minutes for the first 1 hour, then at every 30 minutes for 1 to 2 hours, then at every 1 hour for 2 to 12 hours after the start of infusion, 
and at 24 hours thereafter. In the event that blood sampling for PK are scheduled at the same time as BP measurement, the blood sampling for PK should be
performed first. In the event that BP is scheduled at the same time as the MWT procedures, BP measurement should be performed both before and after the 
MWT procedures. During the MWT procedures, BP may be measured in a sitting position, if necessary.
(g) Vital signs (respiratory rate, body temperature) will be measured during the screening period, within 1 hour predose on Day 1 and Day 3, at 5 hours after the 
start of infusion on Day 1 and Day 3, and at the same time period on Day 2 and Day 4.
(h) 12-Lead ECG will be measured during the screening period, on Day -1, between 2 and 9 hours after the start of infusion on Day 1 and Day 3, and at the same 
time period on Day 2 and Day 4.
(i)
MWT procedures will be conducted:
Day -1: MWT procedures will be completed by 17:00.
Day 1 and 3: MWT procedures will be conducted at 10:00, 12:00, 14:00 and 16:00 following the start of infusion dosing at 7:45.
(j)
ESS will be conducted on Day -1 only.
(k)
(l)
(m) These tests will be conducted using the blood samples collected at the same time point on Day 2 and Day 4.
(n) Blood sampling will be performed only once for each subject after the start of infusion on Day 3.
(o) Only for female subjects of childbearing potential
(p) Blood samples for the PK evaluations of TAK-925 (and its metabolites) will be collected on Day 1, Day 2, Day 3 and Day 4: Predose, 1, 2, 4, 6 and 9 hours after 
the start of infusion, and 0.17 0.5, 1, 2 and 15 hours after end of infusion, just before sleep and right after wake-up.
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4.0
INTRODUCTION
4.1
Background
Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness and 
cataplexy. Narcolepsy is a relatively rare disease beginning in prior to, during and after puberty, 
with a prevalence rate of 0.16-0.18% (1 in 600 people) in Japan [1] . Narcolepsy is reported to be 
caused by a decrease in the level of orexin (OX) peptides with dropouts of orexin-producing 
neurons [2][3]. OX has been shown to significantly affect individual’s ability to maintain an 
appropriate balance between sleep and wakefulness [4].
Patients with narcolepsy suffer from disadvantages in various aspects of daily life, especially 
because of excessive daytime sleepiness. This reduces the patient’s ability to work and learn 
effectively and results in a severely impaired quality of life (QOL). Moreover, patients with 
narcolepsy have a high risk of mistakes during working, loss of employment, traffic accidents and 
occupational injuries, and may suffer serious disadvantages in their social lives as well as in their 
QOLs [5].
The treatment for narcolepsy is intended “to minimize any disadvantages due to excessive daytime 
sleepiness with minimum medication quantities and to inhibit undesirable side effects and the 
development of drug dependence” in accordance with the Guidelines on the Diagnosis and 
Management of Narcolepsy [5]. Therapeutic drugs for narcolepsy currently approved in Japan are 
modafinil, methylphenidate, pemoline, methamphetamine and clomipramine. Among these drugs, 
methamphetamine is designated as a stimulant and has a risk of drug addiction. Therefore, it is not 
recommended as a treatment option in the Guidelines on the Diagnosis and Management of 
Narcolepsy. For excessive daytime sleepiness, modafinil is the first-line drug, however, as the 
effect is moderate, there exist a certain number of patients with unsatisfactory response [6][7]. 
Methylphenidate and pemoline also inhibit excessive daytime sleepiness, but the development of 
drug addiction has become a problem. Consequently, methylphenidate and pemoline can only be 
used when modafinil is not effective [5]. Although clomipramine is the only drug approved for the 
treatment of cataplexy, continuous use leading to reduced therapeutic effects has been concerned
[5]. These drugs are symptomatic treatment that do not directly have effects on the 
pathophysiology of narcolepsy and therefore, the effects themselves may be limited and, 
conventional therapies are almost impossible to improve the level of sleepiness to the normal 
range, especially for excessive daytime sleepiness. In addition, current treatments only exert an 
effect on either excessive daytime sleepiness or cataplexy. This results in the need for combination 
therapies in patients with both symptoms [8]. Thus, a novel drug that directly tackles the 
pathological mechanism of narcolepsy to meet this high medical need and is effective in treating 
both excessive daytime sleepiness and cataplexy with high efficacy.
TAK-925 is an orexin 2 receptor (OX2R)-selective agonist produced by Takeda Pharmaceutical 
Company Limited (TPC). Orexin is a neuropeptide which exerts its action via two different types 
of orexin receptors (OX1R and OX2R). The role of orexin in humans has not been fully identified, 
but animal studies conducted so far indicated that it influenced a variety of behaviors, such as 
feeding, sleep/wakefulness, reward/dependence, and emotion/stress[4]. The physiological action 
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of each receptor has also been identified, which demonstrated that stabilization of sleep and 
wakefulness was mainly involved in OX2R [9], while the development of drug addiction is 
involved in OX1R [10].
In non-clinical studies in mice and monkeys, TAK-925 demonstrated high specificity for OX2R, 
and activated OX2R, penetrated the blood-brain barriers of these animals to reach theie brains and 
increased the duration of wakefulness, and when TAK-925 was given to mouse models of 
narcolepsy-like symptoms[11], it mitigated the fragmentation of waking/sleep and cataplexy-like 
symptoms.
Consequently, TAK-925 may reduce the risk of addiction induced by activation of OX1R and 
improve both symptoms of excessive daytime sleepiness and cataplexy through its selective
effects on OX2R. Currently, no drug with similar mechanism has been tested in humans, and
therefore, TAK-925 would be the first drug to be developed in this class in the world, potentially 
providing an innovative treatment option to patients with narcolepsy, which had been impossible 
with preexisting drugs.
4.2
Rationale for the Proposed Study
In non-clinical studies using mice and monkeys, TAK-925 demonstrated a high specificity for 
OX2R and activates OX2R, penetrated the blood-brain barriers of these animals to reach the brains
and increased the duration of wakefulness, and when TAK-925 was administered to mouse models
of narcolepsy-like symptoms (orexin/ataxin-3 transgenic mice), it improved narcolepsy-like 
symptoms such as fragmentation of sleep and wakefulness, and cataplexy-like symptoms. The 
results of non-clinical studies of TAK-925 revealed no significant toxicity findings to be 
concerned about when TAK-925 is assumed to be administered to humans. Results of the 
preclinical toxicology and safety studies also support the administration of TAK-925 in humans.
This phase 1 single dose study was designed to evaluate the safety, tolerability, pharmacokinetics
(PK) and pharmacodynamics (PD) effects of TAK-925 when it is administered as a single dose to
healthy adults, the healthy elderly and patients with narcolepsy.
4.3
Benefit/Risk Profile
There are no benefits for the subjects of the present study other than receiving medical 
examinations to obtain information about their overall health conditions, but it is possible that the 
information obtained from the present study will become beneficial to the patients with narcolepsy 
in the future.
With respect to the risks of subjects, safety information is limited to the data obtained from 
non-clinical studies.
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 The 
details of the management of BP increase are provided in Section 7.6. As TAK-925 is expected to 
have a short half-life, discontinuation of TAK-925 will lead to a rapid decline in BP if a tolerance
does not develop with continued study drug infusion.
Please refer to the investigator’s brochure for detailed information of TAK-925.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed based on the following hypotheses:
!
One or more safe and well-tolerated IV infusion TAK-925 dosage levels will achieve a Ceoi 
(plasma concentration at the end of infusion) greater than or equal to the threshold estimated to 
be required for efficacy (expected to be 20-30 ng/ml).
!
At least 1 dose of TAK-925 shows a more significant wake-promoting effect when measured 
by the mean sleep latency using the Maintenance Wakefulness Test (MWT) and is safer and 
better tolerated than placebo.
5.2
Trial Objectives
5.2.1
Trial Primary Objectives
!
To evaluate the safety and tolerability of TAK-925 when a single dose of TAK-925 is 
administered to healthy adults, the healthy elderly and patients with type 1 narcolepsy.
!
To evaluate the PK of TAK-925 when a single dose of TAK-925 is administered to healthy 
adults, the healthy elderly and patients with type 1 narcolepsy.
5.2.2
Trial Secondary Objective
!
To evaluate the PD effects of TAK-925 (mainly, sleep latency in the MWT) when a single dose 
of TAK-925 is administered to patients with type 1 narcolepsy.
5.2.3
Trial Exploratory Objectives
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5.3
Endpoints
5.3.1
Primary Endpoints
!
Safety and tolerability: adverse events, vital signs, body weight, 12-lead electrocardiogram 
(ECG) and clinical laboratory tests (hematology, serum chemistry and urinalysis)
!
Pharmacokinetics (PK): plasma concentrations and pharmacokinetic parameters, urine 
pharmacokinetic parameters and cerebrospinal fluid (CSF) concentrations and 
pharmacokinetic parameters of TAK-925 and its metabolites (
).
5.3.2
Secondary Endpoint
!
The average sleep latency in the MWT
5.3.3
Exploratory Endpoints
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This study consists of two parts.
Part 1 is an alternating panel, randomized, double-blind, placebo-controlled, crossover study to 
assess the safety, tolerability and pharmacokinetics (PK) of a single rising dose of TAK-925 in 
healthy adult and elderly volunteers. In Part 1, the safety and tolerability, and the PK including the 
concentration in the cerebrospinal fluid (CSF) at a single dose of TAK-925 in healthy adult 
volunteers will be also evaluated in an open cohort.
Part 2 is a sequential panel, randomized, double-blind (unblinded for the sponsor), 
placebo-controlled, 2-period crossover study to assess the safety, tolerability, PK and PD of one or 
more dose levels of TAK-925 vs. placebo in patients with type 1 narcolepsy.
(1) Part 1
Part 1 of the study will enroll 16 healthy adults into two separate cohorts of 8 subjects each, Cohort 
1 and Cohort 2. In Cohort 3, 8 healthy elderly will be enrolled. In Cohorts 1 and 2 consisting of 8 
subjects each, 6 subjects will receive TAK-925 and 2 subjects will receive placebo, assigned 
randomly in each dosing period (each period is composed of a single dose level),and 2 subjects 
each in Cohorts 1 and 2 will be randomly assigned to Groups A to H. To assess the safety, 
tolerability, and PK of TAK-925 including CSF-PK of TAK-925, 4 healthy adults will be enrolled 
as Cohort 4.
Administration of the study drug in Cohorts 1 and 2 will be performed alternately, with at least a 
3-day interval between the cohorts and with a 7-day interval as well as more than 5 times the 
terminal half-life (t1/2) of TAK-925 within the same cohort. Each subject will be given the study 
drug a maximum of three times.
The first dose level cohort (Cohort 1, Dose Level 1) is designed to obtain the safety and tolerability 
information when a single dose of TAK-925 is administered as well as to obtain the information on
pharmacokinetic parameters that will determine the dosing regimen (infusion rate) and doses in the
subsequent periods in Part 1. For example, if the time required to achieve a steady state at a 
constant intravenous infusion rate is too long, if and the initial dose is safe and well tolerated, the 
infusion rate for the first 2 hours may be accelerated to achieve a steady state earlier in the 
subsequent periods. In Cohort 1 Dose Level 1, a small number of subjects will be given the study 
drug first as a sentinel group. One subject each in the sentinel group (two subjects) will receive 
either TAK-925 or placebo first prior to the remaining six subjects and those remaining 6 subjects
will be dosed at least two hours after the sentinel group was dosed. In Cohort 2 Dose Level 2 and 
subsequent dose levels in Cohorts 1 and 2, Cohort 3, Healthy Adult Supplemental Cohort and 
Healthy Elderly Supplement Cohort (in the event that the cohort is actually added) receive 
TAK-925 or placebo simultaneously. (such that 4 subjects will be dosed at first, and if there are no 
safety issues, the remaining 4 subjects may be dosed about 1 hour later.)
Doses following Cohort 1 Dose Level 1 will be determined depending on the safety, tolerability 
and available PK of previous doses. After evaluating the safety, tolerability and PK in Cohort 1
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Dose Level 1, dosing in Cohort 2 Dose Level 2 will be commenced. After evaluating the safety, 
tolerability and PK in Cohort 2 Dose Level 2, dosing in Cohort 1 Dose Level 3 will be commenced.
After evaluation the safety, tolerability and available PK in Cohort 1 Dose Level 3, dosing in 
Cohort 2 Dose Level 4 will be commenced. In a similar fashion, dosing in Cohort 1 Dose Level 5 
and Cohort 2 Dose Level 6 in a similar fashion. Not all the Cohorts should be run necessarily, and 
the dose may be higher or lower than or the same to that of prior cohort dose levels, or intermediate 
dose between two prior doses.
In the event that further investigation on the safety, tolerability and PK is needed after completion 
of Cohort 2 Dose Level 6, Healthy Adult Supplement Cohorts that will include 8 healthy adults per 
cohort (up to 4 additional cohorts that include 32 healthy adults) may be commenced without 
amendment of the protocol. The cohort names of S1 to S4 will be assigned for Healthy Adult 
Supplement Cohort. Six subjects will be randomly assigned to the TAK-925 group and 2 subjects 
to the placebo group in a cohort, to evaluate the safety, tolerability and PK. In Healthy Adult 
Supplement Cohort, the dose may be higher or lower than or the same to that of prior cohort dose
levels, or an intermediate between two prior doses.
In Cohort 3, 8 healthy elderly subjects will be enrolled. Of these 8 subjects, six will be randomly 
assigned to the TAK-925 group and 2 to the placebo group. This cohort will be initiated after
started with the dose of which the safety and tolerability has been established in healthy adults. In 
the event that further investigation on the safety, tolerability and PK is needed after completion of 
Cohort 3, a maximum of 1 additional cohort for Healthy Elderly Supplement Cohort that enrolls 8 
healthy elderly per cohort will be commenced without amendment of the protocol. The cohort 
name of R1 will be assigned for the Healthy Elderly Supplement Cohort. Six subjects will be 
randomly assigned to the TAK-925 group and 2 subjects to the placebo group, to evaluate the 
safety, tolerability and PK. In Healthy Elderly Supplement Cohort, the dose may be higher or 
lower than or the same to that of prior cohort dose levels, or an intermediate dose between two 
prior doses.
In Cohort 4, 4 healthy adults will be enrolled to evaluate the safety, tolerability and the CSF 
concentration of TAK-925 measured at one time point and the plasma concentration of TAK-925. 
In Cohort 4, subjects, study sites and the sponsor will not be blinded. This cohort will be initiated 
after the safety and tolerability of the dose to be evaluated in Cohort 4 has been established in 
healthy adults.
Cohort 3, Healthy Elderly Supplement Cohort and Cohort 4 may be started at the discretion of the 
sponsor, considering the status of Cohorts 1, 2 and Healthy Adult Supplement Cohort. (Cohorts 3 
and 4 may be implemented in parallel with Cohorts 1 and 2. The doses to be used in Cohorts 3 and 
4 will be determined based on the available safety, tolerability and PK data, and nonclinical study 
results.)
(2) Part 2
In Part 2, patients with type 1 narcolepsy will be enrolled in three cohorts: Cohorts 5 to 7. Part 2 is 
a 2-period crossover study to assess the safety, tolerability, PK and PD effects of a single dose of
TAK-925. Part 2 may begin prior to the completion of Part 1. However, the dose to be used in 
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Cohort 5 should be lower than the one used in Part 1 as well as be lower than 1/3 of the maximum 
dose of TAK-925 of which the safety and tolerability has been already confirmed. If Cohort 3 is 
not completed prior to starting Part 2, subjects aged 56 years or older should not be enrolled in 
Cohorts 5, 6 and 7 until Cohort 3 is completed.
In Cohorts 5 and 6, 4 subjects each will be enrolled, and TAK-925 or placebo will be intravenously 
infused for 9 hours on Day 1 and Day 3. Of 4 subjects in each cohort, 2 subjects each will be 
randomly assigned to one of the defined sequences (Groups I to L, TAK-925 may be given at one 
dose level in each cohort). A maximum of 12 patients with type 1 narcolepsy will be enrolled in 
Cohort 7. Of a maximum of 12 patients, 6 each will be randomly assigned to Group M or Group N.
The dose level to be used in Cohort 5 will be determined based on the safety, tolerability and PK
data obtained from Part 1. After the safety, tolerability, PD effects (MWT) in Cohort 5 and 
available PK have been investigated, dosing in Cohort 6 will be started using another 4 new 
subjects. The same trial design as Cohort 5 will be used in Cohort 6. The dose level to be used in 
Cohort 6 will be discussed by the sponsor's unblinded team. The sponsor's unblinded team must 
not directly be involved in the execution of the study at a study site or directly contact the site. This
team will review unblinded data on the safety, tolerability, PD effects (MWT) and available PK of 
TAK-925, and recommend a dose based on those data. The dose level to be used in Cohort 6 may 
be higher or lower than the one used in Cohort 5. Cohort 7 will be composed of up to 12 subjects. 
The dose and the number of subjects to be used in Cohort 7 will be recommended by the sponsor’s 
unblinded team on the basis of safety, tolerability, PD effects (MWT) obtained from Cohorts 5 and 
6 and available PK data of TAK-925. The dose may be higher or lower than the doses used in 
Cohorts 5 and 6, or intermediate dose between these cohorts.
See section 3.0 for the schedule of tests/observations /evaluations. Summary of Cohorts is shown 
in Table 6.a.
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Table 6.a
Summary of Cohorts
Part
Cohort
Subjects
Sample Size
Study Design
Dosage
Randomization
11)
12)
Healthy adults
n=8
Double-blind,
Cross-over
TAK-925 7 mg
(Dose Level 1)
or placebo
Each Cohort
TAK-925: 6 subjects,
Placebo: 2 subjects
2
TAK-925 14 mg 
(Dose Level 2)
or placebo
1
TAK-925 28 mg
(Dose Level 3)
or placebo
2
TAK-925 56 mg
(Dose Level 4)
or placebo
1
TAK-925 112 mg
(Dose Level 5)
or placebo
2
TAK-925 134.4 mg
(Dose Level 6)
or placebo
S1 – S43)
Healthy adults
n=8
Double-blind, 
parallel group
TAK-925 TBD mg
(Dose Level 7-10)3)
or placebo
3
Healthy elderly
n=8
Double-blind, 
parallel group
TAK-925 112 mg
or placebo
4
Healthy adults
n=4
Unblinded
TAK-925 112 mg
TAK-925: 4 subjects
R14)
Healthy elderly
n=8
Double-blind, 
parallel group
TAK-925 TBD mg
or placebo
TAK-925: 6 subjects,
Placebo: 2 subjects
21)
5
Patients with type 1 
narcolepsy
n=4
Double-blind
(unblinded for the sponsor)
2 x 2 Cross-over
TAK-925 TBD5) mg
or placebo
Each period
TAK-925: 2 subjects,
Placebo: 2 subjects
6
Patients with type 1 
narcolepsy
n=4
Double-blind
(unblinded for the sponsor)
2 x 2 Cross-over
TAK-925 TBD mg
or placebo
7
Patients with type 1 
narcolepsy
n=12
Double-blind
(unblinded for the sponsor)
2 x 2 Cross-over
TAK-925 TBD mg
or placebo
Each period
TAK-925: max. 6 subjects,
Placebo: max. 6 subjects
1)
In Part 1, Dose Levels 1, 3 and 5 will be tested in the same set of subjects, and similarly, Dose Levels 2, 4 and 6 will be 
evaluated in the different set of the same subjects. In Part 2, different subjects will be used in each Cohort.
2)
In Cohort 1 Dose Level 1, 2 subjects will be enrolled and one subject each will be assigned randomly to either the TAK-925 or
placebo group to evaluate the safety and tolerability of TAK-925. Once the safety and tolerability of these two subjects is 
evaluated, additional 6 subjects will be enrolled and 5 subjects and 1 subject of the 6 subjects will be assigned randomly to the 
TAK-925 and placebo groups, respectively, to evaluate the safety and tolerability of TAK-925.
3)
In the event that further investigation on the safety, tolerability and PK of TAK-925 is needed after completion of Cohorts 1 
and 2, up to 4 additional cohorts that include 32 healthy adults can be commenced without amendment of the protocol. The 
Dose Levels 7-10 are planned as follows. However based on the available safety, tolerability and PK data, there is a possibility 
that the dose may be appropriately increased or decreased within the range not exceeding 420 mg. Dose Level 7: 180 mg, Dose 
Level 8: 240 mg, Dose Level 9: 320 mg, Dose Level 10: 420 mg.
4)
In the event that further investigation on the safety, tolerability and PK of TAK-925 is needed after completion of Cohort 3, up 
to 1 additional cohort that include 8 healthy elderly can be commenced without amendment of the protocol.
5)
In Part 2, the dose level to be used in Cohort 5 should be equal or lower than one-third of the maximum dose of TAK-925 of 
which the safety and tolerability has been already confirmed in Part 1.
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Figure 6.a
Overview of the Trial Schedules
<Part 1>
Screening
Baseline
Treatment Period
Follow-up
Period
Washout
Period
Study Drug 
Administration/Sampling
Sampling
Hospital Visit
Day -28--2
Day -1
Day 1
Day 2
Day 7
*Till Day 
TBD
Hospitalization Period
*The washout period will be determined based on the pharmacokinetic data obtained from Cohort 1 Dose Level 1. Subjects will 
re-visit the hospital on Day 7 and the same schedule (after Day -1 and subsequent days) will be applied for the subsequent Dose 
Levels after washout period.
<Part 2>
Screening
Baseline
Crossover period
Follow-up
Period
MWT/
Study Drug 
Administration
/Sampling/MWT
Sampling/
Study Drug 
Administration 
/Sampling/MWT/
Sampling
Hospital Visit
Day -42--2*
Day -1
Day 1
Day 2
Day 3
Day 4
Day 7
Hospitalization Period
*For the subjects receiving prohibited concomitant medications, a washout period will be added arranged during the screening 
period.
6.2
Cohort Transition/Dose Escalation
The starting dose in Cohort 1 Dose Level 1 will be TAK-925 7 mg to be given once a day as 9-hour
continuous intravenous infusion (See Section 6.3.3(1) for further information on starting dose 
selection).
After investigating the safety, tolerability (adverse events, physical examination findings, vital 
signs, laboratory tests and 12-lead ECG findings) in Cohort 1 Dose Level 1 24 hours after the start 
of infusion and pharmacokinetics of TAK-925, the dose level be used in Cohort 2 Dose Level 2
will be selected.
After the investigating the safety, tolerability in Cohort 2 Dose Level 2 until 24 hours after the start 
of infusion and pharmacokinetics of TAK-925, and the dose level to be used in Cohort 1 Dose 
Level 3 will be selected. After investigating the safety and tolerability of TAK-925 in Cohort 1 
Dose Level 3 until 24 hours after the start of infusion, the dose level to be used in Cohort 2 Dose 
Level 4 will be selected based on available PK data. After investigating the safety and tolerability
of TAK-925 in Cohort 2 Dose Level 4 until 24 hours after the start of infusion, the dose level to be 
used in Cohort 1 Dose Level 5 will be selected based on available PK data. After investigating the 
safety and tolerability of TAK-925 in Cohort 1 Dose Level 5until 24 hours after the start of
infusion, the dose level to be used in Cohort 2 Dose Level 6 will be selected based on available PK 
data. The investigator will comprehensively investigate in a blinded manner the safety and 
tolerability (adverse events, physical examination findings, vital signs, laboratory tests and 
12-lead ECG findings) of each Dose Level in Part 1 obtained by 24 hours after the start of infusion 
(Day 2), or those of each Cohort in Part 2 obtaind by 24 hours after the start of final infusion (Day 
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4) as well as available PK data obtained so far, then determine whether to proceed to the next dose 
level or next cohort after discussion(s) with the sponsor (and the medical expert, if necessary).
In Part 1(Cohorts 1-3 and Healthy Adult Supplement Cohort), the AUC and Cmax of the dose to be 
used in the next Dose Level or next Cohort will be estimated based on the available PK data. The 
dosage and infusion rate to be used in the next Dose Level or next Cohort will be determined so 
that the AUC, Cmax and the infusion rate in the next Dose Level or the next Cohort will not be more 
than twice the AUC, Cmax and the infusion rate in the previous Dose Level or the previous Cohort.
Dose escalation or cohort transition will not occur if any of the following is seen in any Dose Level 
or Cohort:
1. A serious adverse event of which causal relationship to the study drug cannot be ruled out
occurred.
2. Severe adverse event(s) of which causal relationship to the study drug cannot be ruled out
occurred in two or more subjects at one dose level during the treatment period (from the 
commencement of treatment to the washout period or at the end of follow-up period).
3. A significant increase in BP defined in Section 7.6, regardless of symptomatic or 
asymptomatic, occurred in three or more subjects at one dose level.
Dose selection for Cohort 5 in Part 2 will be made based on the blinded safety and tolerability data 
of the completed cohorts in Part 1 and the available PK results. The dose to be used in Cohort 5 
should be equal to or less than one-third of the highest tolerated dose in Part 1. The inclusion 
criteria for patients with type 1 narcolepsy in Part 2 includes those aged 18-80, but subjects aged 
56 years or older will be enrolled based on the assessments of the safety results and PK data of
Cohort 3 (and the Healthy Elderly Supplement Cohort) in Part 1.
The maximum dose and the highest infusion rate in Part 2 shall not exceed the maximum dose and 
the highest infusion rate at which the safety and tolerability were confirmed in Part 1.
The sponsor will review the safety, tolerability in Part 1 and the available PK to determine the dose 
for Cohort 5. The investigator will decide whether to start Cohort 5 after discussion with the 
sponsor. The sponsor's unblinded team will review the safety, tolerability, PD effects (MWT 
results) and available PK to recommend the dose for Cohort 6 and the dose and the number of 
subjects for Cohort 7. Based on the recommendation by the sponsor's unblinded team, the 
investigator will decide whether to start Cohort 6 and Cohort 7 after discussion with the sponsor.
The dose for Cohort 6, and the dose and the number of subjects for Cohort 7 will be determined 
before enrollment of subjects. The results of the sponsor's unblinded team's review and the 
information of the dose and the number of subjects determined will remain blinded to the on-site 
clinical study staff, except the administrator of study drug at the site and the sponsor's unblinded 
team.
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6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Population
(1) Part 1
The subjects to be enrolled in Cohorts 1-2 and Healthy Adult Supplement Cohort will be healthy 
adults who do not have any significant diseases, including cardiovascular disease and
cerebrovascular disease to appropriately evaluate the safety, tolerability and PK of TAK-925. The 
subjects to be enrolled in Cohort 3 will be the healthy elderly who do not have any significant 
diseases, including cardiovascular disease and cerebrovascular disease, to appropriately evaluate 
the safety, tolerability and PK of TAK-925 in the healthy elderly, prior to the commencement of 
Part 2. Evaluation of Cohort 3 is particularly important, since elderly patients with type 1 
narcolepsy will be is enrolled in Part 2. Also, considering the possibility of performing Part 2 at 
high doses, the Healthy Elderly Supplement Cohort will be added. In Cohort 4, healthy adults will 
be enrolled in order to appropriately evaluate the safety and tolerability, and PK including the 
concentration of TAK-925 in the CSF six hours after the start of infusion of TAK-925.
(2) Part 2
The subjects to be enrolled in Part 2 will be patients with type 1 narcolepsy in order to apprpriately 
evaluate PD effects of TAK-925, in addition to evaluation of the safety, tolerability and 
pharmocokinetics of TAK-925.
6.3.2
Rationale for Trial Design
(1) Part 1
Cohorts 1-2 will be an alternating panel (consisting of eight subjects per Cohort), dose-escalation, 
double-blind study. In Cohorts 1 and 2, each 2 subjects will be randomly assigned to Groups A to 
H for each dosing period where TAK-925 may be given at one dose level to have 6 subjects dosed 
TAK-925 and 2 subjects dosed placebo. In Healthy Adult Supplement Cohort that consists of 8 
subjects per cohort, 6 and 2 subjects will be randomly assigned to the TAK-925 group or the 
placebo group, respectively. In Cohorts 1 and 2 and Healthy Adult Supplement Cohort, setting the 
placebo group is essential in order to evaluate the safety and tolerability of TAK-925 in an 
unbiased manner. The nonclinical study results of TAK-925 revealed that there were no significant
toxicological findings to be concerned about when the maximum dose of TAK-925 planned in this 
study is assumed to be administered to humans. However, 
 
criteria for discontinuation or withdrawal of a subject, and 
criteria for dose escalation will be established. Since this is a clinical study of a compound having
a novel mechanism to be used in humans for the first time, the initial dose will be 7 mg, and the 
subsequent doses will be increased in a stepwise fashion according to the safety and tolerability of 
TAK-925. Subjects will be hospitalized throughout the trial. The recommended initial dose of 7 
mg was calculated based on the nonclinical study results. This is a dose-escalation study, to 
increase the dose in a stepwise fashion after reviewing the safety data obtained until the time of 
discharge (Day 2) and available pharmacokinetic data. Since Cohort 1 Dose Level 1 is a 
first-in-human study for TAK-925, a sentinel dosing will be used. First, TAK-925 or placebo will 
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be administered to one subject each. Once 2 hours have passed since the infusion was started and it 
was judged to be safe to proceed (eg, in case the subject does not meet the criteria for 
discontinuation or withdrawal of a subject), then the drug will be administered to the remaining 
subjects (5 subjects in the TAK-925 group and 1 subject in the placebo group). After Cohort 2 
Dose Level 2, dosing will not be started simultaneously in all subjects in Cohort 3, Healthy Adult 
Supplement Cohort and Healthy Elderly Supplement Cohort (in the event that a cohort is added). 
(4 subjects will be dosed first, and if there are no safety issues, the remaining 4 subjects will be 
dosed approximately 1 hour later.)
Cohort 4 is an open-label study in order to appropriately evaluate the safety and tolerability, and 
PK of TAK-925 including the plasma and CSF concentrations of TAK-925.
(2) Part 2
In Cohorts 5-7, a double-blind crossover study design will be used. With this design, the results of 
MWT when TAK-925 was administered can be compared to the results of MWT when placebo 
was administered on an individual subject basis, minimizing variability between subjects. This 
will allow for early assessment of potential drug efficacy. It is important that the sponsor reviews 
the data in an unblinded fashion as the dose escalation study will be conducted based on the safety 
and tolerability as well as the mean sleep latency in the MWT. In order to maintain subjects and 
study sites blinded and reduce any sponsor bias, a sponsor's unblinded team will be organized. The 
sponsor's unblinded team must not directly be involved in the execution of the study at a study site 
or directly contact the site. This team will review the safety, tolerability, PD effects (MWT results) 
and available PK to determine the dose for Cohort 6 and the dose and the number of subjects for 
Cohort 7.
The results of nonclinical studies of TAK-925 revealed no significant toxicity findings to be 
concerned about when TAK-925 is assumed to be administered in humans at the maximum dose 
planned in this clinical study.
 
 Therefore, in Part 2, the 
initial dose is to be equal to or less than one-third of the maximum dose of TAK-925 of which the
safety and tolerability has been already confirmed in Part 1. In each Cohort, the washout period to 
be set after the 2nd or subsequent infusions will be set 5 times the t1/2 of TAK-925 as a guide, which 
is considered not to affect the PD effect.
6.3.3
Rationale for Dose
(1) Starting Dose for This Trial
The starting dose of TAK-925 in this phase 1, first-in-human (FIH) trial will be 7 mg to be given as 
continuous intravenous infusion for 9 hours a day.
The starting dose was calculated according to the procedures recommended by the FDA
“Guideline for Industry for Estimating the Maximum Safe Starting Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers” [13] (hereinafter referred to as "FDA Guidance").
As a result of calculation of the human equivalent dose (HED) converted from the 
no-observed-adverse-effect level (NOAEL) based on the body surface area, rats were the animal 
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species with the highest sensitivity. The calculated HED in a human weighing 60 kg calculated 
using the conversion factor provided in the FDA Guideline was 
mg/day (
 
 x 0.16 [conversion factor] = 
mg/day [HED in a human weighing 60 kg]).
Moreover, when the safety factor was conservatively defined as 10, the maximum recommended 
starting dose (MRSD) of TAK-925 was calculated as 
/day.
The FDA Guideline also recommends to consider using the pharmacologically active dose (PAD)
in nonclinical studies when an initial dose is determined. In nonclinical pharmacology studies, the 
pharmacologically active concentration of TAK-925 in monkeys and common marmosets were 
, respectively, which were
 of the Cmax at the 
NOAEL in rats, respectively.
Based on the results of 
 
The 
Cmax (Css) and the AUC when 
 TAK-925 is given as continuous intravenous infusion for 9 
hours a day were calculated
, respectively.
 
As mentioned above, the starting dose in this trial will be 7 mg to be given as continuous 
intravenous infusion for 9 hours a day.
(2) Maximum Dose/Exposure for This Trial
Based on the NOAEL in rats of which the sensitivity was the highest among animals used in the
two-week, nonclinical, repeated-dose, toxicity studies, and the clinical dose of betadex sulfobutyl 
ether sodium (BSES), which is an excipient contained in the study drug, the acceptable upper 
limits of Cmax and AUC and the maximum dose of TAK-925 in this study were set to be 
. Meanwhile, in Cohort 2 Dose Level 6 
of Part 1 in this study, Cmax and AUC of TAK-925 were
(preliminary result), respectively, and were safe and well-tolerated. These exposure levels of Cmax
and AUC are 
 lower than the acceptable Cmax and AUC of TAK-925 in this 
study, respectively, 
. Thus, it 
was judged possible to investigate at higher doses, and the maximum dose (the upper limit) was set 
to be 
.
For example, "VFEND IV 200 MG" approved in Japan, contains BSES, an excipient contained in 
the study drug. Referring to the dosage of VFEND [14], the maximum amount of BSES per dose
was set to be 3840 mg (when VFEND is administered to a human weighing 60 kg, as the 
maintenance dose on and after Day 2) in the protocol (first version and amendment 1). On the other 
hand, based on the result of Cohort 2 Dose Level 6 
of Part 1 of this study and with 
reference to the dosage of CARNEXIV [15] already approved in the United States, the maximum 
amount of BSES per dose was set to
in the study protocol (amendment 2), which is 
within the range of the dose of BSES, to be possibly administered within 9 hours as CARNNEXIV
(CARNEXIV is infused every 6 hours, so this amount corresponds to 2 doses of CARNNEXIV).
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Since TAK-925 used as a study drug contains 
 of BSES as an excipient
mg of 
TAK-925, 
of TAK-925 contains
of BSES.
(3) Infusion Rate for This Trial
In the two-week, nonclinical, repeated-dose, toxicity study, the infusion rate at the NOAEL in rats 
was
 When 
 is converted into the HED, the infusion rate will be 
 per 
adult weighing 60 kg. In the intravenous, single-dose, dose-escalation, toxicity study, convulsion 
was observed 
at an infusion rate of 
. When 
 is converted into 
the HED, the infusion rate will be 
 per adult weighing 60 kg.
The starting dose of TAK-925 in this trial will be 7 mg to be given as continuous intravenous 
infusion for 9 hours a day, and the infusion rate will be
, which is slower than 
 of the
infusin rate at the
 
In order to accurately conduct the MWT procedures in patients with type 1 narcolepsy, the plasma 
concentration of TAK-925 is planned to reach the steady state in 2 hours. If additional PK data are 
newly obtained, the infusion rate may be adjusted accordingly. As the upper limit of Cmax is set to 
be 
, based on the 
 in rats, it is estimated that the rate of increasing 
plasma drug concetration will be controlled to be 
at fastest.
 
 
6.3.4
Rationale for Endpoints
6.3.4.1
Safety Endpoints
Since this is a FIH study of TAK-925, adverse events, vital signs, body weight, 12-lead ECG and 
clinical laboratory tests will be included as safety endpoints. In the safety pharmacological study
of TAK-925 in monkeys, transient mild to moderate BP increased was observed at all the dosages 
tested. In this study, therefore, BP will be measured frequently. See Section 7.6 for the details of 
the criteria for discontinuation or withdrawal of a subject.
6.3.4.2
PK Endpoints
In order to evaluate the PK of TAK-925 in healthy adults, the healthy elderly and patients with 
narcolepsy, the concentrations of TAK-925 and its metabolites (
) in the plasma, urine
and CSF will be evaluated, and the following pharmacokinetic parameters will be calculated.
(1) Part 1
Pharmacokinetic parameters: Cmax, Ceoi, AUClast, AUC∞, tmax, t1/2z, 
 Vss (TAK-925 only), Vz
(TAK-925 only), Ae24, fe24, CLR, CL (TAK-925 only), RCSF/Plasma, SS (=CSF concentration/C6h)
(Cohort 4 only)
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(2) Part 2
Pharmacokinetic parameters: Cmax, Ceoi, AUClast, AUC∞, tmax, t1/2z,
, Vss (TAK-925 only), Vz
(TAK-925 only), CL (TAK-925 only)
In cases where it was considered necessary for interpretation of data, pharmacokinetic parameters 
other than the above may be calculated.
6.3.4.3
PD Endpoints
The PD endpoints will include MWT, 
 
. MWT is a test to measure the time of maintaining wakefulness 
using electroencephalogram, by which objective information about the patient’s ability to sustain 
wakefulness can be obtained. 
.
MWT is an indicator of evaluating objective sleepiness and used as a standardized and established 
method for evaluating the treatment of excessive sleepiness caused by narcolepsy, and this test has 
been widely used in clinical trials of a variety of investigational drugs including modafinil
[16][17][18][19]. Therefore, the MWT will be used as the most important PD endpoint in this 
study. Parameters related to the mean sleep latency will be described in detail in the statistical 
analysis plan.
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures
The purpose of including this section is to specify the order of procedures when two or more 
procedures are scheduled at the same time during the study.
!
Safety evaluation will be performed within the specified time frame as close as possible.
!
Blood samples for pharmacokinetic evaluation must be collected as close as the specified time. 
BP should be measured at the specified time. Frequent BP measurements should be performed,
 
. In the event that BP measurement and blood sampling for PK are scheduled at the 
same time, the blood sampling for PK should be performed first then BP measurement should 
be performed within an acceptable time frame (Appendix C).
!
Other procedures must be completed as close to the specified or scheduled time as possible, 
regardless of before or after the specified time.
!
In the event that blood sampling and ECG or vital sign measurement are scheduled at the same 
time, blood sampling should be prioritized, then ECG or vital sign will be measured within an 
acceptable time frame (Appendix C).
!
Priority ranking may be subject to change based on the agreement after discussion between the 
investigator and the sponsor.
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!
In the event an adverse event occurred, any tests or procedures required for urgently evaluating 
the event for safety purposes must be prioritized over any planned regular procedures, 
whatever it is.
!
Since the secondary objective of this study is to evaluate the PD effects of TAK-925 in patients 
with narcolepsy, MWT to be performed in each Cohort of patients with narcolepsy is an 
important procedure. As BP measurement may interfere the MWT, BP should be measured 
before or after the test if these procedures are scheduled at the same time. If the BP 
measurement is performed during the MWT, it may be performed in a sitting position as 
needed.
!
See the manuals for
 and MWT for further details.
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a FIH study of TAK-925, in which the PK, PD and safety profiles of the compound will be
determined. This protocol is written with some flexibility to accommodate the unique nature of 
phase 1 clinical trial. The above-described dose, dosing regimen and/or clinical procedures and 
test procedures may be modified. Such modification is for scientific purposes of this trial and/or to 
ensure accurate safety monitoring of subjects.
The present dose and/or dosing regimen may be updated based on newly obtained data, but the 
maximum dose/exposure and the infusion rate detailed in Section 6.3.3 will remain unchanged.
The following modifications will be allowed:
!
Addition of cohorts
!
The dose of study drug previously administered may be adopted or may be decreased.
!
Executions entire cohort or dose escalation may be omitted.
!
Prolongation of a washout period based on the safety and pharmacokinetic data obtained. (In 
Part 2, infusion on Day 3 is changed to Day 4)
!
Omission, extension or addition of the pharmacokinetic data review (if it is agreed by the 
sponsor and the investigator.)
The method for collecting PK/PD sampling data currently described in the protocol may be 
modified based on newly obtained PK or PD data during this trial (eg, to obtain data at the time 
closer to the peak plasma concentration achieved). Collected samples may be used in a study to 
explore metabolites and/or additional PD markers.
A maximum of 50 mL of blood samples may be additionally collected for PK and/or biomarker 
analyses during the study. This may occur because repeated sample collection may be needed to 
replace the current data by newly obtained data, or PK/biomarker sampling time points may be 
changed. The total blood volume to be collected from a single subject will not exceed the
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maximum allowable volume (400 mL for subjects weighing 50 kg or more and 200 mL for a 
subject weighing less than 50 kg) during this trial.
The washout period between Period 1 and Period 2 in part 2 can be changed based on the newly 
obtained PK, safety and PD data. If this change occurs, the procedures and the schedule of study
following 
 on the night on Day 2 will be shifted 1 day behind. (When the washout period is set 
to 2 days, refer to protocol Annex 3 in regard to the schedule, etc.)
The specified assessment time points of safety endpoints (eg, vital signs, ECG, laboratory tests) 
currently described in the protocol may be modified based on the newly obtained safety, 
tolerability, PK or PD/biomarker data (eg, to collect data at the time closer to the peak plasma 
concentrations achieved). These changes will not result in an increase the number of trial 
procedures for subjects participating in the trial.
Additional laboratory tests may be performed for additional safety evaluation using the blood 
samples previously collected (eg, to add a creatinine kinase tasting to the serum chemistry blood 
using the samples previously collected).
It is possible that some or none of the alterations described above may be employed in this study.
For any alterations made in this protocol to meet the trial objectives, the sponsor must issue a 
detailed letter and store it in the Trial Master File (TMF) and also ask the investigator to store it. 
This letter may be reviewed by the institutional review board (IRB)/independent ethics committee 
(IEC) at the discretion of the investigator.
After Cohort 2 Dose Level 2, the further dose and the infusion rate will be determined based on the 
safety and pharmacokinetic data obtained from the previous cohorts in this study. In the event that 
further investigation on the safety, tolerability and PK is needed after completion of Cohort 1 and 
Cohort 2 Dose Level 6, up to 4 additional cohorts that include 32 healthy adults can be commenced 
without amendment of the protocol. In the event that further investigation on the safety, 
tolerability and PK of TAK-925 is needed after completion of Cohort 3, up to 1 additional cohort 
that includes 8 healthy elderly can be commenced without amendment of the protocol. In the event 
that a long-term washout period is needed on the basis of the pharmacokinetic or safety evaluation 
results in Part 1, the dosing order of TAK-925 and placebo and Part 2 may be changed to a 
single-blind (only subjects are blinded), fixed-sequence approach (TAK-925 will be given after a 
placebo is given to all subjects).
If the dose to be used in Cohort 7 is to be lower than the dose used in Cohort 5 or Cohort 6 based on 
the results of Cohort 5, Cohort 7 may be executed following Cohort 6.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signed the trial’s informed consent form.
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6.5.2
Definition of End of the Trial
The overall trial ends when the last subject completed the last planned or follow-up visit (or the 
last communication related to the planned visit [this can be a phone contact]) was completed, or 
when the trial was discontinued, or the date of lost to follow-up (ie, the investigator is unable to 
contact the subject).
6.5.3
Definition of Trial Discontinuation
Trial discontinuation may occur because of non-safety reasons, such as:

Findings from other nonclinical or clinical trials of the study drug (eg, PK, PD, efficacy, 
biologic targets) results in the discontinuation of the trial for non-safety reasons.

Data on drug(s) of the same class as the study drug or methodology (ies) used in this trial
become available, which results in the discontinuation of the trial for non-safety reasons.

The trial is discontinued because of non-scientific and non-safety reasons, such as delayed
enrollment.
Trial discontinuation due to safety reasons includes:

Early trial termination because of unexpected safety concerns in subjects being identified in 
the clinical or preclinical trials of the study drug, reference drug(s), drug(s) of the same class as 
the study drug or methodology (ies) used in this trial.
6.5.4
Criteria for Premature Termination or Suspension of the Trial
6.5.4.1
Criteria for Premature Termination or Suspension of Trial
The study will be temporarily suspended or prematurely discontinued if it meets 1 or more of the 
following criteria:
1. Regarding the safety or efficacy of the study drug, new information or alternative evaluation 
that will change the known risk/benefit profile of TAK-925 was obtained, and such risk is no 
longer acceptable for subjects to participate in the study.
2. Significant Good Clinical Practice (GCP) violation that compromises the achievement of the 
primary study objectives or the subject safety.
3. Any events listed in the Takeda Medically Significant List (Table 10.a) occurred in two or 
more subjects at a single or multiple Dose Level(s) or in a single or multiple Cohort(s)
4. Liver function test abnormal:
a.
An elevation over 5 times the upper limit of normal (ULN) of ALT and/or AST occurred in 
two or more subjects at a single or multiple Dose Level(s) or in a single or multiple 
Cohort(s) in the absence of elevation of bilirubin.
b. An elevation over 2 times the ULN of total bilirubin or an elevation over 1.5 times the ULN 
of prothrombin time (PT)-international normalized ratio (INR) with the elevation(s) over 3 
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times the ULN of ALT and/or AST were observed in one or more subjects at a single Dose 
Level or in a single Cohort, and such elevation cannot be explained by cholestasis or other 
factors (ie, Hy's Law case).
c.
An elevation over 3 times the ULT of ALT and/or AST occurred in two or more subjects at 
a single or multiple Dose Level(s) or in a single or multiple Cohort(s) in the presence of 
fatigue, nausea, vomiting, right upper abdominal pain or tenderness, pyrexia, rash or 
eosinophilia (over 5%).
6.5.4.2
Procedures for Premature Termination or Suspension of the Trial
In the event that the sponsor, IRB or regulatory authorities determines to terminate or suspend the 
entire study or the study at a site, study-specific procedures for suspension or early termination 
will be instructed by the sponsor. The procedures for suspension or premature termination of the 
study will be followed by the applicable study site.
6.5.5
Criteria for Premature Termination or Suspension of the Trial at a Site
6.5.5.1
Criteria for Premature Termination or Suspension of the Trial at a Site
The clinical study at study site may be terminated prematurely or suspended if a significant 
violation on GCP, protocol or study site agreement is found at the site (including the investigator), 
or the study at the site cannot be appropriately conducted, or as otherwise permitted by the 
agreement.
6.5.5.2
Procedures for Premature Termination or Suspension of the Trial at a Site
In the event that the sponsor, IRB or regulatory authorities determines to terminate or suspend the 
entire study or the study at a study site, a study-specific procedures for early termination or 
suspension will be instructed by the sponsor. The procedures for suspension or premature 
termination of the study will be followed by the applicable study site.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All inclusion/exclusion criteria, including laboratory test results, need to be confirmed prior to the 
randomization or the first dose of study drug.
7.1
Inclusion Criteria
Subject eligibility will be determined according to the following criteria:
All Subjects
1. In the opinion of the investigators, the subject is capable of understanding the clinical study
and complying with the protocol requirements.
2. A subject (or subject's legally acceptable representative, if needed) is capable of signing and 
dating the informed consent form prior to the initiation of any study procedures.
3. A subject who is male or female.
4. In the opinion of the investigator, the subject is in good health condition to participate in the 
trial. The subject's health condition will be judged based on the clinical evaluations including 
laboratory test results, medical history, physical examination, 12-lead ECG and vital sign 
measurements performed at the screening and before the initial administration of the study 
drug or before an invasive procedure.
5. A male subject who is nonsterilized* and sexually active and has a female partner of 
childbearing potential agrees to use adequate contraception* from the time of signing the
consent form to 12 weeks (84 days) after the last dose of study drug. A female partner of the
male subject should also be advised to use adequate contraception* (See Appendix B).
Healthy Adults
6. A subject who is a healthy adult, aged between 20 and 55 years, at the time of signing the
informed consent form.
7. A subject weighing at least 50 kg and has a BMI of 18.5 to 30 kg/m2 at Screening.
8. A subject who has no history of hypertension or use of antihypertensive medication with 
normal BP. The normal BP is defined as below140 mmHg in systolic blood pressure (SBP)
and below 90 mmHg in diastolic blood pressure (DBP).
9. A Female subjects who is not of child bearing potential (surgically sterile or postmenopausal).
Health Elderly
10. A subject who is the healthy elderly, aged between 65 and 80 years at the time of signing the 
consent form.
11. A subject weighing at least 40 kg and has a BMI of 18.5 to 30 kg/m2 at Screening.
12. A subject who has no history of hypertension or use of antihypertensive medication with 
normal BP. The normal BP is defined as below 140 mmHg in SBP and below 90 mmHg in 
DBP.
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Patients with type 1 narcolepsy
13. A patient aged between18 and 80 years at the time of signing the informed consent form.
14. A patient weighing at least 40 kg at Screening.
15. Patients with type 1 narcolepsy: Those diagnosed with type 1 narcolepsy, as defined by the 
International Classification of Sleep Disorders, Third Edition (ICSD-3)
16. A Patients who is positive for HLA-DQB1*06:02
17. Epworth Sleepiness Scale (ESS) score on Day -1 is ≥10
18. SBP and DBP at screening are <140 mmHg and <90 mmHg, respectively. If the BP
measurements are within the above range, patients who have a history of hypertension and 
patients whose BP is well controlled by a specific dosage and administration of 
antihypertensive medication may be enrolled in this study.
19. A female subject of childbearing potential who is sexually active and has a nonsterilized* male 
partner agrees to use an adequate contraception* from signing the consent form throughout the 
study period (See Appendix B).
* Procedures for adequate contraception and pregnancy reporting are defined in Appendix B.
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7.2
Exclusion Criteria
Subjects who meet any of the following criteria will not be enrolled in the study:
All Subjects
1. A subject who has received another investigational compound within 30 days prior to the first 
dose of the study drug (including the case that the time longer than 5 times the t1/2 of the 
another investigational compound has not passed yet).
2. A subject is a study site employee or his/her family member or has a dependent relationship 
with a study site employee who is involved in the conduct of this study (eg, spouse, parent, 
child, sibling) or may give his/her consent under duress.
3. Hypersensitivity to any components of TAK-925 or related compounds
4. A male subject who intends to donate his sperm during the study period or within 12 weeks (84 
days) after the last dose of the study drug.
5. A subject who has a history of drug abuse (defined as illicit drug use) or alcohol abuse within 2 
years prior to the Screening.
6. Creatinine clearance (Ccr) ≤50 mL/min at the screening or on hospital admission (Day -1)
7. SBP of ≥140 mmHg or DBP of ≥90 mmHg at Screening, Day -1 or before study drug 
administration on Day 1, confirmed by repeated measurements of BP after resting in a supine 
position for approximately 10 or 30 minutes.
8. Excessive intake of caffeine, defined as consumption of over 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, coke, energy drinks, or other 
caffeinated beverages per day
9. A subject who needs to take excluded medications, vitamines, supplements or dietary products 
listed in a table in Section 7.3 during the study.
10. A subject who has a history of cancer, except basal cell carcinoma which has been in remission
for at least 5 years prior to Day 1.
11. A subject who has tested positive for hepatitis B virus surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, or serologic 
reactions for syphilis at Screening.
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12. A subject with poor peripheral venous access.
13. A subject who has undergone whole blood sampling of at least 200 mL within 4 weeks (28 
days), or at least 400 mL within 12 weeks (84 days) in male subjects, within 16 weeks (112 
days) in female subjects prior to the start of study drug administration.
14. A subject who has undergone whole blood sampling of at least 800 mL (male) and 400 mL 
(female) within 52 weeks (364 days) prior to the start of study drug administration.
15. A subject who has undergone blood component sampling within 2 weeks (14 days) prior to the
start of study drug administration.
16. A subject who has a risk of suicide according to the investigator’s judgment based on the 
assessment of the C-SSRS or has made a suicide attempt within 6 months before the start of
study drug administration.
17. A subject who has a current or past history of epilepsy, convulsion, tremor or related
symptoms.
18. A subject who has a history of major psychiatric disorder, including major depression, bipolar 
disorder or schizophrenia.
19. A subject who has a history of clinically significant head injury or trauma.
20. A subject who has a history of cerebral ischemia, transient ischemic attack, intracranial 
aneurysm or arteriovenous malformation.
21. A subject who has known coronary artery disease, and a history of myocardial infarction (MI), 
angina, cardiac rhythm abnormality or heart failure.
22. QT interval with Frederica correction method (QTcF) is >450 milliseconds (male) or >470 ms 
(Female) on a 12-lead ECG at Screening
23. A subject who has a resting heart rate (HR) outside the range of 45 to 100 beats per minute, 
confirmed by a repeated testing performed within a maximum of 30 minutes at Screening or on 
hospital admission (Day -1).
24. A subject who has a clinically significant and unstable cardiovascular, pulmonary, hepatic, 
renal or gastrointestinal disease or other abnormal conditions that may influence the subject's 
participation in this study or study results. (For subjects enrolled in Part 2, the disease under 
study [narcolepsy] will be excluded.)
25. A subject who has abnormal laboratory values detected at Screening or on hospital admission 
(Day -1) that suggest a clinically significant underlying disease or ALT and/or AST of 1.5 
times the ULN.
26. A subject who, in the opinion of the investigators, is unlikely to comply with the protocol or is 
unsuitable for other reasons.
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Healthy Adults or the Healthy Elderly (Cohorts 1-4, Healthy Adult Supplement Cohort and 
Healthy Elderly Supplement Cohort):
27. A subject unwilling to stop smoking during the study period.
28. A female subject of childbearing potential who is sexually active (premenopausal and 
nonsterilized).
29. A subject who has a clinically significant sleep disorder (including sleep apnea syndrome and 
insomnia).
Healthy Adults (only Cohort 4):
30. A subject whose CSF was collected within 14 days prior to hospitalization (Day -1).
31. A subject who has a known hypersensitivity to anesthetics, and medications used for CSF
collection or lumbar puncture.
32. A subject who has clinically significant vertebral deformities (scoliosis or kyphosis) which, in 
the opinion of the investigators, may interfere with lumbar puncture.
33. A subject who has a clinically significant back pain and/or injury.
34. A subject who has a local infection at the puncture site.
35. A subject who has thrombocytopenia or bleeding tendencies before the beginnng of study
procedures.
36. A subject who has signs and symptoms of radiculopathy including leg pain and paresthesia.
37. A subject who has focal neurological deficit that might suggest an increase in intracranial 
pressure.
38. A subject who has abnormal findings on ophthalmological examination /fundoscopy 
suggestive of raised intracranial pressure (eg, optic disc swelling/papilledema, uncontrolled
hypertensive retinopathy).
39. A subject who suffers from moderate to severe headaches requiring analgesics.
Patients with type 1 narcolepsy
40. A patient unwilling to quit smoking 40 minutes before the scheduled MWT and 1 hour before 
sleeping.
41. A patient who has sleep disorder(s) associated with excessive sleepiness (including sleep 
apnea syndrome) other than narcolepsy.
42. Excessive caffeine consumption (>400 mg/day) within seven days before hospital admission 
(Day -1).
43. Use of drugs with stimulating or sedating properties, anti-parkinson drugs or anti-convulsant 
drugs within 7 days before the start of study drug administration or 5 times the half life of each 
drug. For selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, there 
should be a washout period (at least 5 times the elimination half-life of each drug or for 7 days, 
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whichever is longer prior to the start of study drug adoministration), and the administration 
should be discontinued with gradual dose reductions (See Section 7.3).
44. A subject who has a disease requiring excluded medications, including anxiety, depression,
epilepsy, heart disease, serious hepatic, pulmonary or renal disease.
7.3
Excluded Medications, Supplements, Dietary Products
(1) Part 1
Excluded medications, supplements and dietary products are listed in Table 7.a.
Subjects must be instructed not to take any medications including over-the-counter (OTC) drugs, 
other than prescribed medications, without prior consultation with the investigators.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products (Part 1)
From 28 days prior to the 
start of study drug 
administration (Day 1) to 
the follow-up visit
From 7 days prior to the 
start of study drug 
administration (Day 1) to 
the follow-up visit
From 7 days prior to the
start of study drug 
administration (Day 1) to 
the discharge from hospital
From 24 hours prior to the 
start of study drug 
administration (Day 1) to 
the discharge from hospital
Prescribed drugs1)
OTC drugs
Supplements 
(St. John’s wort, ginseng, 
kava kava, Ginkgo biloba 
and melatonin)
Chinese herbal medicine
Vaccination/vaccine
Nicotin-containing foods
Grapefruit/Grapefruit juice
Cruciferous vegetables
(e.g., kale, broccoli, cress, 
collard greens, kohlrabi, 
brussels sprouts, mustard)
Charcoal-grilled meats
Vitamins
Alcohol-containing 
products
Caffeine-containing 
products
OTC drugs: over-the-counter drugs
Note: If medications are required to treat an AE, certain medications may be allowed by the investigators.
1)
Coadministration of moderate to strong CYP3A4 inhibitors or inducers (see (18), Table 7.b) will be prohibited 
from 28 days prior to the start of administration (Day 1) or from at least 5 times the terminal half-life of each drug, 
whichever comes first, to the follow-up visit.
(2) Part 2
Excluded medications and dietary products are shown in Table 7.b. Administration of 
psychostimulants, hypnotics, anti-anxiety drugs, antipsychotics and anticonvulsants must be
discontinued within a minimum of 7 days before the start of the study drug administration. The 
investigators should taper off the dose of each drug and discontinue within the washout period (at 
least 5 times the terminal half-life of the antidepressant), to ensure the appropriateness of the 
washout period. Administration of moderate to strong CYP3A4 inhibitors or inducers should also
be discontinued. Any drugs must not be used from the period shown in Table 7.b until all tests 
planned on Day 4 have been completed. The investigator will review the concomitant medication 
use at screening, and determine the time of discontinuation for relevant drugs that should not be 
used anymore. At the discontinuation, the investigators shuold pay attention to the drugs of which 
gradual recuction of dose is required. Subjects will also be instructed not to take any medications 
including OTC drugs without prior consultation with the investigators.
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Table 7.b
Excluded Medications and Dietary Products (Part 2)
Excluded Medications and Dietary Products
At least 7 days prior to the start of study drug administration or 5 
times the terminal half-life of each drug listed below, whichever is 
longer.
(1)
Psychostimulants
Methylphenidate hydrochloride, modafinil, pemoline, 
methanphetamine hydrochloride
(2)
Antipsychotics
As for depot formulation of antipsychotics, they should be 
determined appropriately in consideration of the period to 
disappearance.
(3)
Antianxiety drugs (Tranquilizers)
Including benzodiazepine
(4)
Antidepressants
The doses of drugs used to control cataplexy, such as tricyclic 
antidepressants, SSRIs and serotonin-noradrenaline reuptake 
inhibitors (SNRIs) must be stepwisely reduced with caution.
(5)
Mood stabilizers
-
(6)
Anticonvulsants
-
(7)
Hypnotics
Including Chinese herbal medicine (Yokukansan, 
Yokukansankachinpihange) used for insomnia.
(8)
Antiparkinson drugs
-
(9)
Corticosteroids
Only for systemic use.
(10) Interferon, interleukin preparation
-
(11) Muscle-relaxants
-
(12) Antihistamines
Oral administration only. OTC drugs and pharmaceutic adjuvants 
are also included.
(13) Central nervous system-acting β-blockers 
-
(14) Central nervous system -acting 
antitussives
-
(15) Central nervous system -acting antiemetics 
-
(16) Narcotic analgesics and non-narcotic 
analgesics (opioid analgesics and 
pregabalin only)
-
(17) St. John's Wort, health foods containing 
melatonin
-
(18) Moderate to strong CYP3A4 inhibitors or 
inducers
1)
Strong CYP3A4 inhibitors: Boceprevir, 
clarithromycin, cobicistat, conivaptan, 
danoprevir, ritonavir, elvitegravir, 
indinavir, saquinavir, idelalisib, 
itraconazole, ketoconazole, lopinavir, 
nefazodone, nelfinavir, paritaprevir, 
ombitasvir, dasabuvir, posaconazole, 
telaprevir, tipranavir, troleandomycin, 
voriconazole
2)
Moderate CYP3A4 inhibitors: 
Amprenavir, aprepitant, atazanavir, 
-
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casopitant, cimetidine, ciprofloxacin, 
diltiazem, clotrimazole, miconazole,
crizotinib, cyclosporine, dronadarone, 
erythromycin, fluconazole, fosamprenavir, 
fluvoxamine, imatinib, istradefylline, 
tofisopam, verapamil
3)
Strong CYP3A4 inducers: Carbamazepine, 
enzalutamide, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampicin
4)
Moderate CYP3A4 inducers: Bosentan, 
efavirenz, etravirine, modafinil
Note: If medications are required to treat an AE, certain medications may be allowed by the investigators.
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Meals and drinks (except water) prior to the laboratory tests must be taken 8 hours prior to the 
tests.
Dinner on the day before laboratory tests must be taken by 21:00.
Prescribed meals must be taken during hospitalization and intake of other foods is prohibited.
After discharge, excessive eating or drinking should be avoided until the follow-up period is
finished.
7.4.2
Activity
Sleeping at non-specified time is prohibited.
Excessive exercise is prohibited during the study period.
Blood donation within at least 12 weeks (84 days) after the last examination in the study is 
prohibited.
If a subject visits another medical institution during the study period, the subject must report to the 
investigators in advance as far as possible. After the visit, the subject must report the background 
of the visit and the details of the treatment that the subject received, to the investigators. Then, the 
investigators will contact with the medical institution to inform that the subject is participating in 
the clinical trial.
In Part 1, smoking is prohibited during the study period. In Part 2, subjects who have a smoking 
habit will be allowed to smoke under limitation, to comply with the followings during 
confinement:

Smoking will not be allowed from 40 minutes before when each MWT is performed. Smoking 
will be allowed after the study drug infusion, but up until 1 hour before sleeping.

The subject must not interfere with any scheduled study procedures and tests by smoking 
during hospital stay.
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In addition to the above, the following instructions will be given to subjects in Part 2
!
!
Subjects will follow the notes shown in the manual for pharmacodynamic tests (
 and 
MWT).
!
In the washout period between Period 1 and Period 2, subjects will be instructed and monitored 
as much as possible that time of each daytime nap should be within 30 minutes and the number 
of daytime nap should be up to 5 times so as not to disturb night time sleep.
7.5
Record of Discontinuation or Withdrawal of a Subject before Study Drug
Administration
The investigators are responsible for all subjects who signed the informed consent form. If a 
subject is withdrawn from the study before the first study drug administration, the investigators
will complete the electronic case report form (eCRF) to record the details.
The primary reason for the withdrawal will be recorded in the eCRF using the following 
categories:
!
Death.
!
Adverse event (AE).
!
Screen Failure (The subject did not meet the inclusion criteria or did meet the exclusion 
criteria.) <specify reason>.
!
Protocol deviation.
!
Lost to follow-up.
!
Pregnancy
!
Voluntary withdrawal <specify reason>.
!
Termination of entire study by the sponsor.
!
Sample size sufficient.
!
Other <specify reason>.
The subject identification number assigned to the subject who withdrew from the study before the 
start of study drug administration should not be reused. However if a reserve subject is to 
participate in another Cohort, the same subject identification number may be used.
7.6
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for withdrawal of subject from the study or discontinuation of study drug
administration should be recorded in the eCRF using the following categories. For subjects who 
withdrew from the study before the start of study drug administration, refer to Section 7.5.
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1. Death.
A subject died during the study period.
Note: If the subject died during the study period, the event will be treated as a serious adverse 
event (SAE). See Section 10.2.9.3 for the reporting procedures.
2. AE.
A subject who has experienced an AE that requires early termination of the study because 
subject's continued participation imposes an unacceptable risk to his/her health or the subject is 
unwilling to continue the study because of the AE.
If a situation that meets any of the following criteria occurs during the study treatment, the 
study drug should be discontinued immediately and an appropriate follow-up will be started 
(eg, Laboratory tests will be repeatedly performed until the subject's laboratory profile returns 
to the normal or baseline level. See Section 9.2.9):
!
Liver function test (LFT) abnormal
-
ALT or AST elevates over 8 times higher than the ULN, or
-
ALT or AST elevates over 5 times higher than the ULN and this elevation persists for 
more than 2 weeks, or
-
ALT or AST elevates over 3 times higher than the ULN and the total bilirubin elevates 
over 2 times higher than the ULN, or INR elevates over 1.5 times higher than the 
ULN, or
-
ALT or AST elevates over 3 times higher than the ULN, which is accompanied by 
fatigue, nausea, vomiting, right upper abdominal pain or tenderness, pyrexia, rash or 
eosinophilia (>5%).
!
Sustained elevation of blood pressure
In non-clinical studies, 
 
 
 
ssuming that BP elevation immediately after the start of infusion may drop down 
over time, the following instructions will be provided,
!
if:
-
SBP of 180 mmHg or higher is persisting
-
DBP of 110 mmHg or higher is persisting
-
40 mmHg or higher increase in SBP from baseline prior to the start of infusion of 
TAK-925 is persisting
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If measured BP meets one or more of the above criteria, the BP will be measured 
again 5 minutes after the first measurement for confirmation. If any cardiovascular or 
neurological related symptoms is observed, administration of the study drug should 
be discontinued immediately and an appropriate medical treatment should be 
provided (eg, lowering BP judged by the investigators), and an emergency test will be 
requested as needed. If any cardiovascular or neurological related symptoms are not 
observed, repeated measurements of BP should be performed every 15 minutes. The 
study drug will be discontinued immediately if SBP and DBP exceeds 200 mmHg and 
120 mmHg, respectively. The study drug will be discontinued if SBP is between 180 
and 200 mmHg, or if DBP is between 110 and 120 mmHg, or if 40 mmHg or higher 
increase in SBP from baseline has been continued over 1 hour, or if the investigators
judged that it would be difficult to continue the study drug administration. If the BP 
does not decrease 30-60 minutes after the discontinuation of the study drug, an 
appropriate treatment should be provided at the discretion of the investigators.
The study drug will not be rechallenged including the case that the discontinuation of 
the study drug is discontinued due to an increase in BP.
3. Protocol deviation.
If it becomes clear after the start of study drug administration that a subject failed to meet the 
inclusion criteria specified in the study protocol or did not adhere to the protocol, and the 
subject's continued participation in the study poses an unacceptable risk to his/her health.
4. Lost to follow-up.
A subject did not return to the study site and attempts to contact the subject were all 
unsuccessful. These attempts to contact the subject must be recorded in the subject’s source 
documents.
5. Pregnancy.
A subjects is found to be pregnant.
Note: If a subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Appendix B
6. Voluntary withdrawal.
A subject wishes to withdraw from the study. If the reason for withdrawal was found, it should 
be recorded in the eCRF.
Note: Any attempts should be made to identify the underlying reason for the withdrawal, and 
where possible, the underlying reason should be recorded as the primary reason for 
withdrawal. (A withdrawal due to an AE should not be put into the “voluntary withdrawal” 
category).
7. Termination of entire study by the sponsor.
The sponsor determined early termination of the study.
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8. Other
Note: The specific reason should be recorded in the eCRF.
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The investigators must discontinue the study at any time during the study period if a subject meets 
the "Criteria for Discontinuation or Withdrawal of a Subject" described in Section 7.6. In addition, 
a subject can discontinue his or her participation in the study at any time during the study period
without giving a reason for discontinuation. When subject's participation in the study is 
discontinued, the investigators should record the primary reason for discontinuation. In addition, 
all procedures for tests/observations/assessments to be performed when the study is discontinued 
should be performed as far as possible.
In the event that a subject discontinued his/her study, Section 9.3.1.1 should be referenced for PK 
sample collection.
7.8
Subject Replacement
When a subject discontinues the trial, an additional subject may be enrolled for replacement, if it is 
deemed appropriate by the investigator and the sponsor. The study site should contact the sponsor 
to report a medication ID number for the subject replaced. The number of subjects to be replaced 
by other subjects in the study will be a maximum of 4 per cohort in Cohorts 1 and 2 in Part 1, and 
a maximum of 8 each in Part 1 and Part 2. In Part 1, the cohort for the replacing subjects will be 
regarded as another cohort separate from the existing cohort.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
[Compound]
Code name: TAK-925
Dosage form and strength:
TAK-925 Injection consists of 
 
 TAK-925 Injection 
will be diluted in saline when used.
TAK-925 Placebo Injection will be supplied as commercially available saline. The saline to be 
administered to the study subjects will not be supplied by the sponsor. The TAK-925 Placebo 
Injection for blind use to be supplied by the sponsor will not be used.
[Manufacturing]
The drug substance of TAK-925 is manufactured by the Takeda Pharmaceutical Company 
Limited. (Osaka Japan).
 
.
8.1.1
Clinical Study Drug Labeling
Each vial of TAK-925 Injection or TAK-925 Placebo Injection for blind use is contained in a box.
In the outer box, the following are indicated: the name of the study drug, the number of study 
drugs, storage condition, manufacturing number, expiration date, protocol number, the name and 
address of the sponsor, and the labeling of "for clinical use".
8.1.2
Clinical Study Drug Inventory and Storage
 
The study drug will be stored in an appropriate and safe place where an access is restricted until it 
is used or until it is returned to the sponsor or its designee for disposal. The study drug will be
stored under the conditions described on the label until it is prepared. The temperature of the 
storage place should be recorded on every working day.
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8.1.3
Randomization Code Creation and Storage
The personnel responsible for randomization (the sponsor's designee) will prepare the 
randomization table/schedule prior to the start of the study. The randomization information will be 
stored in a secured area, accessible only by authorized personnel.
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure
The investigator will stores the emergency key until at the time of emergency opening or until the 
completion of the study.
The blinding may be compromised by the results that should not be reported prior to the opening of 
the randomization code, such as the measurement results of study drug concentrations. In the case 
where these final measurement results are reported to the investigator prior to opening, a measure 
to maintain the blinding should be taken (eg, a medication ID number is replaced by another 
number so that a site staff in charge cannot identify the subject). For the details of the procedures 
for measuring drug concentrations, refer to a manual for measuring drug concentrations to be 
created separately.
Furthermore, the personnel who prepare the study drug (TAK-925 and placebo) or discard the 
vials used for the preparation may have a chance to know the randomization details. Therefore, the 
study site should identify such personnel prior to the start of study and prepare a list of the 
personnel. Since it is difficult for the personnel who may have a chance to know the randomization 
details to be kept blinded, observer blinding should be secured by the separately specified 
procedures.
The personnel who may have a chance to know the randomization details must not disclose the 
information to any third party until opening of all randomization codes, except to follow the 
procedures specified by the sponsor. Furthermore, in the process of preparation and administration 
of the study drug (including disposal of vials after study drug administration), measures should be 
taken so that the study drugs, their vials and so on are not exposed to subjects and study personnel 
other than those designated by the investigator.
In the case that blinding of the study drug is broken, the investigators can obtain study drug 
assignment /randomization information by opening the emergency key.
When the investigators breaks the blinding of the study drug, he/she should report it to the study 
sponsor as promptly as possible. In addition, the date of unblinding and the reason of unblinding
should be specified in the record of emergency key opening. The same information (except the 
time) will be recorded in the eCRF.
When the investigators breaks the blinding of the study drug, he/she should immediately 
discontinue the administration of the study drug and withdraw the relevant subject from the study.
The investigators shall not change any evaluations of the subject after unblinding, except the case 
that the investigators is not informed of unblinding information (ie, when the sponsor breaks the 
blinding to perform an unblinding analysis).
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8.1.5
Accountability and Destruction of Sponsor-Supplied Drugs
The on-site pharmacist (a site's designee) will receive the pharmacy manual created by the 
sponsor, and follow the manual to appropriately store the sponsor-supplied drugs. The investigator 
will also receive the manual from the sponsor. The manual will contain instructions on ensuring 
appropriate receipt, handling, storage, management and prescription of the drugs and the return of 
those drugs to the sponsor or the destruction of unused drugs.
The on-site pharmacist (a site's designee) will immediately return the unused study drugs to the
sponsor after the study is completed at the study site.
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9.0
STUDY PROCEDURES
The investigators should collect the data according to the procedures described in the following 
sections. The tests/observations/assessments for each procedure are to be performed by the same 
investigator, subinvestigator or site's designee. The Schedule of Study Procedures is located in 
Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Each subject's consent to participate in the study must be obtained prior to the initiation of any 
study procedures. The requirements for obtaining subjects' consents are described in Section 13.2.
A separate informed consent pertaining to the collection, storage and analysis of samples for 
pharmacogenomic research to be performed in this study must be obtained prior to collecting 
blood of samples for pharmacogenomic.
9.1.1.1
Assignment of Subject Identification Number
A unique subject identification (ID) number will be assigned to each subject at the time of
explaining informed consent. This subject ID number will be used throughout the study.
9.1.1.2
Study Drug Assignment
In Cohorts 1-3, Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort (if it is 
added), subjects in each cohort will be assigned to each cohort the study drug in order of the 
medication ID number according to the randomization schedule (See Figure 9.a, Figure 9.b and 
Figure 9.c). In Cohort 4, eligible subjects will be assigned with the subject ID number. In Cohorts 
5-7, subjects in each cohort will be assigned to the study drug in order of the medication ID 
number after the subject eligibility is confirmed (See Figure 9.d).
The assigned medication ID number or subject ID number will be used by a study site to 
distinguish each PK sample, and is the only code to identify each subject when a PK sample is 
collected from the subject. This number must be displayed on each sample vial that will be sent to 
the local/central laboratory for pharmacokinetic evaluation. The laboratory will report the 
measurement results using these numbers. These numbers will be used only for the purpose 
described in this section and will not be replaced by 7 digit subject identification numbers that are 
provided when a subject's consent to participate in the study is obtained, and are used to identify 
each subject in all other procedures to be performed during the study period. In the case that the 
study drug is to be administered to a reserve subject, the reserve subject will receive the study drug 
of which the medication ID number, which was assigned to the original subject (only in Cohorts 1 
to 3, Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort). If a subject is 
replaced, the replacing subject will receive the study drug with a different medication ID number 
from the number assigned to the original subject who discontinued the study.
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Figure 9.a
Summary of Cohorts 1 and 2
Dose Level 1
Dose Level 2
Dose Level 3
A
TAK-925 7 mg
E
TAK-925 14 mg
A
TAK-925 28 mg
B
TAK-925 7 mg
→
F
TAK-925 14 mg
→
B
TAK-925 28 mg
C
TAK-925 7 mg
G
TAK-925 14 mg
C
Placebo
D
Placebo
H
Placebo
D
TAK-925 28 mg
Dose Level 4
Dose Level 5
Dose Level 6
E
TAK-925 56 mg
A
TAK-925 112 mg
E
TAK-925 134.4 mg
→
F
TAK-925 56 mg
→
B
Placebo
→
F
Placebo
G
Placebo
C
TAK-925 112 mg
G
TAK-925 134.4 mg
H
TAK-925 56 mg
D
TAK-925 112 mg
H
TAK-925 134.4 mg
1)
Double-blind, crossover study. Each Cohort consists of 8 subjects, and each group consists of 2 subjects. Dose Levels 1, 3 and 
5 will be investigated in the same subjects (Groups A-D in Cohort 1). Similarly, Dose Levels 2, 4 and 6 will be investigated in 
the other same subjects (Groups E-H in Cohort 2).
2)
At Dose Level 1, firstly 2 subjects will be enrolled: one subject will be randomized to one of Groups A to C, and another 
subject to Group D. After confirming the safety and tolerability of TAK-925, 6 more subjects will be enrolled 2 hours after the 
start of infusion, and each of these subjects will be randomly assigned to one of Groups A to D, to evaluate the safety, 
tolerability and PK of TAK-925. Finally, two subjects each will be assigned to Groups A to D. The Doses after Dose Level 2 
and subsequent doses will be determined based on the safety, tolerability and PK data obtained at previous dose levels.
Figure 9.b
Summary of Cohort 3 and Cohort R1 (Healthy Elderly Supplement Cohort)
TAK-925 112 mg/TAK-925 TBD
Placebo
TBD: To be dterminied
1)
Double-blind study. Cohort 3 and Cohort R1 consists of 8 subjects each: 6 subjects in the TAK-925 group and 2 subjects in the 
placebo group. Dose of Cohort 3 will be 112 mg, dose of Cohort R1 to be determined.
Figure 9.c
Summary of Cohorts S1-S4 (Healthy Adult Supplement Cohorts)
TAK-925 TBD
Placebo
TBD: To be dterminied
1)
In the event that further investigation on the safety, tolerability and PK is needed after completion of Cohorts 1 and 2, up to 4 
additional cohorts that include 32 healthy adults can be commenced without amendment of the protocol.
2)
Double-blind study. Each Cohort consists of 8 subjects: 6 subjects in the TAK-925 group and 2 subjects in the placebo group.
3)
The dose can be determined for each Cohort.
Figure 9.d
Summary of Cohorts 5-7
Cohort 5
Cohort 6
Period 1
Period 2
Cohort transfer
Period 1
Period 2
I
TAK-925 TBD
Placebo
→
K
TAK-925 TBD
Placebo
J
Placebo
TAK-925 TBD
L
Placebo
TAK-925 TBD
Cohort 7
Cohort transfer
Period 1
Period 2
→
M
TAK-925 TBD
Placebo
N
Placebo
TAK-925 TBD
TBD: To be dterminied
1)
Double-blind (the sponsor is unblinded), 2x2 crossover study.
2)
Cohorts 5 and 6 consist of 4 subjects each. Two subjects each will be assigned to each group (Groups I-L). Cohort 7 consists of 
a maximum of 12 subjects, and each group (Groups M and N) consists of a maximum 6 subjects.
3)
Each Cohort will be investigated in different subjects.
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9.1.2
Inclusion and Exclusion
Each subject will be assessed according to the inclusion/exclusion criteria described in Section 7.0.
Moreover, C-SSRS will be adopted in order to evaluate the risk of suicide. Only the evaluator who 
has been certified on the C-SSRS will evaluate C-SSRS in this study.
9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, race (reported by the
subject), height, weight, caffeine consumption, alcohol consumption, and smoking status of the 
subject.
Medical history to be obtained will include whether the subject has any clinically significant
conditions or diseases that resolved within 1 year prior to the signing of informed consent.
Ongoing conditions or diseases will be considered concurrent medical conditions. Any conditions 
(ie, diagnoses) associated with clinically significant laboratory test values, ECG or physical 
examination abnormalities observed at screening/baseline should be described. Prior medications
including any medications that the subject completed within 4 weeks (28 days) prior to signing the 
informed consent and medications related to the eligibility criteria and the safety evaluations will 
be investigated.
In Part 2, the following information will be investigated during the screening period.
Primary disease (narcolepsy): the age of onset, the date of diagnosis.
The number of symptoms associated with the primary disease within the past one month (based on 
a subject's self-assessment): The average number of falling asleep in a day, the average number of 
a sleep attacks (overwhelming sleepiness without awareness of falling asleep) in a day, the average 
number of awakenings during sleep in a day, the total number of sleep paralysis symptoms within
1 month, the total number of hypnagogic hallucinations within 1 month, the average number of 
cataplexy episodes within 1 week.
Investigation of biomarkers related to the primary disease: Information about a test for measuring 
the concentration of orexin in the CSF (test performed or not performed;, if the test is performed, 
the concentration of orexin in the CSF will be recorded.), information about the MSLT (Presence 
of information, if available, the mean sleep latency and the number of SOREM periods will be
recorded.)
Status of the sleep-related lifestyle within the past one month: The average number of the naps in a 
day, the average hours of sleep in a day, the average time of wake-up/go to bed.
On Day -1 in Part 2, the investigators will interview whether the number of the above symptoms 
accompanied by the primary disease have changed within a week before the hospital visit when 
compared to that during the screening period. The number of each symptoms observed within a 
week will also be recorded based on the sleep diary and a subject's self-assessment.
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9.1.4
Concomitant Medications
Concomitant medications are any drugs administered except the study drug. Concomitant 
medications include medicines prescribed by a physician or OTC drugs purchased by a subject. 
Concomitant medications do not include any drugs supplied by the sponsor. 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 the initial and final 
administrations and reasons for use must also be recorded in the eCRF.
9.1.5
Epworth Sleepiness Scale (ESS)
The ESS is a self-administered questionnaire with 8 questions. Subjects will be asked how likely 
they are to doze off or fall asleep in the eight different situations in daily life. Respondents will be
asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while 
engaged in eight different activities. The ESS score (the sum of 8 item scores) can range from 0 to 
24. The higher the ESS score, the higher that person's average sleep propensity (daytime 
sleepiness) in daily life. The total scores will be recorded.
The ESS will be performed on Day -1 in Part 2.
9.1.6
HLA-DQB1 *06:02 Typing Gene Analysis
HLA-DQB1 *06:02 typing will be performed only on subjects on whom the presence of 
HLA-DQB1 *06:02 was not confirmed by their backgrounds/medical records in Part 2. In almost 
all narcoleptic patients with cataplexy who also has HLA-DQB1 polymorphism, the concentration 
of orexin in the CSF was reportedly low. Hence, this genotyping is regarded as a biomarker to 
identify a patient with type 1 narcolepsy in an appropriate clinical setting.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
A physical examination will be performed on the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) skin; (7) 
extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
When a physical examination is performed on Day 2 and Day 4 in Part 2, the items described in 
Section 9.3.2.3 will be completed using subjects self assessment and recorded.
9.2.2
Height and Weight
Each subject's height and weight will be measured. 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 one decimal place.
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9.2.3
BMI
BMI will be calculated using the following formula:
Rating index: BMI=weight (kg)/[height (m)2]
The measured value should be rounded off to one decimal place. The inclusion criteria for BMI 
will be defined based on the values after rounding.
9.2.4
Columbia Suicide Severity Rating Scale (C-SSRS)
A risk of suicide will be assessed using the C-SSRS at time points specified in the Schedule of
Study Procedures (On Day 2 in Part 1 and Day 4 in Part 2). Two versions of the C-SSRS (baseline 
/screening and since the last visit) will be used in this trial. Any suicidal ideation or suicidal 
behavior detected by the C-SSRS during the study period will be recorded as an adverse event.
9.2.5
Vital Signs
Vital signs will include body temperature (tympanic temperature), respiratory rate,SBP and DBP
in sitting, lying and standing positions (BP will be measured, except as otherwise noted, after the 
subject is lying in a bed with the head of the bed up to 30 degrees and takes a rest for more than 5 
minutes, using the same arm each time), and pulse rate (heart beats per minute).
The same method (eg, the same and appropriately sized cuff, auscultatory method or manometer) 
must be used for all BP measurements for each subject. All measurement values will be recorded 
in the source documents and the eCRF.
When measurement of vital signs is scheduled at the same time as blood sampling, blood sampling 
should be performed first, then vital signs measurement will be performed within an acceptable 
time window (see Appendix C).
In the event that significantly elevated BP is observed after the stat of infusion of the study drug,
the investigator should monitor the BP carefully and record the subject's status before and after the 
elevation in BP and a possible cause in the source documents.
9.2.6
12-Lead ECG
Measurements performed using a standard 12-lead ECG will be recorded. Subjects should take a 
rest in a recumbent position at least 5 minutes before each ECG measurement. The investigators
(or a specialist working at the study site) will judge the ECG finding as "within normal limit" or 
"abnormal". If the investigators (or a specialist working at the study site) judged "abnormal", 
he/she will assess whether the abnormality is clinically significant. The time when the ECG was 
performed will be recorded. The following parameters will be recorded in the eCRF from the 
subject’s ECG trace: HR, RR interval, PR interval, QT interval, QRS interval, and QTcF.
When 12-lead ECG measurements are scheduled at the same time as blood sampling, blood 
sampling should be performed first, then 12-lead ECG will be measured within an acceptable time 
window (see Appendix C).
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9.2.7
Study Drug Administration
The study drug will be intravenously administered to subjects over 9 hours on Day 1 in Part 1 and 
Day 1 and Day3 in Part 2 (TAK-925 will be administered to each subject only once in Part 2). The 
times of the start and the end of study drug administrations will be recorded. The infusion rate 
where the Cmax (Css) becomes lower than the minimum pharmacologically active concentration 
will be calculated from the nonclinical data and used. Based on the pharmacokinetic data obtained 
from Cohort 1 Dose Level 1 and subsequent dose levels, the infusion rate will be adjusted to reach 
the steady-state concentration in 2 hours in the subsequent dose levels. This adjustment is essential 
to allow the infusion rate to reach the steady state when the first MWT is performed in Part 2.
Regaridng the possible occurrence of interruption or discontinuation of study drug administration, 
whether it occured or not occured, the time of interruption or discontinuation (if it was found) and 
the time of re-administration should be recorded in the eCRF.
9.2.8
AE Monitoring
AE monitoring must be commenced after obtaining the consent form signed by the subject. The 
details of AE collection and the procedures are provided in Section 10.2.
9.2.9
Laboratory Procedures and Assessments
All samples will be collected in accordance with the acceptable laboratory test procedures. 
Laboratory test samples will be collected after at least 8 hour-fasting on the days specified in the
Schedule of Study Procedures (Section 3.0).
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following panels:
Red blood cell (RBC)
White blood cell (WBC) and differential (%)
Hemoglobin
Mean cell hemoglobin (MCH)
Hematocrit
Mean cell hemoglobin concentration (MCHC)
Platelet
Mean cell volume (MCV)
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Serum Chemistry
Serum chemistry will consist of the following standard chemistry panels:
Albumin
Potassium
Alkaline phosphatase
Total protein
ALT
Sodium
AST
C-reactive protein
Total bilirubin
Total cholesterol
Blood urea nitrogen
Lactate dehydrogenase
Calcium
Magnesium
Chloride
Phosphorus
Creatinine
Triglycerides
γ-GTP
Uric acid
Glucose
Urinalysis
Urinalysis will consist of the following panels:
Protein
Ketone bodies
Microscopy 
Glucose
pH
RBC
Occult blood
Specific gravity
WBC
Nitrite
Urobilinogen
Squamous epithelial cell
Other
Tests to be performed at the same time of eligibility judgement:
Serum
Urine
Immunology test
Hepatitis screen (HBsAg and HCV antibody)
HIV antigen-antibody detection assay
Syphilis serum reaction test
Drug screen (phencyclidines, benzodiazepines, cocaines, 
stimulants, cannabinoids, morphines, barbiturates, and 
tricyclic antidepressants)
Cotinine screen(a)
Alcohol screen
(urine test or breath test)(a)
Pregnancy Test(b)
Note: The investigators will directly report the results of immunology test, urine drug screen, cotinine screen and 
alcohol screen to the subjects. The sponsor will confirm the overall test results (“Positive” or “All negative”) and will 
not obtain detailed results for the subjects (including reserve subjects) who will be selected to be given the study drug.
If a subject is positive for a drug screen performed in Part 2, the details should be reviewed to judge the subject 
eligibility.
(a) Part 1 only.
(b) Only for female subjects of childbearing potential in Part 2.
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Hematology, serum chemistry and urinalysis will be performed at each study site. The results of 
laboratory tests will be returned to the investigator, who is responsible for reviewing and filing 
these results.
Ccr will be estimated using the Cockcroft-Gault Equation.
Cockcroft-Gault Equation
Male subjects: Ccr = [(140-Age) x Body Weight (kg)]/[72 x Serum Creatinine Level (mg/dL)]
Female subjects: Ccr = 0.85 x [(140-Age) x Body Weight (kg)]/[72 x Serum Creatinine Level 
(mg/dL)]
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, gamma-GTP and INR) should be performed 
within a maximum of 7 days and preferably within 48-72 hours after the abnormal value was 
detected. (Refer to Section 7.6 and Section 10.2.9.5 for the appropriate guidance on reporting 
abnormal liver function tests.)
The investigator will store a copy of the reference ranges for the laboratory test values.
9.3
PK, PD, and PGx, Samples
Samples for PK, PD, and pharmacogenomics (PGx) analyses will be collected as specified in the 
Schedule of Study Procedures (Section 3.0). Refer to the separately created manual for the detail of 
collection and handling of samples and the shipment of samples to the central laboratory. The 
actual time of sample collection for PK and PD analyses will be recorded in the source documents 
and the eCRF. Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Sample Collections
Sample Name
Primary 
Sampling
Primary 
Sampling 
Fraction
Purpose of Use
Sample 
Collection
Plasma sample for PK
Plasma
-
PK analysis
Mandatory
Urine sample for PK (a)
Urine
-
PK analysis
Mandatory
CSF sample for PK (b)
CSF
-
PK analysis
Mandatory
Blood sample for DNA PGx
Blood
DNA
PGx analysis
Optional
DNA: deoxyribonucleic acid.
(a) Only Part 1
(b) Only Cohort 4 in Part 1
9.3.1
PK Measurements
Pharmacokinetic parameters of TAK-925 and its metabolites (
) will be calculated 
from the concentration-time profile in all evaluable subjects. For all calculations, not the scheduled 
sampling times, but the actual sampling times will be used.
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(1) Part 1
Unless otherwise specified, the following pharmacokinetic parameters will be calculated from the 
plasma concentrations of TAK-925 and its metabolites (
):
Symbol/Term
Definition
Plasma
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration
AUC∞
Area under the concentration-time curve from time 0 to infinity
Cmax
Maximum observed concentration
Ceoi
Concentration at the end of infusion
tmax
Time of first occurrence of Concentration
t1/2z
Terminal disposition phase half-life
Vss
Volume of distribution at state after intravenous administration (only for TAK-925)
Vz
Apparent volume of distribution during the terminal phase (only for TAK-925)
CL
Total clearance after intravenous administration (only for TAK-925)
Unless otherwise specified, the following urinary pharmacokinetic parameters were calculated 
from the urine concentrations of TAK-925 and its metabolites (
):
Symbol/Term
Definition
Urine
Ae24
Amount of drug excreted in urine from time 0 to time 24
fe24
Fraction of administered dose of drug excreted in urine from time 0 to time 24.
CLR
Renal clearance
Unless otherwise specified, the following pharmacokinetic parameters will be calculated from the 
CSF concentrations of TAK-925 and its metabolites (
):
Symbol/Term
Definition
CSF
RCSF/Plasma, ss
CSF/Plasma drug concentration at steady state
(2) Part 2
Unless otherwise specified, the following pharmacokinetic parameters will be calculated from the 
plasma concentrations of TAK-925 and its metabolites (
):
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Symbol/Term
Definition
Plasma
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration
AUC∞
Area under the concentration-time curve from time 0 to infinity
Cmax
Maximum observed concentration
Ceoi
Concentration at end of infusion
tmax
Time of first occurrence of Concentration
t1/2z
Terminal disposition phase half-life
Vss
Volume of distribution at state after intravenous administration (only for TAK-925)
Vz
Apparent volume of distribution during the terminal phase (only for TAK-925)
CL
Total clearance after intravenous administration (only for TAK-925)
9.3.1.1
Plasma Samples for PK Measurements
The timing of PK blood samples may be changed if emerging data indicate that an alteration in the 
sampling scheme is needed to better characterize the PK of TAK-925. To reflect the plasma 
exposure more precisely, blood samples will be collected from the arm opposite to the one on 
which intravenous (IV) infusion is performed. If the opposite arm is not available, blood samples
should be collected at the site as distant to the infusion site as possible, and the site of the blood 
sampling should be documented.
The blood sampling times, times of the start and the end of infusions should be recorded 
accurately, and particularly care should be given when recording the blood sampling times during 
the infusion and around the time close to the infusion.
The details of the preparation, handling, and shipping of samples are provided in the Study and 
Laboratory Manuals.
The blood samples used for pharmacokinetic analysis of TAK-925 and its metabolites (
 
) (3 mL/time in Part 1 and 3-6 mL/time in Part 2) will be collected into a blood sampling tube 
containing an anticoagulant, ethylenediaminetetraacetic acid dipotassium (EDTA-2K).
Blood samples used for pharmacokinetic analysis of TAK-925 and its metabolites (
) 
will be collected according to Table 9.b and Table 9.c.
(1) Part 1
Table 9.b
Collection of Blood Samples for Pharmacokinetic Analysis (Part 1)
Analyte
Sample
Analysis
date
Blood sampling time
TAK-925 and its 
metabolites (
 
)
Plasma
Day 1-2
Before infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of 
infusion, and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6,101) and 15 hours after
the end of infusion
1)
Dose Level 1 and 2 of Cohorts 1 and 2 will be excluded at 10 hours after the end of infusion.
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(2) Part 2
Table 9.c
Collection of Blood Samples for Pharmacokinetic Analysis (Part 2)
Analyte
Sample
Analysis
date
Blood sampling time
TAK-925 and its 
metabolites (
 
)
Plasma
Day 1-4
Before infusion1), 1, 21), 41), 61) and 91) hours after the start of infusion and 
0.17, 0.5, 1, 21) and 151) hours after the end of infusion, at bedtime1) and
right after wake-up.
1)
Blood sampling will be 6 mL. For the other sampling times, 3 mL will be collected.
Blood samples collected for the placebo groups will not be analyzed.
In the case that a subject prematurely discontinues the study between the time from the start of 
study drug administration to the completion of procedures on Day 2 in Part 1 and on Day 4 in Part 
2, the last blood samples to be used for pharmacokinetic analysis will be collected from the subject 
during his/her hospital stay.
If there is a need to interrupt or slow the IV infusion, the sponsor will be contacted to consider to 
replace the subject. If the IV infusion is interrupted, 2 additional PK samples (one will be collected 
when the infusion is stopped and another will be collected when the infusion is restarted) may be 
collected. The date and time of each additional sample collection and the times of the start and 
interruption of the infusion should be recorded accurately.
In the case of premature discontinuation during the period from Day 2 to the follow-up in Part 1, 
and during the period from Day 4 to the follow-up in Part 2, blood samples for pharmacokinetic 
analysis will not be collected from the subject who visits the hospital as an outpatient.
9.3.1.2
Urine samples for PK Measurements
Urine samples used for pharmacokinetic analysis of TAK-925 and its metabolites (
) 
(Part 1 only) will be collected sampled according to Table 9.d.
Table 9.d
Collection of Urine Samples for Pharmacokinetic Analysis
Analyte
Sample
Analysis date
Urine sampling time
TAK-925 and its metabolites 
(
)
Urine
Day 1-2
Before infution, 0-9 hours after the start of infusion, and 
0-3, 3-6 and 6-15 hours after end of infusion
Urine samples collected for the placebo group will not be analyzed.
9.3.1.3
CSF for PK Measurements
CSF samples used for pharmacokinetic analysis of TAK-925 (Cohort 4 only, 2.5 mL/time) will be
collected according to Table 9.e.
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Table 9.e.
Collection of CSF Samples for Pharmacokinetic Analysis
Analyte
Sample
Analysis date
CSF sampling time
TAK-925 and its metabolites 
(
)
CSF
Day 1
6 hours after the start of infusion
9.3.1.4
Bioanalytical Methods
Plasma, urine and CSF concentrations of TAK-925 and its metabolites (
) will be 
measured using
.
Moreover, residual samples after measurements may be used for the purpose of exploring 
unidentified metabolites or biomarkers if needed.
9.3.2
PD Measurements
9.3.2.1
Maintenance of Wakefulness Test (MWT)
In Part 2, the MWT will be conducted to evaluate the subject’s daytime sleepiness objectively in 
patients with narcolepsy.
One session of MWT will be completed in 40 minutes.
One session of 40-minute MWT will be conducted on Day -1 in Part 2 while saline is 
intravenously infused to each subject so that they may become familiar with the MWT. The MWT 
will be conducted 4 times each (at 10:00, 12:00, 14:00 and 16:00) on Day 1 and Day 3, 
respectively. For the MWT on Day -1, sleep latency will be recorded as much as possible. On Day 
1 and Day 3, sleep latency will be recorded in each session. In addition, REM sleep latency, the 
number of wakefulness/N1 to stage REM transitions, time in stage REM sleep without atonia will 
be recorded in each session.
As an exploratory evaluation, additional analysis using electroencephalogram data obtained by 
MWT may be performed after breaking the randomization code.
See the manual for pharmacodynamic tests (
and MWT) for details.
9.3.2.2
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9.3.2.3
9.3.2.4
9.3.2.5
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9.3.3
PGx Measurements
9.3.3.1
Blood Sample for DNA PGx Measurements
If whole blood samples are to be collected for PGx analysis, subjects must sign a consent form to 
agree to the sampling, storage and analysis of their blood for PGx research. Although the PGx 
research is part of this study, subject's participation in the research shall be optional.
On Day 1 (Part 1) or Day 3 (Part 2), 5-mL of whole blood sample for deoxyribonucleic acid 
(DNA) isolation will be collected 
 
after the start of study drug administration.
Samples for PGx should be collected from subjects who signed the consent form and had received 
the study drug at least once, after the start of study drug administration. The participation of study 
subjects in PGx sample collection is optional.
PGx analysis may be conducted to evaluate a potential contribution of polymorphism to a drug 
response, ie, the PK, safety/tolerability and PD of TAK-925. As PGx is a developing area, many 
genes and their functions are not yet fully understood at present. Future data may suggest a role of 
some of these genes in drug response, which may allow to conduct an additional 
hypothesis-generating exploratory research using the stored samples.
9.3.3.2
Blood Sample for RNA PGx Measurements
Not applicable.
9.3.4
Confinement
(1) Part 1
Subjects will be hospitalized in a hospital during the period from Day -1 to Day 2 and discharged 
from the hospital if no clinically significant abnormalities were found at the physical examination 
and tests on Day 2, and confirmed by the investigators. Hospitalization from Day -2 may be 
allowed for Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort as needed.
(2) Part 2
Subjects will be hospitalized in a hospital during the period from Day -1 to Day 4 and discharged 
from the hospital if no clinically significant abnormalities were found at the physical examination 
and tests on Day 4, and confirmed by the investigators.
In addition, hospitalization during the washout period prior to Day -1 may be allowed in each 
cohort as needed, to ensure the subject safety during the washout period. Rebound cataplexy may 
occur during the washout period of drugs used for the treatment of cataplexy. The investigators
must be careful for frequent occurrence of cataplexy episodes and ensure the subject's safety in the 
most appropriate way.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable or unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not it is considered related to the medicinal 
product.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
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related to a study procedure. However, if the subject experiences a worsening or complication 
of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). The Investigator 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, the investigator or the subinvestigator 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, the investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. The investigator 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 informed 
consent form are not considered AEs. However, if a preplanned procedure is performed early 
(eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of the 
condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.
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
All cases of overdose (with or without associated AEs) will be documented 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.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it was more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List
Term
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
"Important Medical Events" satisfying SAE reporting requirements.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The intensity/severity of an AE is categorized as:
Mild:
The event is transient and easily tolerated by the subject
Moderate:
The event causes the subject discomfort and interrupts the subject's usual 
activities
Severe:
The event makes daily activities impossible.
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, i.e., 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 
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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 investigators 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 (Number)
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.
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 
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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 and Abnormal LFTs
10.2.9.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and abnormal LFTs) will be commenced when a subject signs 
the informed consent form, and continued until the follow-up period ends.
10.2.9.2 Reporting AEs
At each study visit, the investigators will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigators concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end dates and times.

Number.

Severity/Intensity.

The investigator’s or subinvestigator's opinion on the causal relationship between the event 
and administration of study drug(s) (Related/Not Related).
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!
The investigator's or subinvestigator's opinion on 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 for the study drug.
!
Outcome.
!
Seriousness.
!
Timing of occurrence (after administration of 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:
At the first onset or notification of the SAE occurred, the investigators must report the SAE to the 
sponsor with relevant information within 1 business day. The investigator must also submit a 
detailed SAE report to the sponsor within 10 calendar days. The report must contain all 
information about the SAE as much as possible, including at least the following:
!
A brief description of the event and the reason why the event was categorized as serious.
!
Subject identification number.
!
Name of the investigators or subinvestigators.
!
Name of the study medication(s).
!
Causality assessment.
Any SAE spontaneously reported to the investigators 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 
investigators should complete a copy of the follow-up SAE form or provide other written 
documentation and submit it immediately within 24 hours of receipt to the sponsor. Copies of any 
relevant data from the hospital notes (eg, ECGs, 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.
10.2.9.4 The Adverse Event Related 
In an acute single-dose intravenous dose-escalation toxicity study in monkeys, 
 
 
 
[24] or those events that resulted in the discontinuation of study drug administration were 
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observed, the investigators must monitor these events continuously and report them to the sponsor 
immediately.
Further investigation may be needed for these events to establish their diagnosis. The same 
reporting method and reporting period as the SAE reporting will be used when the investigator 
reports the events to the sponsor (Refer to Section 10.2.9.3).
10.2.9.5 Reporting of Abnormal LFTs
When elevated ALT or AST elevates over 3 times higher than the ULN and the elevated total 
bilirubin over 2 times higher than the ULN, and these abnormal LFT values cannot be explained 
by other factors, these values will be recorded as SAEs and reported according to Section 10.2.9.3.
In addition, the investigators will report these SAEs to the clinical research associates (CRAs) and 
investigate the cause other than the study drug(s) (possible occurrence of acute viral hepatitis A or 
B, or other acute hepatic diseases, past/current medical history).The follow-up laboratory tests 
described in Section 9.2.9 must also be performed.
10.2.10 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized by the analysis personnel prior to 
database lock. This document will provide further details regarding the definitions of analysis 
variables, and analysis methodologies to address all study objectives.
11.1.1
Analysis Sets
In this study, three analysis sets will be used: the safety analysis set, the PK analysis set, and the
PD analysis set. The definition of each analysis set will be described in the SAP.
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. If necessary, the SAP will be supplemented 
with new handling rules that were not discussed at the planning stage. The SAP must be finalized 
prior to database lock.
11.1.1.1 Safety Analysis Set
The safety analysis set will be defined as all subjects who received at least one 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 one dose of study drug and 
whose plasma or CSF concentration can be measured at least once or whose cumulative urinary 
excretion can be calculated.
11.1.1.3 PD Analysis Set
The PD analysis set will be defined as all subjects who received at least one dose of study drug.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the safety analysis set, 
the PK analysis set and the PD analysis set.
11.1.3
PK Analysis
(1) Endpoints and analysis methodologies
[Endpoints]
Plasma concentrations and pharmacokinetic parameters of TAK-925 and its metabolites (
 
).
Urine pharmacokinetic parameters of TAK-925 and its metabolites (
).
CSF concentrations and pharmacokinetic parameters of TAK-925 and its metabolites (
 
).
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[Analysis methodologies]
The following analysis will be performed using the PK analysis set in Cohorts 1-2 and Healthy 
Adult Supplement Cohort, and Cohorts 3 and Healthy Elderly Supplement Cohort, Cohort 4 and 
Part 2 by dose level.
Plasma and CSF concentrations of TAK-925 and its metabolites (
) will be 
summarized for each scheduled sampling time using descriptive statistics.
Descriptive statistics will be summarized for plasma, urine and CSF pharmacokinetic parameters 
of TAK-925 and its metabolites (
) summarized.
The details will be described in the SAP.
11.1.4
PD Analysis
(1) Endpoints and analysis methodologies
[Endpoints]
The average sleep latency in the MWT, sleep-related parameters in the MWT (sleep latency in 
each session, REM sleep latency, the number of wake/sleep stage 1(N1)-to-REM sleep transitions
total time of REM sleep without atonia), assessment of daytime sleepiness using the KSS, 
assessment by the 
, assessment of sleep-related symptoms of cataplexy and narcolepsy 
using a daily dairy for collecting cataplexy and sleep-related symptoms.
[Analysis methodologies]
The following analysis will be performed using the PD analysis set:
For the average sleep latency in MWT in Part 2, descriptive statistics for the observed values will 
be provided by dose level. An analysis of variance (ANOVA) for crossover design with the 
observed value as a response, the dose level, the group and the period as factors will be conducted. 
The differences in the least square means between each dose level of TAK-925 and placebo (each 
dose level of TAK-925 – the placebo) and two-sided confidence intervals will be provided. 
Bayesian posterior probabilities that the mean differences are greater than the value (specified in 
the SAP) will be provided based on the Bayesian posterior distributions for the mean differences 
between each dose level of TAK-925 and the placebo (each dose level of TAK-925 – the placebo).
The details for endpoints other than the average sleep latency in the MWT will be described in the
SAP.
11.1.5
Safety Analysis
(1) Endpoints and analysis methodologies
[Endpoints]
AEs, Clinical Laboratory Tests, Vital Signs, Weight and 12-Lead ECG
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[Analysis methodologies]
The following analysis will be performed using the safety analysis set in Cohorts 1-2 and Healthy 
Adult Supplement Cohorts, Cohorts 3 and Healthy Elderly Supplement Cohort, Cohort 4 and Part 
2 by dose level.
11.1.5.1 AEs
A treatment emergent adverse event (TEAE) is defined as an AE that occurs on or after the start of 
study drug administration. The analyses of TEAEs will be conducted for the followings. TEAEs
will be coded using the MedDRA dictionary and tabulated by the system organ class (SOC) and 
the Preferred Term (PT).

The number of all TEAEs

The number of drug- related TEAEs

The number of all TEAEs classified by intensity

The number of drug-related TEAEs classified by intensity

The number of TEAEs leading to study drug discontinuation

The number of serious TEAEs
11.1.5.2 Clinical Laboratory Evaluation
For continuous variables, the observed values and changes from baseline will be summarized for 
each scheduled sampling time using descriptive statistics. Case plots will also be presented for the 
observed values. For categorical variables, shift tables showing the number of subjects in each 
category at baseline and each post-baseline scheduled sampling time will be provided.
11.1.5.3 Vital Signs, Weight
The observed values and the changes from baseline will be summarized for each scheduled 
sampling time using descriptive statistics. Case plots will also be presented for the observed 
values.
11.1.5.4 Other Safety Parameters
12-Lead ECG parameters will be summarized as follows: For continuous variables, the observed
values and the changes from baseline will be summarized for each scheduled sampling time using 
descriptive statistics. Case plots will also be presented for the observed values. For categorical 
variables, shift tables showing the number of subjects in each category at baseline and each 
post-baseline scheduled sampling time will be provided. The details for other endpoints will be 
described in the SAP.
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11.2
The Conversion Method of Data, and Handling of Lack of Data
For plasma and CSF concentrations as well as laboratory test results, values below the lower limit 
of quantification will be treated as zero when calculating the descriptive statistics. The details will 
be provided in the SAP.
11.3
Committees Set Up for This Study
In this study, a central review of data from the MWT and the 
 will be performed.
The central reviewer must be a specialist who has an appropriate experience of evaluating 
endpoints. Upon request from the sponsor, the reviewer will perform consistent evaluation of the 
MWT and the 
 of which the results were reported by each study site.
The independent reviewer will review the MWT and 
 results submitted by the investigators.
The details will be described in the manuals for pharmacodynamic tests (
 and MWT) and for 
assessment of the 
 and MWT.
The results of review by the independent reviewer will be reported to each site.
11.4
Interim Data Review and Criteria for Premature Termination
The sponsor's unblinded team will review unblinded data. This team will review the effects on the 
safety tolerability, PK and the average sleep latency in the MWT to recommend a dose level in 
Cohort 6. The dose selected will be reported to the site pharmacist. All other site staff will remain 
blinded. A similar review will be performed for the dose level and the number of subjects in 
Cohort 7. Reviews of each cohort and the dose escalation after completion of each dose level will 
be provided in Section 6.2. Criteria for study termination or interruption are described in Section 
6.5.4.
11.5
Determination of Sample Size
In Cohort 1-3 in Part 1, 8 subjects (6 in the TAK-925 group and 2 in the placebo group) was 
selected as the sample size to evaluate the safety, tolerability and PK of TAK-925 when a single 
dose of TAK-925 is administered intravenously to healthy adults and the healthy elderly. In the 
event that further investigation on the safety, tolerability and PK in healthy adults is needed after 
completion of Cohorts 1-2, a maximum of 4 additional cohorts (a total of 32 healthy adult subjects; 
8 subjects [6 in TAK-925 group, 2 in placebo group] for each cohort) may be enrolled. If further 
investigation on the safety, tolerability and PK in healthy elderly is needed after completion of 
Cohort 3, a maximum of 1 additional cohort (a total of 8 healthy elderly subjects [6 in TAK-925 
group, 2 in placebo group] per cohort) may be enrolled.
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, tolerability, PK s of 
TAK-925 including the concentration of TAK-925 in the CSF when a single dose of TAK-925 is 
administered intravenously to healthy adults.
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For Part 2, 4 patients each in Cohort 5, 6 and a maximum of 12 patients in Cohort 7 will be enrolled 
to evaluate the safety, tolerability, PK and pharmacodynamic effects of TAK-925 when a single 
dose of TAK-925 is administered to patients with type 1 narcolepsy.
These sample sizes are not based on any effect size obtained by the MWT or statistical evidence.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
The sponsor or a designee (Contract Research Organization) will visit study sites for periodic 
monitoring during the study period 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 the original documents, data and records. The investigator and the head of study site 
guarantee that the sponsor or its designee and the IRB/IEC have access to the source documents.
The sponsor or its designee (as long as blinding is not jeopardized) will review the records 
including the Investigator's Binder, study drugs, subjects' medical records, informed consent forms 
to confirm that all aspects of the study are appropriately conducted in accordance with the 
protocol. The consistency between the eCRF and the source documents related to the eCRF should 
also be reviewed. When a monitoring visit is performed at a study site, the investigator, 
subinvestigator and other study personnel must spare time to support that the monitoring is 
proceeded appropriately.
12.2
Protocol Deviations
The investigators can deviate from or change the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from the IRB or IEC. In the event of a deviation or change, the 
principal investigator should notify the sponsor and the head of the study site of the deviation or 
change as well as its reason in a written form, and then retain a copy of the written form. When 
necessary, the principal investigator may consult and agree with the sponsor on a protocol 
amendment. If the protocol amendment is appropriate, the amendment proposal should be 
submitted to the head of the site as soon as possible, and an approval from the IRB should be 
obtained.
The investigators should document all the protocol deviations.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or its designee. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the Medicines and Healthcare products Regulatory 
Agency in the U.K. [MHRA], the Pharmaceuticals and Medical Devices Agency [PMDA] in
Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor should be 
notified immediately. The investigator and the head of the study site guarantee that the auditor can 
have access to all study documents 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 Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and Appendix A.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local rules of each participating 
region. The sponsor or its designee will need to obtain a document containing all names and titles 
of IRB or IEC members. If a member of the IRB or IEC is directly participating in this study, a 
written document regarding his or her abstinence from voting must also be obtained.
The sponsor or its designee will submit study-related documents to the IRB or IEC for review and 
approval of the protocol In addition to the protocol, the investigator’s brochure, a copy of the 
informed consent forms, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to the
central or local IRB or IEC for approval. The sponsor or its designee must obtain a written 
approval for the protocol and informed consent forms from the IRB or IEC before the 
commencement of the study. The documents approved by the IRB or IEC must contain the exact 
protocol title, protocol number, date of creation/amendment; and also edition number and date of 
approval of other documents reviewed (eg, informed consent forms). The sponsor will notify to 
each site after he/she confirmed the appropriateness of the site's regulation documents. Until the 
site receives the notification, no protocol procedures, including screening, will be commenced.
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include amendments of protocol, informed consent form and subject recruitment materials, and 
local safety reporting requirements, update report of the study at the IRB/IEC-specified intervals, 
submission of the End of Study report, etc. The sponsor or its designee must obtain all the above 
documents approved by the IRB/IEC and relevant documents.
Incentives for subjects should not exert undue influence on their participations. Payments to 
subjects must be approved by the IRB or IEC and the sponsor.
Regarding a pharmacogenomic research using collected and stored samples, analysis will be 
carried out when the details are determined. A pharmacogenomic research plan will also be 
created.
13.2
Subject Information, Informed Consent, and Subject Authorization
An informed consent form will contain the detailed elements of the Declaration of Helsinki and the 
ICH Harmonised Tripartite Guideline for GCP and all applicable laws and regulations. The 
informed consent form also contains the planned and permitted usage, transfers, and disclosures of 
the subject's personal information and health information for the purpose of conducting this study.
The form further explains the nature of the study, study objectives, and potential risks and benefits, 
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as well as the date of signature of informed consent form. The form will detail the requirements of 
the participant and the fact that he or she is free to withdraw from the study at any time during the 
study 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. The informed consent form must be approved by both the IRB or IEC and 
the sponsor prior to use.
The informed consent form must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigators to explain the detailed elements of the informed 
consent form 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.
The investigators must give must give the subject ample opportunity to: (1) inquire about details of 
the study, and (2) decide whether or not to participate in the study. If the subject determines that he 
or she will participate in the study, the subject must sign and date the informed consent form. The 
subject should be instructed to sign his/her legal name, not nickname, using blue or black ballpoint 
pen. The investigators must also sign and date the informed consent form at the time of consent 
and prior to the subject's enrollment in the study.
The investigators must store the signed original informed consent form, and also record the date 
the subject signed in the subject’s medical record. Copies of the signed informed consent form 
shall be given to the subject.
If the consent form is revised, the investigators must obtain a signature from the subject again, in 
the same manner as the original informed consent was obtained. The new date of signature should 
be recorded in the subject’s medical record, and a copy of the revised informed consent form
should be given to the subject.
Subjects who consented to provide their DNA samples for a PGx research can withdraw their 
consent and request disposal of stored samples at any time prior to analysis. If a subject withdrew 
his/her consent, the sponsor must be informed of the 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. In this study, the subject’s source data will only be linked to the 
sponsor’s clinical study database or documents via a unique identification number. As permitted 
by all applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth 
may be used to identify the subject and confirm the accuracy of the subject’s unique identification 
number.
To ensure that the study is being conducted according to the protocol and the ICH-GCP guidelines, 
the sponsor, CRAs, sponsor's designees, representatives of each regulatory authorities (eg, FDA, 
MHRA, PMDA), sponsor-designated auditors and the IRBs/IECs can require the investigator to 
permit them to have access to the original documents (source data or documents), including, but 
not limited to, laboratory test results, ECG measurements, admission and discharge records during 
the subject's study participation, and autopsy results. The investigators must obtain authorization 
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from the subject when CRAs, representatives of the regulatory authorities, etc. have access to the 
subject's original medical record as part of the informed consent process (see Section 13.2).
When a copy of the subject's source documents is provided to the sponsor, personally identifiable 
information (eg, subject's name, address, and other identifiers not recorded in the subject's eCRF) 
must be removed.
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with all test results and data derived by the 
study. During and after the study, only the sponsor can disclose the study information to other 
investigators or regulatory authorities, unless otherwise specified by law Any public disclosure 
(including publicly accessible websites) related to the protocol or study results is the sole 
responsibility of the sponsor, unless otherwise agreed in the study site agreement.
The sponsor may publish any data and information obtained from the study (including data and 
information provided by the investigator) without consent of the investigator. The investigator and 
subinvestigator must obtain a prior written approval from the sponsor when externally publishing 
any information obtained from the study to a specific academic society, etc.
13.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it sponsor's anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of the study, as stipulated in the Takeda Policy/Standard. 
Takeda contact information, along with the name, city, state (only for the U.S.), country of each
medical institution that will conduct a clinical trial and the subject recruiting status will be 
registered and available for public viewing.
13.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by the Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject participating 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 needed, the sponsor 
or the 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, contact the sponsor 
or the 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
Ae
amount of drug excreted in urine
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BMI
body mass index
BP
Blood pressure
BSES
betadex sulfobutyl ether sodium
C6h
observed concentration at 6 hours after starting dose
Ccr
Creatinine clearance
CLR
renal clearance
Cmax
maximum observed concentration
CRA
clinical research associate
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
ESS
Epworth Sleepiness Scale
FDA
U.S. Food and Drug Administration
fe
fraction of administered dose of drug excreted in urine
FIH
first-in-human
GCP
Good Clinical Practice
γ-GTP
gamma-glutamyl transferase
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Term
Definition
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HED
human equivalence dose
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICSD-3
International Classification of Sleep Disorders, third edition
IEC
independent ethics committee
INR
international normalized ratio
IRB
Institutional Review Board
IV
intravenous
KSS
Karolinska Sleepiness Scale 
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
The Medicines and Healthcare Products Regulatory Agency
MHW
The Ministry of Health and Welfare
MRSD
maximum recommended starting dose
MSLT
multiple sleep latency test
MWT
maintenance of wakefulness test
NOAEL
no observed adverse effect level
OX
orexin
OX1R
orexin type 1 receptor
OX2R
orexin type 2 receptor
OTC
over-the-counter
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetics
PT
Preferred Term
PMDA
The Pharmaceuticals and Medical Devices Agency
QOL
quality of life
QTcF
corrected QT with Frederica correction method
RBC
red blood cell
REM
rapid eye movement 
SAE
serious adverse event
SAP
statistical analysis plan
CCI
CCI
CCI
CCI
CCI
CCI
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Term
Definition
SBP
systolic blood pressure
SOREM
sleep-onset rapid eye movement
SSRIs
selective serotonin reuptake inhibitors
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
t1/2
half-life period
ULN
upper limit of normal
Vz
volume of distribution
WBC
white blood cell
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15.0
DATA HANDLING AND RECORDKEEPING
The details of procedures for data management will be documented in the Data Management Plan. 
AEs, and past and current medical history will be coded using the MedDRA. Drugs will be coded 
using the World Health Organization Drug Dictionary.
15.1
eCRFs
An eCRF is prepared for each subject who signed the informed consent form.
The sponsor or its designee will allow all study sites to have access to eCRFs. The sponsor will 
teach appropriate site staff how to use and complete the eCRF. The eCRF is used to transmit the 
information collected from the study to the sponsor and the regulatory authorities. The eCRF must 
be completed in English. When an eCRF is prepared, data are entered directly into the eCRF.
After all data are entered, a logic check will be performed by computer to detect incorrect dates, 
missing data, questionable values, etc. If the sponsor (or its designee) asks the study site a guestion 
about the entered data, the study site will answer the question.
A change or the correction of eCRF will be recorded as the audit trail that recorded an information 
before and after a changer or the correction, change or reviser, change or correction day and the 
reason.
The principal investigator must review the eCRF for completeness and accuracy and provide 
his/her electronic signature in an appropriate page. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered in the eCRFs.
The following data will not be recorded in the eCRF:

Pharmacogenomic analysis results

Laboratory results

Drug concentration measurement results
If the investigators modifies or corrects the data in the eCRF or adds new information to the data 
after the clinical study database is locked, such modification or correction should be made using 
the modification and correction record of the eCRF. The principal investigator must review the
modification and correction record of the eCRF for completeness and accuracy, and then provide 
his/her electronic signature within the eCRF.
The sponsor or its designee must review all eCRFs for completeness and accuracy during his/her 
periodic visits to the study site. The sponsor or its designee will also review study-related subjects’ 
medical and hospital records to ensure the accuracy of those subjects' eCRFs. The completed 
eCRFs are the sole property of the sponsor, and the investigators must not disclose the information 
to any third parties, except authorized representatives of the regulatory authorities, without written 
permission of the sponsor.
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15.2
Record Retention
For the purpose of investigation or audit by the regulatory authorities, the sponsor or its designee, 
the investigator or the head of the study site must keep the records stipulated in Section 15.1 and 
the documents including the study-specific documents, subject identification log, medical records, 
original signed and dated informed consent forms, electronic copies of eCRFs including their audit 
trails, and drug accountability log. The investigator and the head of the study site must retain 
essential documents until the following 1 or 2, whichever comes later. However, if the sponsor 
needs to retain those documents longer than the day, the head of the study site and the sponsor 
should discuss how long and how they will be retained.
1. The day when a marketing approval of the study drug was obtained (or the day 3 years after the 
notification of early termination of the study)
2. The day 3 years after the date of early termination or completion of the study
In addition, the investigator and the head of the study site should retain the essential documents 
until the receipt of a sponsor-issued notification that states the retention is no longer required.
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16.0
REFERENCES 
[1]
American Academy of Sleep Medicine. The International Classification of Sleep Disorders, 
Third edition.Darien, IL: American Academy of Sleep Medicine; 2014.
[2]
Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. 
Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469-74.
[3]
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case 
of early onset narcolepsy and a generalized absence of hypocretin peptides in human 
narcoleptic brains. Nat Med. 2000;6(9):991-7.
[4]
Sakurai T. New treatment of sleep disorders. Orexin and sleep-wake regulation system. 
Brain 21. 2015;18(2):53-60.
[5]
Guidelines on the Diagnosis and Management of Narcolepsy. The Japanese Society of Sleep 
Research.
[6]
Kornum BR, Knudsen S,Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, et al. Narcolepsy. 
Nat Rev Dis Primers. 2017;3:Article 16100.
[7]
Moresco M, Riccardi LN, Pizza F, Zenesini C, Caporali L, Plazzi G, et al. Pharmacogenetics 
and treatment response in narcolepsy type 1: Relevance of the polymorphisms of the drug 
transporter gene ABCB1. Clin Neuropharmacol. 2016;39:18-23.
[8]
Lammers GJ. Treatment of Narcolepsy. In: Baumann CR, Bassetti CL, Scammell TE, 
editors. Narcolepsy: Pathophysiology, diagnosis, and treatment. New York: Springer; 2011. 
p. 401-9.
[9]
Sakurai T. Function of orexin and mechanism of action of orexin receptor antagonist . 
Nippon rinsho. 2015; 73(6): 1023-30
[10] Xu TR, Yang Y, Ward R, Gao L, Liu Y. Orexin receptors: multi-functional therapeutic 
targets for sleeping disorders, eating disorders, drug addiction, cancers and other 
physiological disorders. Cell Signal. 2013;25(12):2413-23.
[11] Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, et al. Genetic 
ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 
2001;30(2):345-54.
[12] Huang SC, Dai YW, Lee YH, Chiou LC, Hwang LL. Orexins depolarize rostral ventrolateral 
medulla neurons and increase arterial pressure and heart rate in rats mainly via orexin 2 
receptors. J Pharmacol Exp Ther. 2010;334(2):522-9.
[13] U.S. Food and Drug Administration [Internet]. Pharmacology/Toxicology, Below is a 
sortable table of Pharm/Tox guidances [updated 2005 Jul 28]. Guidance for Industry. 
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers; 2005 Jul [about 30p]. Available from: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm06
5014.htm.
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[14] VFEND for Intravenous use 200 mg, Package leaflet Pfizer Inc. January, 2018 revision (the 
19th edition)
[15] CARNEXIV[prescribing information] Deerfield, IL, USA:Lundbeck, 2016 October.
[16] Modiodal 100 mg tablet, Package leaflet The Mitsubishi Tanabe Pharma Corp. April, 2015 
revision (the 8th edition)
[17] Xyrem[prescribing information]. Palo Alto, CA, USA:Jazz Pharmaceuticals, Inc. 2014 
April.
[18] Xyrem[Summary of product characteristics]. United Kingdom, UCB Pharma Ltd. 2010 
October.
[19] Wakix[Summary of product characteristics]. France, Bioprojet Pharma. 2017 February.
[20] Guidelines for clinical evaluation method of a medicament for use in the elderly, 
Yaku-shin104, Notification of the First Evaluation and Registration Division Chief, 
Pharmaceutical Affairs Bureau, MHW (2 Dec, 1993).
[21] Journal of Japan Society for the Study of Obesity. Obesity diagnostic criteria 2011. Obesity 
research. 2011;10 (extra edition).
[22] Legal Performance Regulations Regarding Security of Safe Supply of Safe Blood 
Formulas(Ordinance of the Ministry of Health and Welfare No.22 of 1956).
[23] General Considerations for Clinical Trials (21 Apr, 1998 Iyaku-shin 380).
[24] The Ministry of Health, Labour and Welfare, The manual for each disease of serious adverse 
events, seizure and epilepsy, in May, 2009
(http://www.info.pmda.go.jp/juutoku/file/jfm0905004.pdf) (access date: 24 July, 2017)
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17.0
APPENDICES
CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
1 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.8-9
1.0 STUDY 
SUMMARY
Trial Design:
･･･
(1) Part 1
In Cohort 3 and Healthy Adult Supplement Cohort following Cohort 2.
･･･
In Cohort 3, 8 healthy elderly will be enrolled. Of these 8 subjects, 6 will 
be randomly assigned to the TAK-925 group and 2 to the placebo group. 
This cohort will be initiated after started with the dose of which the safety 
and tolerability has been established in healthy adults.
･･･
Cohorts 3 and 4 may be started at the discretion of the sponsor, considering 
the status of Cohorts 1, 2 and Healthy Adult Supplement Cohort.
Trial Design:
･･･
(1) Part 1
In Cohort 3, Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort (in the event that a cohort is added) following Cohort 
2.
･･･
In Cohort 3, 8 healthy elderly will be enrolled. Of these 8 subjects, six will 
be randomly assigned to the TAK-925 group and 2 to the placebo group. 
This cohort will be initiated after started with the dose of which the safety 
and tolerability has been established in healthy adults. In the event that 
further investigation on the safety, tolerability and PK is needed after 
completion of Cohort 3, a maximum of 1 additional cohorts for Healthy 
Elderly Supplement Cohorts that enrollse 8 healthy elderly per cohort will
be commenced without amendment of the protocol. The cohort name of R1 
will be assigned for the Healthy Elderly Supplement Cohort. Six subjects 
will be randomly assigned to the TAK-925 group and 2 subjects to the 
placebo group, to evaluate the safety, tolerability and PK. In the Healthy 
Elderly Supplement Cohort, the dose may be higher orlower than or the 
same to that of prior cohort dose levels, or an intermediate dose between 
two prior doses.
･･･
Cohort 3, Healthy Elderly Supplement Cohort and Cohort 4 may be started 
at the discretion of the sponsor, considering the status of Cohorts 1, 2 and 
Healthy Adult Supplement Cohort.
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higer dose.
Clerical 
corrections
p.10
1.0 STUDY 
SUMMARY
Planned Number of Subjects:
(1) Part 1
･･･
• Cohort 4: 4 subjects
In the event that a cohort is added, a maximum of 4 cohorts (32 additional 
subjects) can be enrolled.
Planned Number of Subjects:
(1) Part 1
･･･
• Cohort 4: 4 subjects
In the event that a cohort is added, a maximum of 5 cohorts (40 additional 
subjects) can be enrolled.
p.11
1.0 STUDY 
SUMMARY
Planned Trial Duration:
(1) Part 1
Screening period (Cohort 1 Dose Level 1, Cohort 2 Dose Level 2, Cohorts
3 and 4 and Healthy Adult Supplement Cohort)
Days -28 to -2
Planned Trial Duration:
(1) Part 1
Screening period (Cohort 1 Dose Level 1, Cohort 2 Dose Level 2, Cohorts
3 and 4, Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort)
Days -28 to -2
p.11
1.0 STUDY 
SUMMARY
Main Criteria for Inclusion:
･･･
The Healthy Elderly (Cohort 3)
Main Criteria for Inclusion:
･･･
The Healthy Elderly (Cohort 3 and Healthy Elderly Supplement Cohort)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
2 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.12
1.0 STUDY 
SUMMARY
Main Criteria for Exclusion:
･･･
Healthy Adult and The Healthy Elderly (Cohorts 1-4 and Healthy Adult 
Supplement Cohort)
Main Criteria for Exclusion:
All Subjects
･･･
Healthy Adult and The Healthy Elderly (Cohorts 1-4, Healthy Adult 
Supplement Cohort and Healthy Elderly Supplement Cohort)
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
p.13
1.0 STUDY 
SUMMARY
Statistical Considerations:
PK:
For Cohorts 1-2 in Part 1, Healthy Adult Supplement Cohort and Part 2, the 
following analyses will be performed for each dose level using the PK 
analysis set. For the other cohorts, the analyses will be performed for each 
cohort and each dose level using PK analysis set.
Statistical Considerations:
PK:
For Cohorts 1-2 and Healthy Adult Supplement Cohort, Cohort 3 and
Healthy Elderly Supplement Cohort, Cohort 4, Part 2, the following 
analyses will be performed for each dose level using the PK analysis set.
Plasma and CSF concentrations of TAK-925･･･.
p.14
1.0 STUDY 
SUMMARY
Sample Size Justification:
･･･
If further investigation on the safety, tolerability and PK is needed after 
completion of Cohorts 1-2, a maximum of 4 additional cohorts (a total of 
32 healthy adult subjects; 8 subjects [6 in TAK-925 group, 2 in placebo 
group] per cohort) may be enrolled. Randomized toTAK-925:6 subject, 
placebo: 2 subjects for a maximum of 32 additional subjects. 
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, 
tolerability, PK of TAK-925 including the concentration of TAK-925 in the 
CSF when a single dose of TAK-925 is administered intravenously to 
healthy adults.
Sample Size Justification:
･･･
If further investigation on the safety, tolerability and PK in healthy adults is 
needed after completion of Cohorts 1-2, a maximum of 4 additional cohorts 
(a total of 32 healthy adult subjects; 8 subjects [6 in TAK-925 group, 2 in 
placebo group] per cohort) may be enrolled. If further investigation of 
safety, tolerability and PK in healthy elderly is needed after completion of 
Cohort 3, a maximum of 1 additional cohort (a total of 8 healthy elderly 
subjects [6 in TAK-925 group, 2 in placebo group] per cohort) may be 
enrolled.
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, 
tolerability, PK of TAK-925 including the concentration of TAK-925 in the 
CSF when a single dose of TAK-925 is administered intravenously to 
healthy adults.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
3 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.15
2.0 STUDY 
SCHEMATI
C
Figure 2.a Summsry of the Study Design
<Part 1>
1. Cohorts 1 and 2 (Healthy Adults) and Cohorts S1-S4 (Healthy Adult 
Supplement Cohorts)
Dose Level
Cohort
2
3
4
5
6
1
TBD
TBD
2
TBD
TBD
TBD
･･･
2) The doses should be determined in consideration of the following target plasma 
level: Dose Level 1: 20 ng/mL, Dose Level 2: 40 ng/mL, Dose Level 3: 80 ng/mL, 
Dose Level 4: 150 ng/mL, Dose Level 5: 300 ng/mL, Dose Level 6: 600 ng/mL. The 
steady-state concentration (Css) of TAK-925 is estimated to be 21.3 ng/mL when 7 
mg is administered as Dose level 1
･･･
Figure 2.a Summsry of the Study Design
<Part 1>
1. Cohorts 1 and 2 (Healthy Adults) and Cohorts S1-S4 (Healthy Adult 
Supplement Cohorts)
Dose Level
Cohort
2
3
4
5
6
1
28 mg
112 mg
2
14 mg
56 mg
134.4 mg
･･･
2) The doses of Dose Levels 7-10 are planned as follows. However based on the 
available the safety, tolerability and PK data, there is a possibility that the dose may 
be appropriately increased or decreased within the range not exceeding 420 mg. 
Dose Level 7: 180 mg, Dose Level 8: 240 mg, Dose Level 9: 320 mg, Dose Level 
10: 420 mg
･･･
Specified the dose 
at completed Dose 
Level
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
With the above, It 
was possible to 
investigate in 
healthy elderly at 
higher dose.
p.15
2.0 STUDY 
SCHEMATI
C
Figure 2.a Summsry of the Study Design
<Part 1>
･･･
2. Cohort 3 (The healthy elderly)
Cohort 3
TAK-925 TBD
Placebo
Figure 2.a Summsry of the Study Design
<Part 1>
･･･
2. Cohort 3 (The healthy elderly) and Cohort R1 (The Healthy Elderly 
Supplement Cohort)
Cohort 3/Cohort R1
112 mg/TAK-925 TBD
Placebo
p.15
2.0 STUDY 
SCHEMATI
C
Figure 2.a Summsry of the Study Design
<Part 1>
･･･
3. Cohort 4 (Healthy adults)
Cohort 4
TAK-925 TBD
Figure 2.a Summsry of the Study Design
<Part 1>
･･･
3. Cohort 4 (Healthy adults)
Cohort 4
112 mg
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
4 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.16-18 3.0 
SCHEDULE 
OF STUDY 
PROCEDUR
ES
Part1 (Cohorts 1-4 and Healthy Adult Supplement Cohort)
Day -1
Predose
Day 1
Day 1
Day 2/Early 
Termination
Vital Signs 
(respiratory rate, 
temperature) (d)
X
X
X
Blood Sample 
Collection for 
Preservation and 
Pharmacogenomic 
Research
X (a)
Hospitalization
X
X
X
X
Abbreviations: C-SSRS=The Columbia Suicide Severity Rating Scale; HIV= human
immunodeficiency virus, CSF= cerebrospinal fluid･･･
(c)･･･
Day -1: Measurements will be performed at 15:00 and 19:00, totally 2 times.
Day1: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 
hours postdose
･･･
Orthostatic BP (1 and 5 minutes after standing up) will also be measured after the 
above vital signs were measured 1, 2 and 4 hours after the start of infusion.
･･･
Part1 (Cohorts 1-4 and Healthy Adult Supplement Cohort)
Day -1
Predose
Day 1
Day 1
Day 2/Early 
Termination
Vital Signs 
(respiratory rate, 
body temperature) 
(d)
X
X
X
Blood Collection for 
Retained Samples
and 
Pharmacogenomic 
Research
X (a)
Hospitalization
X (i)
X
X
X
Abbreviations: BMI=body mass index, C-SSRS=The Columbia Suicide Severity 
Rating Scale, HIV= human immunodeficiency virus, CSF= cerebrospinal fluid･･･
(c)･･･
Day -1: Measurements will be performed at 15:00 and 19:00, totally 2 times. (No 
Measurement in Healthy Adult Supplement Cohort and Healthy Elderly Supplement 
Cohort)
Day1: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 
hours after the start of infusion
On Day -1 and Day 1 in Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort, measurement will be performed at following the same time 
point.
Day -1: -24, -23.75, -23.5, -23.25, -23, -22.5, -22, -21.5, -21, -20.5, -20, -19, -18, 
-17, -16, -15, -14, -13 and -12 hours after the start of infusion.
Day 1: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11 and 12 
hours after the start of infusion.
On Day 1, Measurement at well as 24 hours after the start of infusion will also be 
performed.
･･･
Orthostatic BP (1 and 5 minutes after standing up) will also be measured after the 
above vital signs were measured 1, 2 and 4 hours after the start of infusion (only on 
Day 1).
･･･
i) Hospitalization from Day -2 may be allowed for Healthy Adult Supplement 
Cohort and Healthy Elderly Supplement Cohort as needed.
Decided to 
evaluate vital 
signs in more 
detail in Healthy 
adult Supplement 
Cohort and 
Healthy Elderly 
Supplement 
Cohort based on 
the result of 
Cohort 2 Dose 
Level 6 of Part 1.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
5 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.27-28 6.1 Trial 
Design
(1) Part 1
･･･
In Cohort 2 Dose Level 2 and subsequent dose levels in Cohorts 1 and 2, 
Cohort 3 and Healthy Adult Supplemental receive TAK-925 or placebo 
simultaneously. (such that 4 subjects will be dosed at first, and if there are 
no safety issues, the remaining 4 subjects may be dosed about 1 hour later.)
･･･This cohort will be initiated after started with the dose of which the
safety and tolerability has been established in healthy adults.
･･･
Cohort 3 and 4 may be started at the discretion of the sponsor, considering 
the status of Cohorts 1, 2 and the Healthy Adult Supplement Cohort. 
(Cohorts 3 and 4 may be implemented in parallel with Cohorts 1 and 2. The 
doses to be used in Cohorts 3 and 4 will be determined based on the 
available safety, tolerability and PK data, and nonclinical study results.)
(1) Part 1
･･･
In Cohort 2 Dose Level 2 and subsequent dose levels in Cohorts 1 and 2, 
Cohort 3, Healthy Adult Supplemental Cohort and Healthy Elderly 
Supplement Cohort (in the event that the cohort is actually added) receive 
TAK-925 or placebo simultaneously. (such that 4 subjects will be dosed at 
first, and if there are no safety issues, the remaining 4 subjects may be 
dosed about 1 hour later.).
･･･This cohort will be initiated after s started with the dose of which the
safety and tolerability has been established in healthy adults. In the event 
that further investigation on the safety, tolerability and PK is needed after 
completion of Cohort 3, a maximum of 1 additional cohorts for Healthy 
Elderly Supplement Cohort that enrolls 8 healthy elderly per cohort will be 
commenced without amendment of the protocol. The cohort name of R1 
will be assigned for the Healthy Elderly Supplement Cohort. Six subjects 
will be randomly assigned to the TAK-925 group and 2 subjects to the 
placebo group, to evaluate the safety, tolerability and PK. In the Healthy 
Elderly Supplement Cohort, the dose may be higher or lower than or the 
same to that of prior cohort dose levels, or an intermediate dose between 
two prior doses.
･･･
Cohort 3, Healthy Elderly Supplement Cohort and Cohort 4 may be started 
at the discretion of the sponsor, considering the status of Cohorts 1, 2 and 
Healthy Adult Supplement Cohort. (Cohorts 3 and 4 may be implemented 
in parallel with Cohorts 1 and 2. The doses to be used in Cohorts 3 and 4 
will be determined based on the available safety, tolerability and PK data, 
and nonclinical study results.)
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
p.30
6.1 Trial 
Design
Table 6.a Summary of Cohorts
Part
Cohort
Dosage
11)
12)
TAK-925 7 mg (Dose Level 1) or placebo
2
TAK-925 TBD mg (Dose Level 2) or placebo
1
TAK-925 TBD mg (Dose Level 3) or placebo
2
TAK-925 TBD mg (Dose Level 4) or placebo
1
TAK-925 TBD mg (Dose Level 5) or placebo
2
TAK-925 TBD mg (Dose Level 6) or placebo
S1 – S43)
TAK-925 TBD mg or placebo
3
TAK-925 TBD mg or placebo
4
TAK-925 TBD mg
Table 6.a Summary of Cohorts
Part
Cohort
Dosage
11)
12)
TAK-925 7 mg (Dose Level 1) or placebo
2
TAK-925 14 mg (Dose Level 2) or placebo
1
TAK-925 28 mg (Dose Level 3) or placebo
2
TAK-925 56 mg (Dose Level 4) or placebo
1
TAK-925 112 mg (Dose Level 5) or placebo
2
TAK-925 134.4 mg (Dose Level 6) or placebo
S1 – S43)
TAK-925 TBD mg (Dose Level 7-10)3) or placebo
3
TAK-925 112 mg or placebo
4
TAK-925 112 mg
Specified the dose 
at completed Dose 
Level
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
6 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.30
6.1 Trial 
Design
Table 6.a Summary of Cohorts
･･･
Table 6.a Summary of Cohorts
Part
Cohort
Subjects
Sample Size
Study Design
Dosage
Randomization
11)
R14)
Healthy elderly
n=8
Double-blind,
parallel group
TAK-925
TBD mg or 
placebo
TAK-925: 6 
subjects,
Placebo: 2 
subjects
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
p.30
6.1 Trial 
Design
Table 6.a Summary of Cohorts
1) In Part 1, Dose Levels 1, 3 and 5 will be tested in the same set of, and 
similaly, Dose Levels 2, 4 and 6 will be evaluated in the different set of the 
same subjects. In Part 2, different subjects will be used in each Cohort. The 
target plasma level totake into consideration as a standard is as follows. 
Dose Level 1: 20 ng/mL, Dose Level 2: 40 ng/mL, Dose Level 3: 
80 ng/mL, Dose Level 4: 150 ng/mL, Dose Level 5: 300 ng/mL, Dose 
Level 6: 600 ng/mL. The steady-state concentration (Css) of TAK-925 is 
estimated to be 21.3 ng/mL when 7 mg is administered as Dose level 1.
･･･
3) In the event that further investigation on the safety, tolerability and PK 
of TAK-025 is needed after completion of Cohorts 1 and 2, up to 4 
additional cohorts that include 32 healthy adults can be commenced 
without amendment of the protocol. 
4) In Part 2, the dose level to be used in Cohort 5 should be equal or less 
than one-third of the maximum dose of TAK-925 of which the safety and 
tolerability has been already confirmed.
Table 6.a Summary of Cohorts
1) In Part 1, Dose Levels 1, 3 and 5 will be tested in the same set of 
subjects, and similarly, Dose Levels 2, 4 and 6 will be evaluated in the
different set of the same subjects. In Part 2, different subjects will be used 
in each Cohort.
･･･
3) In the event that further investigation on the safety, tolerability and PK 
of TAK-925 is needed after completion of Cohorts 1 and 2, up to 4 
additional cohorts that include 32 healthy adults can be commenced 
without amendment of the protocol. The Dose Levels 7-10 are planned as 
follows. However based on the available safety, tolerability and PK data, 
there is a possibility that the dose may be appropriately increased or 
decreased within the range not exceeding 420 mg. Dose Level 7: 180 mg, 
Dose Level 8: 240 mg, Dose Level 9: 320 mg, Dose Level 10: 420 mg.
4) In the event that further investigation on the safety, tolerability and PK 
of TAK-925 is needed after completion of Cohort 3, up to 1 additional 
cohorts that include 8 healthy elderly can be commenced without 
amendment of the protocol.
5) In Part 2, the dose level to be used in Cohort 5 should be equal or less 
than one-third of the maximum dose of TAK-925 of which the safety and 
tolerability has been already confirmed in Part 1.
p.31
6.1 Trial 
Design
Figure 6.a. Overview of the Trial Schedulee
Figure 6.a. Overview of the Trial Schedules
Correction of 
errors
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
7 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.32
6.2 Cohort 
transition/Do
se Escalation
･･･
The inclusion criteria for patients with type 1 narcolepsy includes those 
aged 18-80, but subjects aged 56 years or older will be enrolled based on 
the assessments of the safety results and PK data of Chohort 3 in Part 1.
･･･
The inclusion criteria for patients with type 1 narcolepsy in Part 2 includes 
those aged 18-80, but subjects aged 56 years or older will be enrolled based 
on the assessments of the safety results and PK data of Cohort 3 (and the 
Healthy Elderly Supplement Cohort) in Part 1.
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
Correction of 
description
p.33
6.3.1 
Rationale of 
population
(1) Part 1
･･･with type 1 narcolepsy is enrolled in Part 2. In Cohort 4, healthy 
adults･･･
(1) Part 1
･･･with type 1 narcolepsy will be is enrolled in Part 2. Also, considering 
the possibility of performing Part 2 at high doses, the Healthy Elderly 
Supplement Cohort will be added. In Cohort 4, healthy adults･･･
p.34
6.3.2
Rationale of 
Trial Design
(1) Part 1
･･･
After Cohort 2 Dose Level 2 and subsequent dose levels in Cohorts 1 and 
2, Cohort 3 and Healthy Adult Supplement Cohort. (4 subjects will be 
dosed first, and if there are no safety issues, the remaining 4 subjects will 
be dosed approximately about 1 hour later.)
(1) Part 1
･･･
After Cohort 2 Dose Level 2 , dosing will not be started simultaneously in 
all subjects in Cohort 3, Healthy Adult Supplement Cohort and Healthy 
Elderly Supplement Cohort (in the event that a cohort is added). (4 subjects 
will be dosed first, and if there are no safety issues, the remaining 4 
subjects will be dosed approximately 1 hour later.)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
8 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.35-36 6.3.3
Rationale for 
Dose
(2) Maximum Dose/Exposure for This Trial
Based on the NOAEL in rats of which the sensitivity was the highest 
among animals used in the two-week, nonclinical, repeat-dose, toxicity 
studies, and the clinical dose of betadex sulfobutyl ether sodium (BSES), 
which is an excipient contained in the study drug, the acceptable upper 
limits of Cmax and AUC and the maximum dose of TAK-925 in this study 
were set to be 
For example, "VFEND IV 200 MG", approved, contains BSES, an 
excipient contained in the study drug. When VFEND is administered to a 
weighing 60 kg, the maximum dose of BSES per dose as the maintenance 
dose on and after Day 2 will be 3840 mg (VFEND IV 200 MG is given 
twice a day).The dose of BSES to be used in this study was set to be 
3840 mg by using this calculation as reference. Since TAK-925 used as a 
study drug contains 100 mg of BSES as an excipient per 3.5 mg of 
TAK-925, the maximum dose of TAK-925 to be used in this study will be 
134.4 mg.
(2) Maximum Dose/Exposure for This Trial
Based on the NOAEL in rats of which the sensitivity was the highest 
among animals used in the two-week, nonclinical, repeat-dose, toxicity 
studies, and the clinical dose of betadex sulfobutyl ether sodium (BSES), 
which is an excipient contained in the study drug, the acceptable upper 
limits of Cmax and AUC and the maximum dose of TAK-925 in this study 
were set to be 
. 
Meanwhile, in Cohort 2 Dose Level 6
 of Part 1 in this study, 
Cmax and AUC of TAK-925 were 
(preliminary result), respectively, and were safe and well-tolerated. These 
exposure levels of Cmax and AUC are 
 lower than the 
acceptable Cmax and AUC of TAK-925 in this study, respectively, 
 
Thus, it was judged 
possible to investigate at higher doses, and the maximum dose (the upper 
limit) was set to be 
For example, "VFEND IV 200 MG", approved in Japan, contains BSES, an 
excipient contained in the study drug. Referring to the dosage of VFEND 
[14], the maximum amount of BSES per dose was set to be 3840 mg (when 
VFEND is administered to a human weighing 60 kg, as the maintenance 
dose on and after Day 2) in the protocol (first version and amendment 1). 
On the other hand, based on the result of Cohort 2 Dose Level 6 (134.4 mg) 
of Part 1 of this study and referring to the dosage of CARNEXIV [15] 
already approved in the United States, the maximum dose of BSES per 
dose was set to 12000 mg in the study protocol (amendment 2), within in 
the range of the amount of BSES, to be possibly administered within 9 
hours as CARNNEXIV (CARNEXIV is infused every 6 hours, so this 
amount corresponds to 2 doses of CARNNEXIV). Since TAK-925 used as 
a study drug contains 100 mg of BSES as an excipient per 3.5 mg of 
TAK-925, 420 mg of TAK-925 contains 12000 mg of BSES.
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
9 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.39
6.4 Trial 
Design/Dosi
ng/Procedure
s 
Modification
s Permitted 
Within 
Protocol 
Parameters
･･･In the event that further investigation on the safety, tolerability and PK 
is needed after completion of Cohort 1 and Cohort 2 Dose Level 6, up to 4 
additional cohorts that include 32 healthy adults can be commenced 
without amendment of the protocol. In the event that a long-term washout 
period is needed on the basis of the pharmacokinetic or safety evaluation 
results in Part 1, the dosing order of TAK-925 and placebo and Part 2 may 
be changed to a single-blind (only subjects are blinded), fixed-sequence 
approach (TAK-925 will be given after a placebo is given to all subjects).
･･･In the event that further investigation on the safety, tolerability and PK 
is needed after completion of Cohort 1 and Cohort 2 Dose Level 6, up to 4 
additional cohorts that include 32 healthy adults can be commenced 
without amendment of the protocol. In the event that further investigation 
on the safety, tolerability and PK of TAK-925 is needed after completion of 
Cohort 3, up to 1 additional cohort that includes 8 healthy elderly can be 
commenced without amendment of the protocol. In the event that a 
long-term washout period is needed on the basis of the pharmacokinetic or 
safety evaluation results in Part 1, the dosing order of TAK-925 and 
placebo and Part 2 may be changed to a single-blind (only subjects are 
blinded), fixed-sequence approach (TAK-925 will be given after a placebo 
is given to all subjects).
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
p.46
7.2
Exclusion 
Criteria
Healthy Adults or the Healthy Elderlys (Cohorts 1-4 and Healthy Adult 
Supplement Cohorts):
Healthy Adults or the Healthy Elderly (Cohorts 1-4, Healthy Adult 
Supplement Cohort and Healthy Elderly Supplement Cohort):
p.58
9.1.1.2 Study 
Drug 
Assignment
In Cohorts 1-3 and Healthy Adult Supplement Cohort (if it will be added), 
subjects in each cohort will be assigned to each cohort the study drug in 
order of the medication ID number (See Figure 9.a, Figure 9.b and Figure 
9.c).
･･･
In the case that the study drug is to be administered to a reserve subject, the 
reserve subject will receive the study drug of which the medication ID 
number was assigned to the original subject only in Cohorts 1 to 3, Healthy 
Adult Supplement Cohort) a subject is replaced, the replacing subject will 
receive the study drug with a different medication ID number from the 
number assigned to the original subject who discontinued the study.
In Cohorts 1-3, Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort (if it is added), subjects in each cohort will be assigned 
to each cohort the study drug in order of the medication ID number 
according to the randomization schedule (See Figure 9.a, Figure 9.b and 
Figure 9.c).
･･･
In the case that the study drug is to be administered to a reserve subject, the 
reserve subject will receive the study drug of which the medication ID 
number was assigned to the original subject only in Cohorts 1 to 3, Healthy 
Adult Supplement Cohort and Healthy Elderly Supplement Cohort) a 
subject is replaced, the replacing subject will receive the study drug with a 
different medication ID number from the number assigned to the original 
subject who discontinued the study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
10 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.59
9.1.1.2 Study 
Drug 
Assignment
Figure 9.a Summary of Cohorts 1 and 2
Dose Level 1
Dose Level 2
Dose Level 3
A
TAK-925 7 mg
E
TAK-925 TBD
A
TAK-925 TBD
B
TAK-925 7 mg
→
F
TAK-925 TBD
→
B
TAK-925 TBD
C
TAK-925 7 mg
G
TAK-925 TBD
C
Placebo
D
Placebo
H
Placebo
D
TAK-925 TBD
Dose Level 4
Dose Level 5
Dose Level 6
E
TAK-925 TBD
A
TAK-925 TBD
E
TAK-925 TBD
→
F
TAK-925 TBD
→
B
Placebo
→
F
Placebo
G
Placebo
C
TAK-925 TBD
G
TAK-925 TBD
H
TAK-925 TBD
D
TAK-925 TBD
H
TAK-925 TBD
Figure 9.a Summary of Cohorts 1 and 2
Dose Level 1
Dose Level 2
Dose Level 3
A
TAK-925 7 mg
E
TAK-925 14 mg
A
TAK-925 28 mg
B
TAK-925 7 mg
→F
TAK-925 14 mg
→
B
TAK-925 28 mg
C
TAK-925 7 mg
G
TAK-925 14 mg
C
Placebo
D
Placebo
H
Placebo
D
TAK-925 28 mg
Dose Level 4
Dose Level 5
Dose Level 6
E
TAK-925 56 mg
A
TAK-925 112 mg
E
TAK-925 
134.4 mg
→F
TAK-925 56 mg
→B
Placebo
→F
Placebo
G
Placebo
C
TAK-925 112 mg
G
TAK-925 
134.4 mg
H
TAK-925 56 mg
D
TAK-925 112 mg
H
TAK-925 
134.4 mg
Specified the dose 
at completed Dose 
Level
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
Decided to 
evaluate vital 
signs in more 
detail in Healthy 
adult Supplement 
Cohort and 
Healthy Elderly 
Supplement 
Cohort based on 
the result of 
Cohort 2 Dose 
Level 6 of Part 1
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
11 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.59
9.1.1.2 Study 
Drug 
Assignment
Figure 9.b Summary of Cohort 3
TAK-925 TBD
Placebo
1) Double-blind study. Cohort 3 consists of 8 subjects: 6 subjects in the TAK-925 
group and 2 subjects in the placebo group.
Figure 9.b Summary of Cohort 3 and Cohort R1 (Healthy Elderly 
Supplement Cohort)
TAK-925 112 mg/TAK-925 TBD
Placebo
1) Double-blind study. Cohort 3 and Cohort R1 consists of 8 subjects: 6 subjects in 
the TAK-925 group and 2 subjects in the placebo group. Dose of Cohort 3 is 112 mg, 
dose of Cohort R1 to be determined.
Specified the dose 
at completed Dose 
Level
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
Decided to 
evaluate vital 
signs in more 
detail in Healthy 
adult Supplement 
Cohort and 
Healthy Elderly 
Supplement 
Cohort based on 
the result of 
Cohort 2 Dose 
Level 6 of Part 1
p.71
9.3.4 
Confinement
(1) Part 1
Subjects will be hospitalized in a hospital during the period from Day -1 to 
Day 2 and discharged from the hospital if no clinically significant 
abnormalities were found at the physical examination and tests on Day 2, 
and confirmed by the investigators.
(1) Part 1
Subjects will be hospitalized in a hospital during the period from Day -1 to 
Day 2 and discharged from the hospital if no clinically significant 
abnormalities were found at the physical examination and tests on Day 2, 
and confirmed by the investigators. Hospitalization from Day -2 may be 
allowed for Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort as needed.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
12 / 14
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(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.81
11.1.3 PK 
Analysis
(1) Endpoints and analysis methodologies
[Analysis methodologies]
The following analysis will be performed using the PK analysis set in 
Cohorts 1-2 and Cohorts S1-S4 (if additional Cohort is enrolled) in Part 1 
and in Part 2 by dose level, and in the other cohorts by cohort and by dose 
level.･･･
(1) Endpoints and analysis methodologies
[Analysis methodologies]
The following analysis will be performed using the PK analysis set in 
Cohorts 1-2 and Healthy Adult Supplement Cohort, and Cohorts 3 and 
Healthy Elderly Supplement Cohort, Cohort 4 and Part 2 by dose level.
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
p.81
11.1.5 Safety 
Analysis
(1) Endpoints and analysis methodologies
[Analysis methodologies]
The following analysis will be performed using the Safety analysis set in 
Cohorts 1-2 and Cohorts S1-S4 (if additional Cohort is enrolled) in Part 1 
and in Part 2 by dose level, and in the other cohorts by cohort and by dose 
level.
(1) Endpoints and analysis methodologies
[Analysis methodologies]
The following analysis will be performed using the safety analysis set in 
Cohorts 1-2 and Healthy Adult Supplement Cohorts, Cohorts 3 and Healthy 
Elderly Supplement Cohort, Cohort 4 and Part 2 by dose level.
p.83
11.5
Determinatio
n of Sample 
Size
･･･In the event that further investigation on the safety, tolerability and PK 
is needed after completion of Cohorts 1-2, a maximum of 4 additional 
cohorts (a total of 32 healthy adult subjects; 8 subjects [6 in TAK-925 
group, 2 in placebo group] for each cohort) may be enrolled.
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, 
tolerability, PK of TAK-925 including the concentration of TAK-925 in the 
CSF when a single dose of TAK-925 is administered intravenously to 
healthy adults.
･･･In the event that further investigation on the safety, tolerability and PK 
in healthy adults is needed after completion of Cohorts 1-2, a maximum of 
4 additional cohorts (a total of 32 healthy adult subjects; 8 subjects [6 in 
TAK-925 group, 2 in placebo group] for each cohort) may be enrolled.
If further investigation on the safety, tolerability and PK in healthy elderly 
is needed after completion of Cohort 3, a maximum of 1 additional cohort 
(a total of 8 healthy elderly subjects [6 in TAK-925 group, 2 in placebo 
group] per cohort) may be enrolled.
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, 
tolerability, PK of TAK-925 including the concentration of TAK-925 in the 
CSF when a single dose of TAK-925 is administered intravenously to 
healthy adults.
p.93-94 16.0
REFERENC
ES
[13] U.S. Food and Drug Administration [Internet]. 
Pharmacology/Toxicology, Below is a sortable table of Pharm/Tox 
guidances [updated 2005 Jul 28]. Guidance for Industry. Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers; 2005 Jul [about 30p]. Available from: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/ucm065014.htm.
[14] Modiodal 100 mg tablet, Package leaflet The Mitsubishi Tanabe 
Pharma Corp. April, 2015 revision (the 8th edition)･･・
[13] U.S. Fo1od and Drug Administration [Internet]. 
Pharmacology/Toxicology, Below is a sortable table of Pharm/Tox 
guidances [updated 2005 Jul 28]. Guidance for Industry. Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers; 2005 Jul [about 30p]. Available from: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/ucm065014.htm.
[14] VFEND for Intravenous use 200 mg, Package leaflet Pfizer Inc. 
January, 2018 revision (the 19th edition)
[15] CARNEXIV[prescribing information] Deerfield, IL, USA:Lundbeck, 
2016 October.
[16] Modiodal 100 mg tablet, Package leaflet The Mitsubishi Tanabe 
Pharma Corp. April, 2015 revision (the 8th edition)･･･
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
13 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.98-99 Appendix C 
Acceptable 
Time 
Windows for 
Study 
Procedures
Part 1 (Cohorts 1-4 and Healthy Adult Supplement Cohort)
Item
Operation Schedule (standard)
Allowance
Vital Signs 
(pulse rate, SBP
and diastolic 
blood pressure)
Baseline
Day -1: once at 15:00 and 
19:00 each, totally 2 times
12:00-17:00 and 
19:00 to bedtime
Treatment 
period
Day 1: Predose
Right after waking 
up to just before 
dosing
Day 1: 0.25, 0.5, 0.75, 1.5, 2.5 
and 3.5 hours after the start of 
infusion
Within ±10 minutes
Day 1: 1, 2, 3 and  4 hours 
after the start of infusion
Within ±15 minutes
Day1: 5, 6, 7, 8, 9, 10, 11 and 
12 hours after the start of 
infusion
Within ±20 minutes
Day 2: 24 hours after the start 
of infusion
Within ±1 hour
･･･
(b) Will be performed after fasting for more than 8 hours.
(c) except dose level 1 and 2 of cohorts 1 and 2.
Part 1 (Cohorts 1-4 and Healthy Adult Supplement Cohort)
Item
Operation Schedule (standard)
Allowance
Vital Signs (pulse 
rate, SBP and 
diastolic blood 
pressure)
Baseline
Day -1: once at 15:00 and 
19:00 each, totally 2 times (c)
12:00-17:00 and 
19:00 to bedtime
Day -1 (d) (e): 24 hours from 
the start of infusion.
-24.5 to -24 hours
Day -1 (d) (e): -23.75, -23.5, 
-23.25, -23, -22.5, -22, -21.5, 
-21, -20.5 and -20 hours after 
the start of infusion.
Within ±15 minutes
Day -1 (d) (e): -19, -18, -17, 
-16, -15, -14, -13 and -12 
hours after the start of 
infusion.
Within ±20 minutes
Treatment 
period
Day 1 (e): Predose
Right after waking 
up to just before 
dosing (c) or -30 
minutes to just 
before dosing (d)
Day 1 (e): 0.25, 0.5, 0.75, 1.5, 
2.5 and 3.5 hours after the 
start of infusion
Within ±10 minutes
Day 1 (e): 1, 2, 3 and 4 hours 
after the start of infusion
Within ±15 minutes
Day1 (e): 5, 6, 7, 8, 9, 10, 11 
and 12 hours after the start of 
infusion
Within ±20 minutes
Day 2 (e): 24 hours after the 
start of infusion
Within ±1 hour
･･･
(b) Will be performed after fasting for more than 8 hours.
(c) Not implemented or applied in in Healthy Adult Supplement Cohort and Healthy 
Elderly Supplement Cohort
(d) Only in Healthy Adult Supplement Cohort and Healthy Elderly Supplement 
Cohort
(e) In Healthy Adult Supplement Cohort and Healthy Elderly Supplement Cohort, 
measurement will be porfromed at the same time period.
(f) Except dose level 1 and 2 of Cohorts 1 and 2.
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
Decided to 
evaluate vital 
signs in more 
detail in Healthy 
adult Supplement 
Cohort and 
Healthy Elderly 
Supplement 
Cohort based on 
the result of 
Cohort 2 Dose 
Level 6 of Part 1
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy (Amendment 1→Amendment 2)
14 / 14
Page Edited
(3rd version)
Existing Text
Amendment 1: 22 Jan 2018
Revised Text
Amendment 2: 06 Mar 2018
Rationale for 
Amendment
Page
Item
p.102
Appendix C 
Acceptable 
Time 
Windows for 
Study 
Procedur
The total blood volume (rough estimate) to be collected from each subject 
is shown below.
･･･
Part 1 (Cohort 3-4 and Healthy Adult Supplement Cohort)
The total blood volume (rough estimate) to be collected from each subject 
is shown below.
･･･
Part 1 (Cohort 3-4, Healthy Adult Supplement Cohort and Healthy Elderly 
Supplement Cohort)
Judged to be 
possible to 
investigate at 
higher dose and 
changed 
maximum dose 
based on the result 
of Cohort 2 Dose 
Level 6 of Part 1.
Along with the 
above, It was 
enabled to 
investigate in 
healthy elderly at 
higher dose.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
1 / 18
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(2nd version)
Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
Page
Item
p.9
1.0 STUDY 
SUMMARY
Trial Design:
(2) Part 2
･･･
In Cohorts 5 and 6, 4 subjects each will be enrolled, and to give them 
TAK-925 or placebo will be intravenously infused for 9 hours on Day 1 
and Day 2.
Trial Design:
(2) Part 2
･･･
In Cohorts 5 and 6, 4 subjects each will be enrolled, and TAK-925 or 
placebo will be intravenously infused for 9 hours on Day 1 and Day 3.
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
p.10
1.0 STUDY 
SUMMARY
Dose Levels:
･･･
(2) Part 2
A single dose of TAK-925 or placebo will be administered intravenously 
for 9 hours on Day 2 alternately.
If placebo is given on Day 1, TAK-925 is to be given on Day 2. If 
TAK-925 is given on Day 1, placebo is to be given on Day 2.
Dose Levels:
･･･
(2) Part 2
A single dose of TAK-925 or placebo will be administered intravenously 
for 9 hours on Day 1 and Day 3 alternately.
If placebo is given on Day 1, TAK-925 is to be given on Day 3. If 
TAK-925 is given on Day 1, placebo is to be given on Day 3.
p.10
1.0 STUDY 
SUMMARY
Duration of Treatment:
･･･
(2) Part 2
A single administration on Day 1 and Day 2 for each cohort (TAK-925 
will be given only once)
Duration of Treatment:
･･･
(2) Part 2
A single administration on Day 1 and Day 3 for each cohort (TAK-925 
will be given only once)
p.11
1.0 STUDY 
SUMMARY
Planned Trial Duration:
･･･
(2) Part 2
Screening period: Days -42 to -2
Admission day: Day -1
Crossover period: Day 1 to 3
Planned Trial Duration:
･･･
(2) Part 2
Screening period: Days -42 to -2
Admission day: Day -1
Crossover period: Day 1 to 4
p.12
1.0 STUDY 
SUMMARY
Main Criteria for Exclusion:
Healthy Adults (Cohort 4 only)
･･･
• A subject who has clinically significant spinal deformities (scoliosis or 
kyphosis), which, in the opinion of the investigator, may interfere with 
lumbar puncture.
Main Criteria for Exclusion:
Healthy Adults (Cohort 4 only)
･･･
• A subject who has clinically significant vertebral deformities (scoliosis 
or kyphosis), which, in the opinion of the investigator, may interfere with 
lumbar puncture.
Correction of 
errors
p.14
2.0 STUDY 
SCHEMATIC
Figure 2.a Summary of the Study Design
＜Part 2＞
･･･
3) Cohorts 5 and 6 consist of 4 subjects, each respectively. 2 subjects each 
in a group will be randomized to each sequence. On Days 1 and 2, 
TAK-925 or placebo will be administered intravenously to these 
subjects for 9 hours.
Cohort 7 consists of a maximum of 12 subjects, and 6 subjects each at 
maximum in a group will receive TAK-925 or placebo intravenously for 
9 hours on Days 1 and 2, TAK-925 or placebo will be administered 
intravenously to these subjects for 9 hours.
Figure 2.a Summary of the Study Design
＜Part 2＞
･･･
3) Cohorts 5 and 6 consist of 4 subjects, each respectively. 2 subjects each 
in a group will be randomized to each sequence. On Days 1 and 3, 
TAK-925 or placebo will be administered intravenously to these 
subjects for 9 hours.
Cohort 7 consists of a maximum of 12 subjects, and 6 subjects each at 
maximum in a group will receive TAK-925 or placebo intravenously for 
9 hours on Days 1 and 3, TAK-925 or placebo will be administered 
intravenously to these subjects for 9 hours.
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
2 / 18
Page Edited
(2nd version)
Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
Page
Item
p.16
3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part1(Cohorts 1-4 and Healthy Adult Supplement Cohort)
･･･
(f) Blood samples for TAK-925 PK analysis will be collected: Predose, 
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 9 hours after the start of infusion, and 0.17, 
0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 15 hours after the end of infusion.
Part1(Cohorts 1-4 and Healthy Adult Supplement Cohort)
･･･
(f) Blood samples for TAK-925 PK analysis will be collected: Predose, 
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 9 hours after the start of infusion, and 0.17, 
0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours after the end of 
infusion. However, Dose Level 1 and 2 of Cohorts 1 and 2 will be
excluded at 10 hours after the end of infusion.
Added 
pharmacokinetic 
sample to 
evaluate 
pharmacokinetic 
more accurately 
based on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1.
p.18-19 3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
Screening 
Day -42 to 
Day-2
Day -1
Predose
Day 1, 2
Day 1, 2
Day 3/
Early
Termination
Follow-Up 
Visit (a)
Part 2 – Patients with Narcolepsy
Screening 
Day -42
to Day-2
Day -1
Predose
Day 1
Day 1
Day 2
Predose
Day 3
Day 3
Day 4/
Early
Termination
Follow-Up 
Visit (a)
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
p.18
3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
･･･
Clinical Procedures/Assessments
Day 1、2
 
Part 2 – Patients with Narcolepsy
･･･
Clinical Procedures/Assessments
Day 1
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
CCI
C
C
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
3 / 18
Page Edited
(2nd version)
Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
Page
Item
p.18
3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
･･･
Part 2 – Patients with Narcolepsy
･･･
Clinical Procedures/Assessments
Day 2
Predose
Day 3
Day 3
Full Physical Examination 
X
X
Height
Weight
X
BMI
Vital Signs (pulse rate, SBP and DBP) (f)
X
X
X
Vital Signs (respiratory rate, body 
temperature) (g)
X
X
X
12-Lead Electrocardiogram (h)
X
X
C-SSRS
TAK-925/Placebo Administration
X
MWT (Maintenance of Wakefulness Test) 
(i)
X
Adverse Events
Continuous Monitoring
Changed the
schedule due to 
the change 
washout period 
of Part 2.
p.19
3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
･･･
Laboratory 
test/Assessments
Predose
Day 1、2
Day 1、2
Hematology
X(m)
Urinalysis
X(m)
Serum Chemistry
X(m)
･･･
Blood Collection for 
Retained Samples and 
Pharmacogenomic 
Research
X(n)
Part 2 – Patients with Narcolepsy
･･･
Laboratory 
test/Assessments
Predose
Day 1
Day 1
Hematology
Urinalysis
Serum Chemistry
･･･
Blood Collection for 
Retained Samples and
Pharmacogenomic 
Research
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
4 / 18
Page Edited
(2nd version)
Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
Page
Item
p.19
3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
･･･
Part 2 – Patients with Narcolepsy
･･･
Laboratory test/Assessments
Day 2
Predose
Day 3
Day 3
Hematology
X(m)
X
Urinalysis
X(m)
X
Serum Chemistry
X(m)
X
Urine Drug Screen 
Hepatitis Screen, HIV Antigen-Antibody 
Detection Assay, Syphilis Serum Reaction 
Test
Blood Collection for Retained Samples and 
Pharmacogenomic Research
X(n)
Pregnancy Test(o)
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
p.19
3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
･･･
Laboratory test/Assessments
Day 3/Early Termination
Hematology
X
Urinalysis
X
Serum Chemistry
X
Part 2 – Patients with Narcolepsy
･･･
Laboratory test/Assessments
Day 4/Early Termination
Hematology
X(m)
Urinalysis
X(m)
Serum Chemistry
X(m)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
5 / 18
Page Edited
(2nd version)
Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
Page
Item
p.19-20 3.0
SCHEDULE 
OF STUDY 
PROCEDURES
Part 2 – Patients with Narcolepsy
･･･
(f) Vital signs (pulse rate, SBP and DBP) will be measured:
･･･
Days 1 and 2: Predose, 0.25, 0.5, 0.75, 1, 1.5,  2, 3, 4, 5, 6, 7, 8, 9, 10, 11 
and 12 hours after the start of the infusion. 
Day 2: 24 hours after the start of infusion
･･･
(g) Vital signs (respiratory rate, body temperature) will be measured
during the screening period, within 1 hour predose on Day 1, at 5 hours 
after the start of infusion on Day 1 and Day2, and Day 3. 
(h) 12-Lead ECG will be measured during the screening period, on Day 
-1, between 2 and 9 hours after the start of infusion on Day 1 and Day 2, 
and Day 3
(i) MWT procedure will be conducted: 
Day -1: MWT procedures will be completed by 17:00.
Day 1 and 2: MWT procedures will be conducted at 10:00, 12:00, 14:00 
and 16:00 following the start of infusion dosing at 7:45.
(j) 
 
ESS will be conducted on Day -1 only.
 
(k) 
 
(l)
 
(m) These tests will be conducted only before the start of infusion on Day 
2.
(n) Blood sampling will be performed only once for each subject after the 
start of infusion on Day 2.
･･･
(p) Blood samples for the PK evaluations of TAK-925 (and its 
metabolites) will be collected on Day 1, Day 2 and Day 3: Predose (Day 1 
only), 1, 2, 4, 6 and 9 hours after the start of infusion, and 0.17 0.5, 1, 2 
and 15 hours after end of infusion, and just before sleep.
Part 2 – Patients with Narcolepsy
･･･
(f) Vital signs (pulse rate, SBPc and DBP) will be measured:
･･･
Days 1 and 3: Predose, 0.25, 0.5, 0.75, 1, 1.5,  2, 3, 4, 5, 6, 7, 8, 9, 10, 11 
and 12 hours after the start of the infusion. 
Day 2 and Day 4: 24 hours after the start of infusion
･･･
(g) Vital signs (respiratory rate, body temperature) will be measured
during the screening period, within 1 hour predose on Day 1 and Day 3, at
5 hours after the start of infusion on Day 1 and Day 3, and at the same 
time period on Day 2 and Day 4.
(h) 12-Lead ECG will be measured during the screening period, on Day 
-1, between 2 and 9 hours after the start of infusion on Day 1 and Day 3, 
and at the same time of the dayperiod on Day 2 and Day 4.
(i) MWT procedures will be conducted: 
Day -1: MWT procedures will be completed by 17:00.
Day 1 and 3: MWT procedures will be conducted at 10:00, 12:00, 14:00 
and 16:00 following the start of infusion dosing at 7:45.
(j) 
 
ESS will be conducted on Day -1 only.
 
(k
 
(l)
 
(m) These tests will be conducted using the blood samples collected at the 
same timepoint on Day 2 and Day 4.
(n)Blood sampling will be performed only once for each subject after the 
start of infusion on Day 3.
･･･
(p) Blood samples for the PK evaluations of TAK-925 (and its 
metabolites) will be collected on Day 1, Day 2, Day 3 and Day 4: Predose, 
1, 2, 4, 6 and 9 hours after the start of infusion, and 0.17 0.5, 1, 2 and 15 
hours after end of infusion, just before sleep and right after wake-up.
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
6 / 18
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Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
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Item
p.24
5.2.3 Trial 
Exploratory 
Objectives
p.25
5.3.3
Exploratory 
Endpoints
p.27
6.1 Trial Design (2) Part 2
･･･
In Cohorts 5 and 6, 4 subjects each will be enrolled, and to be given 
TAK-925 will be intravenously infused for 9 hours on Day 1 and Day 2.
(2) Part 2
･･･
In Cohorts 5 and 6, 4 subjects each will be enrolled, and TAK-925 or 
placebo will be intravenously infused for 9 hours on Day 1 and Day 3.
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
p.30
6.1 Trial Design Figure 6.a Overview of the Trial Schedules
･･･
<Part 2>
Screening
Baseline
Treatment Period
Follow-up
Period
MWT
Study Drug 
Administration
/Sampling/MW
T/
Study Drug 
Administration 
/Sampling/MWT/
Sampling
Hospital 
Visit
Day -42--2*
Day -1
Day 1
Day 2
Day 3
Day 7
!∀∀∀∀∀∀∀∀∀Hospitalization Period
∀∀∀∀∀∀∀∀∀#
Figure 6.a Overview of the Trial Schedules
･･･
<Part 2>
Screening
Baseline
Crossover period
Follow-up
Period
MWT/
Study Drug 
Administration
/Sampling/M
WT
Sampling/
Study Drug 
Administration 
/Sampling/MWT/
Sampling
Hospital 
Visit
Day -42--2*
Day -1
Day 1
Day 2
Day 3
Day 4
Day 7
!∀∀∀∀∀∀∀∀∀Hospitalization Period
∀∀∀∀∀∀∀∀∀#
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
Clerical 
corrections
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
7 / 18
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Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
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p.30-31 6.2 Cohort 
transition / 
Dose Escalation
･･･The investigator will comprehensively investigate in a binded manner
the safety and tolerability (adverse events, physical examination findings, 
vital signs, laboratory tests and 12-lead ECG findings) and available PK
data of TAK-925 obtained in a blinded manner from the commencement 
of infusion at each Dose Level in Part 1 to 24 hours after the infusion 
(Day 2), or from the commencement of the final infusion at each Dose 
Level in Part 2 to 24 hours after the infusion (Day 3), and determine 
whether to proceed to the next dose level or next cohort after discussion(s) 
with the sponsor (and the medical expert, if necessary).･･･
･･･The investigator will comprehensively investigate in a binded manner
the safety and tolerability (adverse events, physical examination findings, 
vital signs, laboratory tests and 12-lead ECG findings) of each Dose Level 
in Part 1 obtained, by 24 hours after the start of infusion (Day 2), or those 
of each Cohort in Part 2 obtained by 24 hours after the start of final 
infusion (Day 4), as well as available PK data obtained so far, then
determine whether to proceed to the next dose level or next cohort after 
discussion(s) with the sponsor (and the medical expert, if necessary).
･･･
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
p.33
6.3.2 Rationale 
of Trial Design
(2) Part 2
･･･In each Cohort, the washout period to be set after the 2nd or subsequent 
infusions will be set 5 times the t1/2 of TAK-925.
(2) Part 2
･･･In each Cohort, the washout period to be set after the 2nd or subsequent 
infusions will be set 5 times the t1/2 of TAK-925, as a guide, which is 
considered not to affect the PD effect.
p.35
6.3.4.3 PD 
Endpoints
The PD endpoints will include MWT, 
 
･･･
The PD endpoints will include MWT, 
 
･･･
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
p.37
6.4 Trial 
Design/Dosing/
Procedures 
Modifications 
Permitted 
Within Protocol 
Parameters
• Prolongation of a washout period based on the safety and 
pharmacokinetic data obtained
• Prolongation of a washout period based on the safety and 
pharmacokinetic data obtained. (In Part 2, infusion on Day 3 is changed to 
Day 4)
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
8 / 18
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Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
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Item
p.37
6.4 Trial 
Design/Dosing/
Procedures
Modifications 
Permitted 
Within Protocol 
Parameters
･･･The total blood volume to be collected from a single subject will not 
exceed the maximum allowable volume (400 mL for subjects weighing 50 
kg or more and 200 mL for a subject weighing less than 50kg) during this 
trial.
The specified assessment time points of safety endpoints (eg, vital signs, 
ECG, laboratory tests) currently described in the protocol may be 
modified based on the newly obtained safety, tolerability, PK or 
PD/biomarker data (eg, to collect data at the time closer to the peak 
plasma concentrations achieved).･･･
･･･The total blood volume to be collected from a single subject will not 
exceed the maximum allowable volume (400 mL for subjects weighing 50 
kg or more and 200 mL for a subject weighing less than 50kg) during this 
trial.
The washout period between Period 1 and Period 2 in part 2 can be 
changed based on the newly obtained PK, safety and PD data. If this 
change occurs, the procedures and the schedule of study following
 
on the night on Day 2 will be shifted 1 day behind. (When the washout 
period is set to 2 days, refer to protocol Annex 3 in regard to the schedule, 
etc.)
The specified assessment time points of safety endpoints (eg, vital signs, 
ECG, laboratory tests) currently described in the protocol may be 
modified based on the newly obtained safety, tolerability, PK or 
PD/biomarker data (eg, to collect data at the time closer to the peak 
plasma concentrations achieved).･･･
In order to enable 
to change the 
washout period 
of Part 2 without 
amendment of 
the protocol 
based on further 
pharmacokinetic 
data.
p.41
7.1 Inclusion 
Criteria
All Subjects
･･･
5. A male subject who is nonsterilized and sexually active and has a 
female partner of childbearing potential agrees to use adequate 
contraception from the time of signing the consent form to 12 weeks (84 
days) after the last dose of study drug. A female partner of the male 
subject should also be advised to use adequate contraception (See 
Appendix B).
All Subjects
･･･
5. A male subject who is nonsterilized* and sexually active and has a 
female partner of childbearing potential agrees to use adequate 
contraception* from the time of signing the consent form to 12 weeks (84 
days) after the last dose of study drug. A female partner of the male 
subject should also be advised to use adequate contraception* (See 
Appendix B).
Clerical 
corrections
p.45
7.2 Exclusion 
Criteria
All Subjects
･･･
32.
A subject who has clinically significant spinal deformities (scoliosis 
or kyphosis) which, in the opinion of the investigators, may interfere with 
lumbar puncture.
All Subjects
･･･
32.
A subject who has clinically significant vertebral deformities 
(scoliosis or kyphosis) which, in the opinion of the investigators, may 
interfere with lumbar puncture.
Clerical 
corrections
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
9 / 18
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Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
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p.47
7.3 Excluded 
Medications, 
Supplements, 
Dietary 
Products
(2) Part 2
･･･Any drugs must not be used from the period shown in Table 7.b untill 
all tests planned on Day 3 have been completed.･･･
(2) Part 2
･･･Any drugs must not be used from the period shown in Table 7.b untill 
all tests planned on Day 4 have been completed.･･･
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2. Added a
new subject 
management 
regulation in the 
washout period.
p.50
7.4.2 Activity
･･･
･
 
･Subjects will follow the notes shown in the manual for 
pharmacodynamic tests 
MWT).
･･･
･
 
･Subjects will follow the notes shown in the manual for 
pharmacodynamic tests (
MWT).
･In the washout period between Period 1 and Period 2, subjects will be 
instructed and monitored as much as possible that time of each daytime 
nap should be within 30 minutes and the number of daytime nap should be 
up to 5 times so as not to disturb night time sleep.
p.50
7.5 Record of 
Discontinuation 
or Withdrawal 
of a Subject 
before Study 
Drug 
Administration
･･･
･Lost to follow-up.
･Voluntary withdrawal <specify reason>.
･･･
･･･
･Lost to follow-up.
･Pregnancy
･Voluntary withdrawal <specify reason>.
･･･
Due to omission
p.52-53 7.6 Criteria for 
Discontinuation 
or Withdrawal 
of a Subject
5. Voluntary withdrawal.
･･･
6. Termination of entire study by the sponsor.
･･･
7. Other
･･･
5. Pregnancy.
A subjects is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn 
immediately. The procedure is described in Appendix B
6. Voluntary withdrawal.
･･･
7. Termination of entire study by the sponsor.
･･･
8. Other
･･･
p.57
9.1.1.2 Study 
Drug 
Assignment
In Cohorts 1-3 and Healthy Adult Supplement Cohort, subjects in each 
cohort will be assigned to each cohort the study drug in order of the 
medication ID number according to the randomization schedule (See 
Figure 9.a, Figure 9.b and Figure 9.c). In Cohorts 5-7,,･･･.
The assigned medication ID number or subject ID number will to be･･･
In Cohorts 1-3 and Healthy Adult Supplement Cohort (if it will be added),
subjects in each cohort will be assigned to each cohort the study drug in 
order of the medication ID number according to the randomization
schedule (See Figure 9.a, Figure 9.b and Figure 9.c). In Cohort 4, eligible 
subjects will be assigned with the subject ID number. In Cohorts 5-7,･･･.
The assigned medication ID number or subject ID number will to be used 
by･･･
In order to clarify 
the regulation on 
Cohort 4.
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
10 / 18
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Existing Text
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Amendment 1: 22 Jan 2018
Rationale for 
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p.60
9.2.1 Full 
Physical Exam
･･･When a physical examination is performed on Day 2 and Day 3 in Part 
2,･･･.
･･･When a physical examination is performed on Day 2 and Day 4 in Part 
2,･･･.
Changed the 
washout period 
of Part 2 based 
on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1 and 
Cohort 2 Dose 
Level 2.
p.61
9.2.4 Columbia 
Suicide 
Severity Rating 
Scale (C-SSRS)
A risk of suicide will be assessed using the C-SSRS at time points 
specified in the Schedule of Study Procedures (On Day 2 in Part 1 and 
Day 3 in Part 2).
A risk of suicide will be assessed using the C-SSRS at time points 
specified in the Schedule of Study Procedures (On Day 2 in Part 1 and 
Day 4 in Part 2).
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
p.62
9.2.7 Study 
Drug 
Administration
The study drug will be intravenously administered to subjects over 9 hours 
on Day 1 in Part 1 and Day 1 and Day 2 in Part 2 (TAK-925 will be 
administered to each subject only once in Part 2).
The study drug will be intravenously administered to subjects over 9 hours 
on Day 1 in Part 1 and Day 1 and Day 3 in Part 2 (TAK-925 will be 
administered to each subject only once in Part 2).
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
p.66
9.3.1.1 Plasma 
Samples for PK 
Measurements
(1) Part 1
Table 9.b Collection of Blood Samples for Pharmacokinetic Analysis (Part 
1)
Blood sampling time
Before infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion, 
and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 15 hours after the end of infusion
(1) Part 1
Table 9.b Collection of Blood Samples for Pharmacokinetic Analysis (Part 
1)
Blood sampling time
Before infusion, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion, 
and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 101) and 15 hours after the end of 
infusion
1) Dose Level 1 and 2 of Cohorts 1 and 2 will be excluded at 10 hours after the end 
of infusion.
Added 
pharmacokinetic 
sample to 
evaluate 
pharmacokinetic 
more accurately 
based on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1.
p.67
9.3.1.1 Plasma 
Samples for PK 
Measurements
(2) Part 2
Table 9.c Collection of Blood Samples for Pharmacokinetic Analysis (Part 
2)
Analysis date
Blood sampling time
Day 1-3
Before infusion1, 2), 1, 22), 42), 62) and 92) hours after the 
start of infusion and 0.17, 0.5, 1, 22) and 152) hours after 
the end of infusion, and at bedtime2).
1) Since "before infusion" on Day 2 is the same time as "15 hours after the end of 
infusion" on Day 1, blood sampling is unnecessary.
2) Blood sampling will be 6 mL. For the other sampling times, 3 mL will be
collected.
(2) Part 2
Table 9.c Collection of Blood Samples for Pharmacokinetic Analysis (Part 
2)
Analysis date
Blood sampling time
Day 1-4
Before infusion1), 1, 21), 41), 61) and 91) hours after the start of 
infusion and 0.17, 0.5, 1, 21) and 151) hours after the end of 
infusion, at bedtime and right after1) wake-up.
1) Blood sampling will be 6 mL. For the other sampling times, 3 mL will be
collected.
Added 
pharmacokinetic 
sample to 
evaluate 
pharmacokinetic 
more accurately 
based on the 
pharmacokinetic 
data of Cohort 1 
Dose Level 1.
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
11 / 18
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Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
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p.67
9.3.1.1 Plasma 
Samples for PK 
Measurements
(2) Part 2
･･･
In the case that a subject prematurely discontinues the study between the 
time from the start of study drug administration to the completion of 
procedures on Day 2 in Part 1 and on Day 3 in Part 2,･･･
･･･
In the case of premature discontinuation during the period from Day 2 to 
the follow-up in Part 1, and during the period from Day 3 to the follow-up 
in Part 2,･･･
(2) Part 2
･･･
In the case that a subject prematurely discontinues the study between the 
time from the start of study drug administration to the completion of 
procedures on Day 2 in Part 1 and on Day 4 in Part 2,･･･
･･･
In the case of premature discontinuation during the period from Day 2 to 
the follow-up in Part 1, and during the period from Day 4 to the follow-up 
in Part 2,･･･
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
p.68
9.3.2.1
Maintenance of 
Wakefulness 
Test (MWT)
･･･The MWT will be conducted 4 times each (at 10:00, 12:00, 14:00 and 
16:00) on Day 1 and Day 2, respectively. For the MWT on Day -1, sleep 
latency will be recorded as much as possible. On Day 1 and Day 2, sleep 
latency will be recorded in each session. In addition, REM sleep latency 
(RL), the number of wakefulness/N1 to stage REM transitions, time in 
stage REM sleep without atonia will be recorded in each session.
See the manual for PD tests (
 MWT) for details.
･･･The MWT will be conducted 4 times each (at 10:00, 12:00, 14:00 and 
16:00) on Day 1 and Day 3, respectively. For the MWT on Day -1, sleep 
latency will be recorded as much as possible. On Day 1 and Day 3, sleep 
latency will be recorded in each session. In addition, REM sleep latency, 
the number of wakefulness/N1 to stage REM transitions, time in stage 
REM sleep without atonia will be recorded in each session.
As an exploratory evaluation, additional analysis using 
electroencephalogram data obtained by MWT may be performed after 
breaking the randomization code.
See the manual for PD tests (
 MWT) for details.
In order to 
investigate 
electroencephalo
gram data 
obtained by 
MWT as an 
exploratory 
evaluation.
p.68
9.3.2.2
 
 
p. 69
9.3.2.3
p.69
9.3.2.4
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
12 / 18
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(2nd version)
Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
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p.69
9.3.2.5
 
 
 
 
 
 
p.70
9.3.3.1 Blood 
Sample for 
DNA PGx 
Measurements
･･･
On Day 1 (Part 1) or Day 2 (Part 2), 5-mL of whole blood sample･･･
･･･
On Day 1 (Part 1) or Day 3 (Part 2), 5-mL of whole blood sample･･･
Changed the 
schedule due to 
the change 
washout period 
of Part 2.
p.70
9.3.4
Confinement
(2) Part 2
Subjects will be hospitalized in a hospital during the period from Day -1 
to Day 3 and discharged from the hospital if no clinically significant 
abnormalities were found at the physical examination and tests on Day 
3,･･･
(2) Part 2
Subjects will be hospitalized in a hospital during the period from Day -1 
to Day 4 and discharged from the hospital if no clinically significant 
abnormalities were found at the physical examination and tests on Day 
4,･･･
p.80
11.1.4 PD 
Analysis
(1) Endpoints and analysis methodologies
[Endpoints]
The average sleep latency in the MWT, sleep-related parameters in the 
MWT (sleep latency in each session, REM sleep latency, the number of 
wake/sleep stage 1(N1)-to-REM sleep transition, total time of REM sleep 
without atonia), sleep-related parameters in the 
 (wake time after 
sleep onset, the number of nocturnal awakenings, the number of arousal 
reactions, sleep latency, REM sleep latency, the number of REM sleep 
latency, wake/sleep stage 1(N1)-to-REM sleep transition, sleep-onset 
REM periods without atonia, apnea-hypopnea index, periodic limb 
movement arousal index in sleep, total sleep time, sleep efficiency, the 
incidence rate of each sleep stage), assessment of daytime sleepiness using 
the KSS, assessment by the 
 assessment of sleep-related symptoms 
of cataplexy and narcolepsy using a daily dairy for collecting cataplexy 
and sleep-related symptoms.
(1) Endpoints and analysis methodologies
[Endpoints]
The average sleep latency in the MWT, sleep-related parameters in the 
MWT (sleep latency in each session, REM sleep latency, the number of 
wake/sleep stage 1(N1)-to-REM sleep transition, total time of REM sleep 
without atonia), assessment of daytime sleepiness using the KSS, 
assessment by the 
 assessment of sleep-related symptoms of 
cataplexy and narcolepsy using a daily dairy for collecting cataplexy and 
sleep-related symptoms.
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
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Revised Text
Amendment 1: 22 Jan 2018
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p.98
Appendix C
p.99
Appendix C
p.99
Appendix C
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
14 / 18
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Existing Text
Original Version: 11 Sep 2017
Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
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p.99
Appendix C
p.99
Appendix C
p.99
p.99
Appendix C
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
15 / 18
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Existing Text
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Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
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p.99
p.99
p.99
Appendix C
p.100
Appendix C
p.100
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
16 / 18
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Existing Text
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Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
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p.100
Appendix C
p.100
Appendix C
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
17 / 18
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Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
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p.100
Appendix C
p.101
Appendix C
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Protocol No. TAK-925-1001
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult 
and Elderly Volunteers and Patients with Narcolepsy（Original Version→Amendment 1）
18 / 18
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(2nd version)
Existing Text
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Revised Text
Amendment 1: 22 Jan 2018
Rationale for 
Amendment
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SAP_001.pdf: 
 
 
Title: A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of a single dose of TAK-925 in Healthy Adult and Elderly 
Volunteers and Patients with Narcolepsy 
 
NCT Number: NCT03332784 
Statistical analysis plan Approve Date: 02-OCT-2018 
 
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: 
z 
Named persons or organizations associated with the study. 
z 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
z 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
z 
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-925-1001 
A First-in-Human, Two-Part Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of TAK-925 in Healthy Adult and Elderly 
Volunteers and Patients with Narcolepsy
Phase 1 TAK-925 Study in Healthy Adult and Elderly Volunteers and Patients with 
Narcolepsy 
Version: 2nd 
Date: 2 October 2018 
 
Prepared by: 
 
 
Based on: 
Protocol Version: Amendment  
Protocol Date: 6 March 2018 
 
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TAK-925-1001 
Page 2 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 
of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
TAK-925-1001 
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CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.1 
Approval Signatures ....................................................................................... 2 
2.0 
TABLE OF CONTENTS ...................................................................................... 3 
List of In-Text Tables ................................................................................................. 4 
List of In-Text Figures................................................................................................ 4 
3.0 
LIST OF ABBREVIATIONS ............................................................................... 5 
4.0 
OBJECTIVES ...................................................................................................... 7 
4.1 
Primary Objectives ......................................................................................... 7 
4.2 
Secondary Objectives...................................................................................... 7 
4.3 
Additional Objectives ..................................................................................... 7 
4.4 
Study Design .................................................................................................. 7 
5.0 
ANALYSIS ENDPOINTS .................................................................................. 12 
5.1.1
Primary Endpoint .................................................................................... 12 
5.1.2
Secondary Endpoints ............................................................................... 12 
5.1.3
Exploratory Endpoints ............................................................................ 12 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................ 13 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ........................................ 14 
7.1 
General Principles ......................................................................................... 14 
7.1.1
Study Definitions .................................................................................... 14 
7.1.2
Definition of Study Visit Windows ......................................................... 15 
7.2 
Analysis Sets ................................................................................................ 15 
7.3 
Disposition of Subjects ................................................................................. 16 
7.3.1
Study Information ................................................................................... 16 
7.3.2
Screen Failures........................................................................................ 16 
7.3.3
Subject Eligibility ................................................................................... 16 
7.3.4
Disposition of Subjects ........................................................................... 17 
7.3.5
Protocol Deviations and Analysis Sets .................................................... 19 
7.4 
Demographic and Other Baseline Characteristics .......................................... 22 
7.4.1
Cohort 1~2 .............................................................................................. 22 
7.4.2
Cohort S1~S2.......................................................................................... 23 
7.4.3
Cohort 3 .................................................................................................. 23 
7.4.4
Cohort 4 .................................................................................................. 23 
7.4.5
Cohort 5~7 .............................................................................................. 23 
7.5 
Medical History and Concurrent Medical Conditions .................................... 24 
7.5.1
Cohort 5~7 .............................................................................................. 24 
7.6 
Medication History and Concomitant Medications ........................................ 25 
7.6.1
Cohort 5~7 .............................................................................................. 25 
7.7 
Study Drug Exposure and Compliance .......................................................... 26 
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TAK-925-1001 
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Statistical Analysis Plan 2nd  
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CONFIDENTIAL 
7.7.1
Cohort 1~2 .............................................................................................. 26 
7.7.2
Cohort 5~7 .............................................................................................. 26 
7.8 
Efficacy Analysis .......................................................................................... 26 
7.8.1
Primary Efficacy Endpoint(s) .................................................................. 26 
7.8.2
Secondary Efficacy Endpoint(s).............................................................. 26
7.8.3
Additional Efficacy Endpoint(s) .............................................................. 26 
7.8.4
Statistical/Analytical Issues ..................................................................... 26 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis ............................................... 28 
7.9.1
Pharmacokinetic Analysis ....................................................................... 28 
7.9.2
Pharmacodynamic Analysis .................................................................... 36
7.10 
Other Outcomes ............................................................................................ 38 
7.10.1 Scatter Plot for PK Concentration and Change from Time-matched 
Baseline in Vital Signs Parameters .......................................................... 38 
7.11 
Safety Analysis ............................................................................................. 40 
7.11.1 Adverse Events ....................................................................................... 40 
7.11.2 Clinical Laboratory Evaluations .............................................................. 44 
7.11.3 Vital Signs and Weight ........................................................................... 48 
7.11.4 12-Lead ECGs ........................................................................................ 53 
7.11.5 Other Observations Related to Safety ...................................................... 54 
7.12 
Interim Analysis ........................................................................................... 55 
7.13 
Changes in the Statistical Analysis Plan ........................................................ 55 
8.0 
REFERENCES ................................................................................................... 56 
LIST OF IN-TEXT TABLES 
Table 4.a  Summary of Cohorts ...................................................................................... 10 
LIST OF IN-TEXT FIGURES 
Figure 4.a  Summary of Cohort 1 and Cohort 2 .............................................................. 11 
Figure 4.b  Summary of Cohort 3 and Cohort R1 (Healthy Elderly Supplement Cohort). 11 
Figure 4.c  Summary of Cohort S1~S4 (Healthy Adult Supplement Cohorts) ................. 11 
Figure 4.d  Summary of Cohort 5~7 ............................................................................... 11 
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TAK-925-1001 
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Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
Ae 
amount of drug excreted in urine 
ALT
alanine aminotransferase
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI
body mass index
CL R 
renal clearance 
Cmax 
maximum observed concentration 
CRF 
case report form 
CSF 
cerebrospinal fluid 
ECG 
electrocardiogram 
ESS 
epworth sleepiness scale 
fe 
fraction of administered dose of drug excreted in urine 
Ȗ-GTP 
gamma-glutamyl transferase 
KSS 
karolinska sleepiness scale 
LDH
lactate dehydrogenase 
Lambda z 
terminal disposition phase rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MWT 
maintenance of wakefulness test 
PD 
pharmacodynamics 
PK
pharmacokinetics
 
 
 
 
QTc 
corrected QT 
RBC 
red blood cell 
REM
rapid eye movement 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE
treatment-emergent adverse event 
tmax
time of first occurrence of Cmax
t1/2z 
half-life period 
ULN
upper limit of normal 
Vz 
volume of distribution 
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TAK-925-1001 
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Statistical Analysis Plan 2nd  
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CONFIDENTIAL 
WBC 
white blood cell 
WHO Drug 
World Health Organization Drug Dictionary 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
TAK-925-1001 
Page 7 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
4.0 
OBJECTIVES 
4.1 
Primary Objectives 
z 
To evaluate the safety and tolerability of TAK-925 when a single dose of TAK-925 is 
administered to healthy adults, the healthy elderly and patients with type 1 narcolepsy. 
z 
To evaluate the PK of TAK-925 when a single dose of TAK-925 is administered to 
healthy adults, the healthy elderly and patients with type 1 narcolepsy. 
4.2 
Secondary Objectives 
z 
To evaluate the PD effects of TAK-925 (mainly, sleep latency in the MWT) when a 
single dose of TAK-925 is administered to patients with type 1 narcolepsy. 
4.3 
Additional Objectives 
4.4 
Study Design 
This study consists of two parts. 
Part 1 is an alternating panel, randomized, double-blind, placebo-controlled, crossover study 
to assess the safety, tolerability and pharmacokinetics (PK) of a single rising dose of TAK-
925 in healthy adult and elderly volunteers. In Part 1, the safety and tolerability, and the PK 
including the concentration in the cerebrospinal fluid (CSF) at a single dose of TAK-925 in 
healthy adult volunteers will be also evaluated in an open cohort. 
Part 2 is a sequential panel, randomized, double-blind (unblinded for the sponsor), placebo-
controlled, 2-period crossover study to assess the safety, tolerability, PK and PD of one or 
more dose levels of TAK-925 vs. placebo in patients with type 1 narcolepsy. 
(1) Part 1 
Part 1 of the study will enroll 16 healthy adults into two separate cohorts of 8 subjects each, 
Cohort 1 and Cohort 2. In Cohort 3, 8 healthy elderly will be enrolled. In Cohorts 1 and 2 
consisting of 8 subjects each, 6 subjects will receive TAK-925 and 2 subjects will receive 
placebo, assigned randomly in each dosing period (each period is composed of a single dose 
level),and 2 subjects each in Cohorts 1 and 2 will be randomly assigned to Groups A to H. To 
assess the safety, tolerability, and PK of TAK-925 including CSF-PK of TAK-925, 4 healthy 
adults will be enrolled as Cohort 4. 
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TAK-925-1001 
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Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Administration of the study drug in Cohorts 1 and 2 will be performed alternately, with at 
least a 3-day interval between the cohorts and with a 7-day interval as well as more than 5 
times the terminal half-life (t1/2) of TAK-925 within the same cohort. Each subject will be 
given the study drug a maximum of three times. 
The first dose level cohort (Cohort 1, Dose Level 1) is designed to obtain the safety and 
tolerability information when a single dose of TAK-925 is administered as well as to obtain 
the information on pharmacokinetic parameters that will determine the dosing regimen 
(infusion rate) and doses in the subsequent periods in Part 1. For example, if the time required 
to achieve a steady state at a constant intravenous infusion rate is too long, if and the initial 
dose is safe and well tolerated, the infusion rate for the first 2 hours may be accelerated to 
achieve a steady state earlier in the subsequent periods. In Cohort 1 Dose Level 1, a small 
number of subjects will be given the study drug first as a sentinel group. One subject each in 
the sentinel group (two subjects) will receive either TAK-925 or placebo first prior to the 
remaining six subjects and those remaining 6 subjects will be dosed at least two hours after 
the sentinel group was dosed. In Cohort 2 Dose Level 2 and subsequent dose levels in 
Cohorts 1 and 2, Cohort 3, Healthy Adult Supplemental Cohort and Healthy Elderly 
Supplement Cohort (in the event that the cohort is actually added) receive TAK-925 or 
placebo simultaneously. (such that 4 subjects will be dosed at first, and if there are no safety 
issues, the remaining 4 subjects may be dosed about 1 hour later.) 
Doses following Cohort 1 Dose Level 1 will be determined depending on the safety, 
tolerability and available PK of previous doses. After evaluating the safety, tolerability and 
PK in Cohort 1 Dose Level 1, dosing in Cohort 2 Dose Level 2 will be commenced. After 
evaluating the safety, tolerability and PK in Cohort 2 Dose Level 2, dosing in Cohort 1 Dose 
Level 3 will be commenced. After evaluation the safety, tolerability and available PK in 
Cohort 1 Dose Level 3, dosing in Cohort 2 Dose Level 4 will be commenced. In a similar 
fashion, dosing in Cohort 1 Dose Level 5 and Cohort 2 Dose Level 6 in a similar fashion. Not 
all the Cohorts should be run necessarily, and the dose may be higher or lower than or the 
same to that of prior cohort dose levels, or intermediate dose between two prior doses.
In the event that further investigation on the safety, tolerability and PK is needed after 
completion of Cohort 2 Dose Level 6, Healthy Adult Supplement Cohorts that will include 8 
healthy adults per cohort (up to 4 additional cohorts that include 32 healthy adults) may be 
commenced without amendment of the protocol. The cohort names of S1 to S4 will be 
assigned for Healthy Adult Supplement Cohort. Six subjects will be randomly assigned to the 
TAK-925 group and 2 subjects to the placebo group in a cohort, to evaluate the safety, 
tolerability and PK. In Healthy Adult Supplement Cohort, the dose may be higher or lower 
than or the same to that of prior cohort dose levels, or an intermediate between two prior 
doses. 
In Cohort 3, 8 healthy elderly subjects will be enrolled. Of these 8 subjects, six will be 
randomly assigned to the TAK-925 group and 2 to the placebo group. This cohort will be 
initiated after started with the dose of which the safety and tolerability has been established in 
healthy adults. In the event that further investigation on the safety, tolerability and PK is 
needed after completion of Cohort 3, a maximum of 1 additional cohort for Healthy Elderly 
Supplement Cohort that enrolls 8 healthy elderly per cohort will be commenced without 
amendment of the protocol. The cohort name of R1 will be assigned for the Healthy Elderly 
Supplement Cohort. Six subjects will be randomly assigned to the TAK-925 group and 2 
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TAK-925-1001 
Page 9 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
subjects to the placebo group, to evaluate the safety, tolerability and PK. In Healthy Elderly 
Supplement Cohort, the dose may be higher or lower than or the same to that of prior cohort 
dose levels, or an intermediate dose between two prior doses. 
In Cohort 4, 4 healthy adults will be enrolled to evaluate the safety, tolerability and the CSF 
concentration of TAK-925 measured at one time point and the plasma concentration of TAK-
925. In Cohort 4, subjects, study sites and the sponsor will not be blinded. This cohort will be 
initiated after the safety and tolerability of the dose to be evaluated in Cohort 4 has been 
established in healthy adults. 
Cohort 3, Healthy Elderly Supplement Cohort and Cohort 4 may be started at the discretion 
of the sponsor, considering the status of Cohorts 1, 2 and Healthy Adult Supplement Cohort. 
(Cohorts 3 and 4 may be implemented in parallel with Cohorts 1 and 2. The doses to be used 
in Cohorts 3 and 4 will be determined based on the available safety, tolerability and PK data, 
and nonclinical study results.) 
(2) Part 2  
In Part 2, patients with type 1 narcolepsy will be enrolled in three cohorts: Cohorts 5 to 7. 
Part 2 is a 2-period crossover study to assess the safety, tolerability, PK and PD effects of a 
single dose of TAK-925. Part 2 may begin prior to the completion of Part 1. However, the 
dose to be used in Cohort 5 should be lower than the one used in Part 1 as well as be lower 
than 1/3 of the maximum dose of TAK-925 of which the safety and tolerability has been 
already confirmed. If Cohort 3 is not completed prior to starting Part 2, subjects aged 56 
years or older should not be enrolled in Cohorts 5, 6 and 7 until Cohort 3 is completed. 
In Cohorts 5 and 6, 4 subjects each will be enrolled, and TAK-925 or placebo will be 
intravenously infused for 9 hours on Day 1 and Day 3. Of 4 subjects in each cohort, 2 
subjects each will be randomly assigned to one of the defined sequences (Groups I to L, 
TAK-925 may be given at one dose level in each cohort). A maximum of 12 patients with 
type 1 narcolepsy will be enrolled in Cohort 7. Of a maximum of 12 patients, 6 each will be 
randomly assigned to Group M or Group N. The dose level to be used in Cohort 5 will be 
determined based on the safety, tolerability and PK data obtained from Part 1. After the 
safety, tolerability, PD effects (MWT) in Cohort 5 and available PK have been investigated, 
dosing in Cohort 6 will be started using another 4 new subjects. The same trial design as 
Cohort 5 will be used in Cohort 6. The dose level to be used in Cohort 6 will be discussed by 
the sponsor's unblinded team. The sponsor's unblinded team must not directly be involved in 
the execution of the study at a study site or directly contact the site. This team will review 
unblinded data on the safety, tolerability, PD effects (MWT) and available PK of TAK-925, 
and recommend a dose based on those data. The dose level to be used in Cohort 6 may be 
higher or lower than the one used in Cohort 5. Cohort 7 will be composed of up to 12 
subjects. The dose and the number of subjects to be used in Cohort 7 will be recommended 
by the sponsor’s unblinded team on the basis of safety, tolerability, PD effects (MWT) 
obtained from Cohorts 5 and 6 and available PK data of TAK-925. The dose may be higher 
or lower than the doses used in Cohorts 5 and 6, or intermediate dose between these cohorts. 
See section 3.0 in the Protocol for the schedule of tests/observations /evaluations. Summary 
of Cohorts is shown in Table 4.a. 
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TAK-925-1001 
Page 10 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Table 4.a  Summary of Cohorts 
Part 
Cohort 
Subjects 
Sample Size 
Study Design 
Dosage 
Randomization 
11) 
12) 
Healthy adults 
n=8 
Double-blind, 
Cross-over 
TAK-925 7 mg 
(Dose Level 1) 
or placebo 
Each Cohort 
TAK-925: 6 subjects, 
Placebo: 2 subjects 
2 
TAK-925 14 mg 
(Dose Level 2) 
or placebo 
1 
TAK-925 28 mg 
(Dose Level 3) 
or placebo 
2 
TAK-925 56 mg 
(Dose Level 4) 
or placebo 
1 
TAK-925 112 mg 
(Dose Level 5) 
or placebo 
2 
TAK-925 134.4 mg 
(Dose Level 6) 
or placebo 
S1 – S43) 
Healthy adults 
n=8 
Double-blind,  
parallel group 
TAK-925 TBD mg 
(Dose Level 7-10)3) 
or placebo 
3 
Healthy elderly 
n=8 
Double-blind,  
parallel group 
TAK-925 112 mg 
or placebo 
4 
Healthy adults 
n=4 
Unblinded 
TAK-925 112 mg 
TAK-925: 4 subjects 
R14) 
Healthy elderly 
n=8 
Double-blind,  
parallel group 
TAK-925 TBD mg 
or placebo 
TAK-925: 6 subjects, 
Placebo: 2 subjects 
21) 
5 
Patients with type 1 
narcolepsy 
n=4 
Double-blind 
(unblinded for the sponsor) 
2 x 2 Cross-over 
TAK-925 TBD5) mg 
or placebo 
Each period 
TAK-925: 2 subjects, 
Placebo: 2 subjects 
6 
Patients with type 1 
narcolepsy 
n=4 
Double-blind 
(unblinded for the sponsor) 
2 x 2 Cross-over 
TAK-925 TBD mg 
or placebo 
7 
Patients with type 1 
narcolepsy 
n=12 
Double-blind 
(unblinded for the sponsor) 
2 x 2 Cross-over 
TAK-925 TBD mg 
or placebo 
Each period
TAK-925: max. 6 subjects, 
Placebo: max. 6 subjects 
1) 
In Part 1, Dose Levels 1, 3 and 5 will be tested in the same set of subjects, and similarly, Dose Levels 2, 4 and 6 will be 
evaluated in the different set of the same subjects. In Part 2, different subjects will be used in each Cohort. 
2) 
In Cohort 1 Dose Level 1, 2 subjects will be enrolled and one subject each will be assigned randomly to either the 
TAK-925 or placebo group to evaluate the safety and tolerability of TAK-925. Once the safety and tolerability of these 
two subjects is evaluated, additional 6 subjects will be enrolled and 5 subjects and 1 subject of the 6 subjects will be 
assigned randomly to the TAK-925 and placebo groups, respectively, to evaluate the safety and tolerability of TAK-
925. 
3) 
In the event that further investigation on the safety, tolerability and PK of TAK-925 is needed after completion of 
Cohorts 1 and 2, up to 4 additional cohorts that include 32 healthy adults can be commenced without amendment of the 
protocol. The Dose Levels 7-10 are planned as follows. However based on the available safety, tolerability and PK data, 
there is a possibility that the dose may be appropriately increased or decreased within the range not exceeding 420 mg. 
Dose Level 7: 180 mg, Dose Level 8: 240 mg, Dose Level 9: 320 mg, Dose Level 10: 420 mg. 
4) 
In the event that further investigation on the safety, tolerability and PK of TAK-925 is needed after completion of 
Cohort 3, up to 1 additional cohort that include 8 healthy elderly can be commenced without amendment of the 
protocol. 
5) 
In Part 2, the dose level to be used in Cohort 5 should be equal or lower than one-third of the maximum dose of TAK-
925 of which the safety and tolerability has been already confirmed in Part 1. 
 
Dose Level 1 
 
Dose Level 2 
 
Dose Level 3 
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E 
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TAK-925 28 mg 
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-9
la
Terms of Use


 
TAK-925-1001 
Page 11 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
C 
TAK-925 7 mg 
 
G 
TAK-925 14 mg 
 
C 
Placebo 
D 
Placebo 
 
H 
Placebo 
 
D 
TAK-925 28 mg 
 
Dose Level 4 
 
Dose Level 5 
 
Dose Level 6 
 
E 
TAK-925 56 mg 
 
A 
TAK-925 112 mg 
 
E 
TAK-925 134.4 mg 
ń 
F 
TAK-925 56 mg 
ń 
B 
Placebo 
ń 
F 
Placebo 
G
Placebo
C
TAK-925 112 mg
G
TAK-925 134.4 mg
 
H 
TAK-925 56 mg 
 
D 
TAK-925 112 mg 
 
H 
TAK-925 134.4 mg 
1) 
Double-blind, crossover study. Each Cohort consists of 8 subjects, and each group consists of 2 subjects. Dose Levels 1, 
3 and 5 will be investigated in the same subjects (Groups A-D in Cohort 1). Similarly, Dose Levels 2, 4 and 6 will be 
investigated in the other same subjects (Groups E-H in Cohort 2). 
2) At Dose Level 1, firstly 2 subjects will be enrolled: one subject will be randomized to one of Groups A to C, and 
another subject to Group D. After confirming the safety and tolerability of TAK-925, 6 more subjects will be enrolled 2 
hours after the start of infusion, and each of these subjects will be randomly assigned to one of Groups A to D, to 
evaluate the safety, tolerability and PK of TAK-925. Finally, two subjects each will be assigned to Groups A to D. The 
Doses after Dose Level 2 and subsequent doses will be determined based on the safety, tolerability and PK data 
obtained at previous dose levels. 
Figure 4.a  Summary of Cohort 1 and Cohort 2 
TAK-925 112 mg/TAK-925 TBD 
Placebo 
TBD: To be dterminied 
1) Double-blind study. Cohort 3 and Cohort R1 consists of 8 subjects each: 6 subjects in the TAK-925 group and 2 subjects in the placebo 
group. Dose of Cohort 3 will be 112 mg, dose of Cohort R1 to be determined. 
Figure 4.b  Summary of Cohort 3 and Cohort R1 (Healthy Elderly Supplement Cohort) 
TAK-925 TBD 
Placebo 
TBD: To be dterminied 
1) 
In the event that further investigation on the safety, tolerability and PK is needed after completion of Cohorts 1 and 2, 
up to 4 additional cohorts that include 32 healthy adults can be commenced without amendment of the protocol. 
2) 
Double-blind study. Each Cohort consists of 8 subjects: 6 subjects in the TAK-925 group and 2 subjects in the placebo 
group. 
3) 
The dose can be determined for each Cohort. 
Figure 4.c  Summary of Cohort S1~S4 (Healthy Adult Supplement Cohorts) 
Cohort 5 
 
Cohort 6 
 
Period 1 
Period 2 
Cohort 
transfer 
 
Period 1 
Period 2 
I 
TAK-925 TBD 
Placebo 
ĺ 
K 
TAK-925 TBD
Placebo 
J 
Placebo 
TAK-925 TBD 
 
L 
Placebo 
TAK-925 TBD 
Cohort 7 
Cohort 
transfer 
 
Period 1 
Period 2 
ĺ 
M 
TAK-925 TBD 
Placebo
N
Placebo
TAK-925 TBD
TBD: To be dterminied 
1) 
Double-blind (the sponsor is unblinded), 2x2 crossover study. 
2) 
Cohorts 5 and 6 consist of 4 subjects each. Two subjects each will be assigned to each group (Groups I-L). Cohort 7 
consists of a maximum of 12 subjects, and each group (Groups M and N) consists of a maximum 6 subjects. 
3) 
Each Cohort will be investigated in different subjects. 
Figure 4.d  Summary of Cohort 5~7 
of Takeda: 
aceb
ce
a:
Cohort
Cohort
tran
tran
For 
or
5 TBD
5 TBD
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of Use


 
TAK-925-1001 
Page 12 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
5.0 
ANALYSIS ENDPOINTS 
5.1.1
Primary Endpoint 
x Safety and tolerability: adverse events, vital signs, body weight, 12-lead 
electrocardiogram (ECG) and clinical laboratory tests (hematology, serum chemistry and 
urinalysis) 
x 
Pharmacokinetics (PK): plasma concentrations and pharmacokinetic parameters, urine 
pharmacokinetic parameters and cerebrospinal fluid (CSF) concentrations and 
pharmacokinetic parameters of TAK-925 and its metabolites (M-I and M-II).  
5.1.2 Secondary Endpoints 
x 
The average sleep latency in the MWT
5.1.3 Exploratory Endpoints 
CCI
of Takeda: For non-commercial 
al use only and 
ct 
subject to the applicable 
urine
urine
I)I).  . 
Terms of Use


 
TAK-925-1001 
Page 13 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
6.0 
DETERMINATION OF SAMPLE SIZE 
In Cohort 1-3 in Part 1, 8 subjects (6 in the TAK-925 group and 2 in the placebo group) was 
selected as the sample size to evaluate the safety, tolerability and PK of TAK-925 when a 
single dose of TAK-925 is administered intravenously to healthy adults and the healthy 
elderly. In the event that further investigation on the safety, tolerability and PK in healthy 
adults is needed after completion of Cohorts 1-2, a maximum of 4 additional cohorts (a total 
of 32 healthy adult subjects; 8 subjects [6 in TAK-925 group, 2 in placebo group] for each 
cohort) may be enrolled. If further investigation on the safety, tolerability and PK in healthy 
elderly is needed after completion of Cohort 3, a maximum of 1 additional cohort (a total of 8 
healthy elderly subjects [6 in TAK-925 group, 2 in placebo group] per cohort) may be 
enrolled. 
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, tolerability, PK s of 
TAK-925 including the concentration of TAK-925 in the CSF when a single dose of TAK-
925 is administered intravenously to healthy adults. 
For Part 2, 4 patients each in Cohort 5, 6 and a maximum of 12 patients in Cohort 7 will be 
enrolled to evaluate the safety, tolerability, PK and pharmacodynamic effects of TAK-925 
when a single dose of TAK-925 is administered to patients with type 1 narcolepsy. 
These sample sizes are not based on any effect size obtained by the MWT or statistical 
evidence. 
 
Property of Takeda: For non-commercial use only and 
en
e obtain
obtain
subject 
12 patie
12 pat
macodyna
codyn
nts with
ts wi
to 
a 
the
y, tole
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each
ach
n health
health
rt (a tota
rt (a tot
) may be
may b
rab
Terms 
otal 
otal 
h
of Use


 
TAK-925-1001 
Page 14 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1
Study Definitions 
The following definitions and calculation formulas will be used. 
x 
Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs 
on or after the start of study drug 
x 
Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to 
administration of study drug 
x 
Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles 
x 
Coefficient of variation (CV) (%): Standard deviation / mean * 100  
x 
QTcF interval (msec): QT interval (msec) / (RR interval (sec))0.33 (rounded to the nearest 
whole number) 
x 
Period for diagnosis (year): The value of age of onset subtracted from the value of age at 
date of informed consent 
x 
Change from time-matched baseline: Values of Day -1subtracted from values of Day 1 in 
the matching column in the table below for each subject 
Day 
Time postdose㸦hour㸧 
Day -1 -24 
-23.75 -23.5 -23.25 
-23 
-22.5 
-22 
-21.5 
-21 
-20.5 
-20 
-19 
-18 
-17 
-16 
-15 
-14 
-13 
-12 
0* 
Day 1 
0* 
0.25 
0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
7 
8 
9 
10 
11 
12 
24 
*㸸Just prior to dosing 
y 
Dose level
- 
Cohort 1~2 
 Placebo  
 TAK-925 7, 14, 28, 56, 112, 134.4 mg 
- 
Cohort S1~S2 
 Placebo  
 TAK-925 180, 240 mg 
- 
Cohort 3 
 Placebo 
 TAK-925 112 mg 
- 
Cohort 4 
 Placebo 
 TAK-925 112 mg 
- 
Cohort 5~7 
Property of Takeda: 

Coh
Coh
For
Place
lace
TA
T
non-commercial 
-22 
-22 
al
rc
1.5.5
rc
rc
rc
m rc
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and 
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subject
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an * 
val (sec)
al (se
to the 
on, m
on, m
applicable 
t oc
oc
investig
nvesti
rior to
or to
Terms 
cur
of Use


 
TAK-925-1001 
Page 15 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 Placebo 
 TAK-925 44.8, 11.2, 5 mg 
y 
Group 
- 
Part1 (Healthy Adults or The Healthy Elderly) 
 Cohort 1 and Cohort 2: See Figure 4.a 
 Cohort 3: TAK-925, Placebo 
 Cohort 4: TAK-925 
 Cohort S1~S2: TAK-925, Placebo 
- 
Part2 (Patients with Narcolepsy) 
 Cohort 5~7: See Figure 4.d 
7.1.2 Definition of Study Visit Windows 
For all variables, evaluable data will be used as entered in the CRF according to the 
scheduled Study Time. 
7.2 
Analysis Sets 
x 
Safety analysis set: All subjects who received at least one dose of study drug 
x 
Pharmacokinetic analysis set: All subjects who received at least one dose of study drug 
and whose plasma or CSF concentration can be measured at least once or whose 
cumulative urinary excretion can be calculated. 
x 
Pharmacodynamic analysis set: All subjects who received at least one dose of study drug. 
Property of Takeda: For non-commercial
an be
an be
s set:
set: A
use
jects
ect
ration 
ration 
c
only 
eived at 
ved a
s w
and subject 
n the CR
the CR
to the applicable Terms of Use


 
TAK-925-1001 
Page 16 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
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 Receive Study Drug 
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 
7.3.3.1 Cohort 1~2 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Study Drug Administration Status 
 
[Treated, Not Treated] 
 
Primary Reason for Subject Not 
Being Treated 
[Adverse Event, Death, Lost to 
Follow-up, Pregnancy, Protocol 
Deviation, Sample Size Sufficient, 
Screen Failure, Study Terminated by 
Sponsor, Withdrawal by Subject, 
Other] 
 
Property of Takeda: 
ysis Set
is Set
Analysis
nalysi
Vari
Vari
For 
hort 1
hort 1
non-commercial 
ures
res
distribu
stribu
inuous 
nuous 
Eligibi
ligibi
use only and 
e Study
tudy
subject 
les 
es 
to 
sect
sect
the applicable Terms of Use


 
TAK-925-1001 
Page 17 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
(1) Study Drug Administration Status 
Frequency distributions will be provided. When calculating percentages for 
the primary reasons for subject not being treated, the total number of not 
treated subjects will be used as the denominator. 
7.3.3.2 Cohort S1~S2 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 
S1~S2 
7.3.3.3 Cohort 3 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 3 
7.3.3.4 Cohort 4 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 4 
7.3.3.5 Cohort 5~7 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 5~7 
7.3.4
Disposition of Subjects 
7.3.4.1 Cohort 1~2 
Analysis Set: All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
 
Study Completion Status 
 
Property of 
7
Takeda: 
Se
Se
ytical
tical
Method
ethod
For 
rt 5
et:
et:
non-commercial 
Who Si
ho Si
ame ana
me an
5~7
~7
use only 
n 7.3.3.
7.3.3
and 
rmed C
med C
subject to 
me
the 
ed for
d for
applicable Terms of Use


 
TAK-925-1001 
Page 18 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
[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, Pregnancy, Protocol 
Deviation, Study Terminated by 
Sponsor, Withdrawal by Subject, 
Other] 
Analytical 
Method(s) : 
 
(1) Disposition of Subjects 
Frequency distributions will be provided by group and overall. 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. 
7.3.4.2 Cohort S1~S2 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort S1~S2 
7.3.4.3 Cohort 3 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort 3 
7.3.4.4 Cohort 4 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort 4 
Property of 
7
Takeda: 
al
od(s) :
) :
7.3.4
3
For non-commercial 
ysis as 
is as 
ll Subj
ubj
use 
d St
d S
only 
Study
tud
and subject 
contin
ontin
ned 
ed study
stud
to
p and 
and
the 
o
applicable 
by 
by 
Subject,
ubjec
Terms of Use


 
TAK-925-1001 
Page 19 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.3.4.5 Cohort 5~7 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort 5~7 
7.3.5
Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Cohort 1~2
Analysis Set: All Subjects Who Received Study Drug 
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 group and overall for each 
deviation category. 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. 
Cohort S1~S2 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort S1~S2 
Cohort 3 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
Property of Takeda: 
ytical
ical
Method
ethod(
For 
All
non-commercial
y. A su
. A su
appropr
propr
ssified 
sified
l S
use 
will b
will b
only and
med P
d P
al 
al Cri
Cri
subject 
Concom
oncom
Per P
Per
to the applicable Terms 
7
of Use


 
TAK-925-1001 
Page 20 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort 3 
Cohort 4 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort 4 
Cohort 5~7 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort 5~7 
Property of Takeda: For non-commercial use only 
3.5.1 
.5.1
and 
"C
subject to the applicable 
erformed
form
Terms of Use


 
TAK-925-1001 
Page 21 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.3.5.2 Analysis Sets 
Cohort 1~2 
Analysis Set: All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
 
Handling of Subjects 
 
[Categories are based on the 
specifications in Subject Evaluability 
List] 
 
Analysis Sets 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
(1) Subjects Excluded from Analysis Sets 
(2) Analysis Sets 
Frequency distributions will be provided by group and overall. 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. 
Cohort S1~S2 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort S1~S2 
Cohort 3 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort 3 
Property of
S
Takeda: 
rt 3
t 3
ed
Analy
Analy
For
Co
Co
non-commercial 
Who
ho R
he sam
e sam
ho
h
use 
am
am
only
fo
ect who
ct wh
me ca
me c
and 
ided 
ed 
or exc
r exc
subject 
by
by
to the applicable 
valuabili
aluabi
Terms of Use


 
TAK-925-1001 
Page 22 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Cohort 4 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort 4 
Cohort 5~7 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
 
Handling of Subjects 
 
[Categories are based on the 
specifications in Subject Evaluability 
List] 
 
Analysis Sets 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Pharmacodynamic Analysis Set 
 
[Included] 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort 5~7 
7.4
Demographic and Other Baseline Characteristics
7.4.1
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
 
 
Gender 
[Male, Female] 
 
Height (cm)
 
 
Weight (kg)
 
 
BMI (kg/m2) 
 
 
Smoking Classification
[Never, Current, Former] 
Property of
V
Takeda:
is Set
is Set
Analy
Analy
V
For
rt 1~2
rt 1~
non-commercial 
ysis as 
is as 
phic an
hic an
use 
isis S
nalys
nalys
only 
Setet
and
Lis
Li
subject 
egories a
gories 
pec
ecificat
ificat
st]
to the applicable Terms 
the
the
of Use


 
TAK-925-1001 
Page 23 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
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 group and overall. 
7.4.2
Cohort S1~S2 
Analysis 
Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analytical 
Method(s) : 
 
The same analysis as section 7.4.1 will be performed for the Cohort S1~S2 
7.4.3
Cohort 3
Analysis 
Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analytical 
Method(s) : 
 
The same analysis as section 7.4.1 will be performed for the Cohort 3 
7.4.4
Cohort 4 
Analysis 
Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analytical 
Method(s) : 
 
The same analysis as section 7.4.1 will be performed for the Cohort 4 
7.4.5
Cohort 5~7 
Analysis Set: Safety Analysis Set 
Pharmacokinetic Analysis Set 
Pharmacodynamic Analysis Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
[Min<= - <65, 65<= - <=Max]  
 
Gender 
[Male, Female] 
Property of Takeda: 
d(s) :
) :
7.4.5
7.4.5
For 
Ph
Ph
non-commercial 
sis as
s as se
se
fety An
ty A
harm
harm
use 
is Set
is Set
only and subject 
e perfor
perfor
to the applicable 
tistics
stics
Terms of Use


 
TAK-925-1001 
Page 24 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
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] 
 
MWT (sleep latency) 
 
 
ESS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age of onset (year) 
 
 
Period for diagnosis (year) 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 group and overall. 
7.5 
Medical History and Concurrent Medical Conditions 
7.5.1
Cohort 5~7 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medical History 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of Takeda: 
al
od(s(s) :
) :
For
or
or 
om
ommerc
ercialal
(y
al 
rcia
merc
omm
n-com
no
non-
n-
non
no
se
se 
use
ear
only 
ly 
only
o ly
onl
d
and
and
nd 
an
an
ect 
bjec
subj
s
to
to the 
th
ble 
cable
plica
app
a
Terms 
r
Ter
Ter
A 
Te
of Use


 
TAK-925-1001 
Page 25 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
Concurrent Medical Conditions 
Analytical 
Method(s) : 
 
(1) Medical History by System Organ Class and Preferred Term 
(2) Concurrent Medical Conditions by System Organ Class and Preferred 
Term 
Frequency distributions will be provided by group and overall. MedDRA 
dictionary will be used for coding. Summaries will be provided using SOC 
and PT, where SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency.  
A subject with multiple occurrences of medical history or concurrent 
medical condition within a SOC will be counted only once in that SOC. A 
subject with multiple occurrences of medical history or concurrent medical 
condition within a PT will be counted only once in that PT. 
7.6 
Medication History and Concomitant Medications 
7.6.1
Cohort 5~7 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medication History 
 
Concomitant Medications
Analytical 
Method(s) : 
 
(1) Medication History by Preferred Medication Name 
(2) Concomitant Medications That Started and Stopped Prior to Baseline 
by Preferred Medication Name 
(3) Concomitant Medications That Started Prior to and Were Ongoing at 
Baseline by Preferred Medication Name
(4) Concomitant Medications That Started After Baseline by Preferred 
Medication Name 
(5) Concomitant Medications That Started Prior to and Were Ongoing at  
Baseline as well as Those That Started After Baseline by Preferred 
Medication Name 
Frequency distributions will be provided by group and overall. WHO Drug 
dictionary will be used for coding. Summaries will be provided using 
preferred medication names and sorted in decreasing frequency based on the 
number of reports. A subject who has been administered several 
Property of Takeda: For 
(
non-commercial 
ory
ory
Medic
Medi
Medica
edica
2) Con
Con
use only and 
edicati
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subject 
history
stor
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once 
to
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DRA 
DRA
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Terms of Use


 
TAK-925-1001 
Page 26 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
medications with the same preferred medication name will be counted only 
once for that preferred medication name. 
7.7 
Study Drug Exposure and Compliance
7.7.1
Cohort 1~2  
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Number of Times the Study Drug was Taken 
 
[1, 2, 3] 
Analytical 
Method(s) : 
 
(1) Study Drug Exposure 
Frequency distributions will be provided by group. 
7.7.2
Cohort 5~7
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Number of Times the Study Drug was Taken 
 
[1, 2] 
Analytical 
Method(s) : 
 
(1) Study Drug Exposure 
Frequency distributions will be provided by group. 
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. 
Property of 
7
Takeda:
icabl
cab
2
Se
Se
Not ap
Not ap
For
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non-commercial
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and 
a
subject 
roup
up.
to the applicable Terms of Use


 
TAK-925-1001 
Page 27 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.8.4.2 Handling of Dropouts or Missing Data 
Missing test results will not be used for hypothesis testing and estimations.  
For plasma and CSF concentrations and laboratory test results, values below the lower limit 
of quantification will be treated as zero. For laboratory test results, values above the upper 
limit of quantification will be treated as the upper limit value. 
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. 
 
 
Property of Takeda: For non-commercial use only and subject 
alence or
lence o
to the applicable Terms of Use


 
TAK-925-1001 
Page 28 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1
Pharmacokinetic Analysis 
7.9.1.1 Plasma/CSF Concentrations 
Cohort 1~2 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Visit: 
Predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 Hours Postdose;  
0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 Hours after End of Infusion 
(10 Hours after End of Infusion is excluded for dose level 1 and 2 in Cohort 
1~2) 
Analytical 
Method(s) : 
 
The following summaries will be provided. Subjects administered placebo 
will be excluded from the analysis. 
 
(1) Summary of Plasma Concentrations by Visit by Dose Level 
Descriptive statistics will be provided by visit by dose level. 
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented by dose level. The 
vertical axis will be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable 
by dose level. 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 for each analysis variable by dose level. 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. 
Cohort S1~S2 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Property of Takeda: For non-commercial
me for 
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is will 
s will
and Sta
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 and 
Terms of Use


 
TAK-925-1001 
Page 29 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
The following summaries will be provided. Subjects administered placebo 
will be excluded from the analysis. The definition of the visit is the same as 
section 7.9.1.1 "Cohort 1~2". 
 
(1) Summary of Plasma Concentrations by Visit by Dose Level 
Descriptive statistics will be provided by visit by dose level. 
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented by dose level. The 
vertical axis will be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable 
by dose level. 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 for each analysis variable by dose level. 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. 
 
(5) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each dose level by each 
analysis variable, including the data of Cohort 1~2. 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. 
 
(6) Mean Plot of Plasma Concentrations 
Mean will be plotted for each dose level by each analysis variable, 
including the data of Cohort 1~2. 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.
Cohort 3 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Property of Takeda: For
(6
(6
non-c
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Terms of Use


 
TAK-925-1001 
Page 30 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
The following summaries will be provided. Subjects administered placebo 
will be excluded from the analysis. The definition of the visit is the same as 
section 7.9.1.1 "Cohort 1~2". 
 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided by visit.
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented. The vertical axis will 
be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable. 
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 for each analysis variable. 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. 
 
(5) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each dose level by each 
analysis variable, including the data of Cohort 1~2. 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. 
 
(6) Mean Plot of Plasma Concentrations 
Mean will be plotted for each dose level by each analysis variable, 
including the data of Cohort 1~2. 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.
Cohort 4 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
CSF Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Visit: 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Property of 
C
Takeda: For non-commercial 
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applicable 
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Terms of Use


 
TAK-925-1001 
Page 31 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 Hours Postdose;  
0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 Hours after End of 
Infusion
CSF Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
6 Hours Postdose 
Analytical 
Method(s): 
The following (1) ~ (6) summaries will be provided for the plasma 
concentrations of TAK-925 and its metabolites (M-I and M-II). 
The following (1) summary will be provided for the CSF 
concentrations of TAK-925 and its metabolites (M-I and M-II). 
 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided by visit.
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented. The vertical axis will 
be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable. 
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 for each analysis variable. 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. 
 
(5) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each dose level by each 
analysis variable, including the data of Cohort 1~2. 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. 
 
(6) Mean Plot of Plasma Concentrations 
Mean will be plotted for each dose level by each analysis variable, 
including the data of Cohort 1~2. 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.
Property of Takeda: For non-commercial 
of Plasm
f Plasm
will be p
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Terms of Use


 
TAK-925-1001 
Page 32 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Cohort 5~7 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Visit: 
Predose; 1, 2, 4, 6 and 9 Hours Postdose; 0.17, 0.5, and 2 Hours after End of 
Infusion; Bedtime; Wake up time; 15 Hours after End of Infusion 
Analytical 
Method(s) : 
 
The following summaries will be provided. Subjects administered placebo 
will be excluded from the analysis. 
 
(1) Summary of Plasma Concentrations by Visit by Dose Level 
Descriptive statistics will be provided by visit by dose level. 
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented by dose level. The 
vertical axis will be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable 
by dose level. 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 for each analysis variable by dose level. 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. 
 
(5) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each dose level by each 
analysis variable. 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. 
 
(6) Mean Plot of Plasma Concentrations 
Mean will be plotted for each dose level by each analysis variable. 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. 
Property of Takeda: For
(5
(5
non-commercial 
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of Plas
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will be p
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of Use


 
TAK-925-1001 
Page 33 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.9.1.2 Pharmacokinetic Parameters 
Cohort 1~2 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Pharmacokinetic Parameters of TAK-925 and Its Metabolites (M-I and M-
II) 
 
AUClast 
AUCinf 
Cmax 
 
Ceoi 
tmax 
t1/2z 
 
Vss (for TAK-925) 
Vz (for TAK-925) 
CL (for TAK-925) 
 
AUCinf D (for TAK-
925)
Cmax D (for TAK-925) AUC24 
 
MR (for M-I and M-
II) 
 
 
Analytical 
Method(s) : 
 
The following (1) summary will be provided for each analysis variables by 
dose level. The following (2) summary will be provided for AUCinf D and 
Cmax D. Subjects administered placebo will be excluded from the analysis. 
 
(1) Summary of Pharmacokinetic Parameters 
For AUClast, AUCinf, AUC24, Cmax and Ceoi, descriptive statistics, 
geometric mean, and CV will be provided. For tmax, descriptive 
statistics will be provided. For all other variables, descriptive statistics 
and CV will be provided. 
 
(2) Scatter Plot for each Analysis Variables and Dose Level, including the 
data of Cohort S1 and S2
Scatter plot for each analysis variables and dose Level, including the 
data of Cohort S1 and S2 will be provided. 
Cohort S1~S2 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.2 "Cohort 1~2" (1) will be conducted for 
the Cohort S1~S2. 
Property of 
A
Takeda: 
Cohor
Cohor
T
For non-commercial
 AUC
AUC
c mean
mean
ics
cs wil
wil
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CV 
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and 
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A
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(for
for
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AUC2
applicable 
d M
r TA
r TA
Terms 
M-
of Use


 
TAK-925-1001 
Page 34 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Cohort 3 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.2 "Cohort 1~2" (1) will be conducted for 
the Cohort 3. 
Cohort 4 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Pharmacokinetic and CSF Parameters of TAK-925 and Its Metabolites (M-I 
and M-II) 
 
AUClast 
AUCinf 
Cmax 
 
Ceoi 
tmax 
t1/2z 
 
Vss (for TAK-925) 
Vz (for TAK-925) 
CL (for TAK-925) 
 
R CSF/Plasma,SS 
AUCinf D (for TAK-
925) 
Cmax D (for TAK-925)  
 
AUC24 
MR (for M-I and M-II) 
 
Analytical 
Method(s) : 
 
The following summary will be provided by dose level. 
 
(1) Summary of Pharmacokinetic Parameters 
For AUClast, AUCinf, AUC24, Cmax and Ceoi, descriptive statistics, 
geometric mean, and CV will be provided. For tmax, descriptive 
statistics will be provided. For all other variables, descriptive statistics 
and CV will be provided. 
Cohort 5~7
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.2 "Cohort 1~2" (1) will be conducted for 
the Cohort 5~7. 
7.9.1.3 Urine Pharmacokinetic Parameter 
Cohort 1~2 
Analysis Set: Pharmacokinetic Analysis Set 
Property of 
M
Takeda: 
5~7
5~7
da
Analysi
Analysi
Ana
Ana
For non-commercial 
mmar
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TAK-925-1001 
Page 35 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
 
 
 
Analysis 
Variable(s) : 
 
Urine Pharmacokinetic Parameters of TAK-925 and its metabolites (M-I 
and M-II) 
 
Ae24 
fe24 
CL R 
Analytical 
Method(s) : 
 
The following summary will be provided by dose level. Subjects 
administered placebo will be excluded from the analysis. 
 
(2) Summary of Urine Pharmacokinetic Parameter 
Descriptive statistics and CV will be provided. 
Cohort S1~S2 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.3 "Cohort 1~2" will be conducted for the 
Cohort S1~S2. 
Cohort 3 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.3 "Cohort 1~2" will be conducted for the 
Cohort 3. 
Cohort 4 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.3 "Cohort 1~2" will be conducted for the 
Cohort 4. 
 
Property of Takeda:
is Set
is Set
alytical
alytica
Metho
Metho
For non-commercial 
c Anal
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ort 3.
use only and 
.3 3 "C
"C
subject to the applicable Terms of Use


 
TAK-925-1001 
Page 36 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.9.2
Pharmacodynamic Analysis 
7.9.2.1 Average Sleep Latency in MWT/Sleep Related Parameters in MWT 
Cohort 5~7 
Analysis Set: Pharmacodynamic Analysis Set 
Analysis 
Variable(s): 
 
Average Sleep Latency in MWT, 
 
 
 
Visit: 
: 
10㸸00, 12㸸00, 14㸸00, 16㸸00 
Analytical 
Method(s): 
 
The following summaries will be provided. 
 
(1) For the average sleep latency in MWT, descriptive statistics for the 
observed values will be provided by dose level. An analysis of variance 
(ANOVA) for crossover design with the observed value as a response, 
the dose level, the group and the period as factors, the subject as a 
random effect will be conducted. Least square (LS) means, the standard 
errors, and the two-sided 90% and 95% confidence intervals will be 
provided for each dose level. The difference in the LS means between 
each dose level of TAK-925 and the placebo (each dose level of TAK-
925 - the placebo), the standard error of the difference, and the two-
sided confidence intervals and p-value will be provided. Bayesian 
posterior probabilities that the mean differences are greater than the 
values (3, 4, 5 and 6 minutes) will be provided based on the Bayesian 
posterior distributions for the mean differences between each dose level 
of TAK-925 and the placebo (each dose level of TAK-925 - the 
placebo).   
 
(2) For analysis variables other than the average sleep latency in MWT, 
descriptive statistics of the observed values will be provided for each 
dose level by visit. An ANOVA for crossover design with the observed 
value as a response, the dose level, the group and the period as factors, 
the subject as a random effect will be conducted by visit. LS means, the 
standard errors, and the two-sided 90% and 95% confidence intervals 
will be provided for each dose level by visit. The difference in the LS 
means between each dose level of TAK-925 and the placebo (each dose 
CCI
CCI
Property of Takeda: For non-commercial 
wo
wo
r each 
each 
se leve
e leve
- the p
the p
ided c
ed c
pos
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p and th
 and th
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and
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n w
n w
subject 
d.
WT, de
WT, d
to the applicable 
cable
pplica
Terms of Use


 
TAK-925-1001 
Page 37 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
level of TAK-925 - the placebo), the standard error of the difference, 
and the two-sided confidence intervals and p-value will be provided for 
each dose level by visit.
7.9.2.2 
 
7.9.2.3 
 
CCI
CCI
CCI
CCI
Property of 
keda: 
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Take
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For non-commercial use only and subject to the 
able 
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Terms of Use


 
TAK-925-1001 
Page 38 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.9.2.4 
 
7.10 
Other Outcomes 
7.10.1 Scatter Plot for PK Concentration and Change from Time-matched Baseline in 
Vital Signs Parameters 
7.10.1.1 Cohort1~2, S1~S2 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Plasma Concentrations of TAK-925 
Change from time-matched baseline in Pulse Rate, Systolic Blood Pressure 
in Sitting, and Diastolic Blood Pressure in Sitting 
Visit: 
Predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 9, 10, 11, 12 and 24 Hours Postdose 
Analytical 
Method(s): 
 
The following summary will be provided. 
 
(1) Scatter Plot for PK Concentration and Change from Time-matched 
Baseline in Vital Signs Parameters 
CCI
CCI
CCI
Property of Takeda:
sis Set
is Set
nalysis
alysis
Variab
Variab
For
hort1~
hort1~
non-comme
for PK
or PK
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Para
mercial use only and subject to the 
ble
able 
applicab
Terms 
T
of Use


 
TAK-925-1001 
Page 39 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Scatter plot for PK concentrations of TAK-925 and changes from time-
matched baseline in vital signs parameters listed above will be provided 
with a fitted loess curve and 90% confidence interval. 
 
Change from time-matched baseline in each analysis variable is defined as 
below. 
Cohort 1~2 
The observed value of the each analysis variable at above visit in Placebo 
administration period subtracted from the observed value of the each 
analysis variable at the same visit in TAK-925 administration period. If a 
subject has no observed value at a Placebo administration period or all 
TAK-925 administration period, the change from time-matched baseline at 
the visit will be treated as missing. If a subject has three observed values at 
the same visit (i.e., two TAK-925 administration periods and one Placebo 
administration period), two changes from time-matched baseline will be 
calculated at the visit for the subject. 
Cohort S1~ S2 
Refer to section 7.1.1.   
 
7.10.1.2 Cohort 5~7 
Analysis Set: Pharmacokinetic Analysis Set 
Visit: 
Predose; 1, 2, 4, 6, 9, 11 and 24 Hours Postdose 
Analytical 
Method(s): 
 
The same analysis as section 7.10.1.1 will be conducted for the cohort 5~7. 
 
Time-matched baseline in each analysis variable is defined same as cohort 
1~2 in section 7.10.1.1. 
Property of Takeda: For
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Terms of Use


 
TAK-925-1001 
Page 40 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.11 
Safety Analysis 
In this study, safety will be evaluated as the primary endpoint. 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Cohort 1~2
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 level. 
 
(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 for each 
dose level will be based on the number of subjects who were treated by that 
dose level in the safety analysis set. 
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TAK-925-1001 
Page 41 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
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. 
Cohort S1~S2 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort S1~S2. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
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Terms of Use


 
TAK-925-1001 
Page 42 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
7.11.1.2 Displays of Treatment-Emergent Adverse events 
Cohort 1~2 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution by 
dose level. 
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 
 
(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 
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TAK-925-1001 
Page 43 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
The frequency distribution will be provided according to the rules below. 
Percentages for each dose level will be based on the number of subjects 
who were treated by that dose level in the safety analysis set. 
Number of subjects 
• Summary tables other than (5) and (6) 
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. 
 
Cohort S1~S2 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort S1~S2. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
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Terms of Use


 
TAK-925-1001 
Page 44 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
PTE 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution. 
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 Clinical Laboratory Evaluations 
7.11.2.1 Hematology and Serum Chemistry
Cohort 1~2 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Hematology 
 
 
 
 
 
Serum Chemistry 
CCI
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TAK-925-1001 
Page 45 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
 
 
 
 
 
 
Visit: 
Predose, Day 2, Day7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
 
The following summaries will be provided by dose level.
 
(1) Summary of Laboratory Test Results and Change from Baseline by 
Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. 
For each laboratory test, the laboratory values will be classified as 
"Low", "Normal" or "High" relative to the normal reference range. The 
shift tables will be based on these classifications. 
Cohort S1~S2 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort S1~S2. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort 3. 
CCI
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TAK-925-1001 
Page 46 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Visit: 
Predose, 1 day Postdose 
(For the period 1, data obtained at Day -1 will be used as the "Predose" visit 
and data obtained at Day 2 will be used as the "1 day Postdose" visit. For 
the period 2, data obtained at Day 3 will be used as the "Predose" visit and 
data obtained at Day 4 will be used as the "1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
7.11.2.2 Urinalysis 
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Specific Gravity 
 
 
 
 
 
 
 
 
 
CCI
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TAK-925-1001 
Page 47 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
 
Visit: 
Predose, Day 2, Day 7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
For specific gravity, summaries (1) , (2) and (4) will be provided by dose 
level. 
For Microscopy (RBC, WBC, Squamous Epithelial Cell), summary (3) will 
be provided by dose level. 
For each variable other than specific gravity and Microscopy, summaries 
(3) and (4) will be provided by dose level.
 
(1) Summary of Urine Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Urine Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Number of Subjects in Categories of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. 
 
(4) Summary of Shifts of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. The laboratory value for 
specific gravity will be classified as "Low", "Normal" or "High" 
relative to the normal reference range. If applicable, the laboratory 
value for each urine laboratory test other than specific gravity will be 
classified as "Normal" or "Abnormal" relative to the normal reference 
range. The shift tables will be based on these classifications. 
Cohort S1~S2 
Analysis Set: Safety Analysis Set
CCI
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Term of Use


 
TAK-925-1001 
Page 48 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort S1~S2 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort 3 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort 4 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Visit: 
Predose, 1 day Postdose 
(For the period 1, data obtained at Day -1 will be used as the "Predose" visit 
and data obtained at Day 2 will be used as the "1 day Postdose" visit. For 
the period 2, data obtained at Day 3 will be used as the "Predose" visit and 
data obtained at Day 4 will be used as the "1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort 5~7 
7.11.3 Vital Signs and Weight 
7.11.3.1 Body Temperature, Respiratory Rate, Systolic and Diastolic Blood Pressure in 
Sitting Position, Pulse Rate and Weight 
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Property of
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Terms of Use


 
TAK-925-1001 
Page 49 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analysis 
Variable(s) : 
 
Temperature 
 
 
Systolic Blood Pressure in Sitting 
 
 
Diastolic Blood Pressure in Sitting 
 
 
Respiration Rate 
 
 
Pulse Rate 
 
 
Weight 
 
Visit: 
Pulse Rate, Systolic Blood Pressure in Sitting, Diastolic Blood Pressure in 
Sitting: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 
12, and 24 Hours Postdose, Day 7 
Respiration Rate, Temperature : Predose, 5 Hours Postdose, Day 2 
Weight: Predose, Day 2, Day 7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
The following summaries will be provided by dose level. 
 
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Vital Signs Parameters and Weight 
Plots over time for each subject will be presented. 
Cohort S1~S2 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Temperature 
 
 
Systolic Blood Pressure in Sitting 
 
 
Diastolic Blood Pressure in Sitting 
 
 
Respiration Rate 
 
 
Pulse Rate 
 
 
Weight 
 
Visit: 
Pulse Rate, Systolic Blood Pressure in Sitting, Diastolic Blood Pressure in 
Sitting : -24, -23.75, -23.5, -23.25, -23, -22.5, -22, -21.5, -21, -20.5, -20, -
19, -18, -17, -16, -15, -14, -13, and -12 Hours Predose, Predose, 0.25, 0.5, 
0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 Hours Postdose, 
Day 7 
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Terms of Use


 
TAK-925-1001 
Page 50 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Respiration Rate, Temperature : Predose, 5 Hours Postdose, Day 2 
Weight: Predose, Day 2, Day 7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
The following (1) ~ (3) summaries will be provided for Pulse Rate, Systolic 
Blood Pressure in Sitting, and Diastolic Blood Pressure in Sitting by dose 
level. 
The following (4) summary will be provided for Pulse Rate, Systolic Blood 
Pressure in Sitting, and Diastolic Blood Pressure in Sitting. 
The following (1), and (3) summaries will be provided for Respiration Rate, 
Temperature, and Weight by dose level. 
 
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Summary of Change from time-matched baseline by Visit 
Descriptive statistics for Change from time-matched Baseline will be 
provided. 
 
(3) Case Plots of Vital Signs Parameters and Weight
Plots over time for each subject will be presented. 
 
(4) For each post-treatment time point, change from time-matched baseline 
in each analysis variable will be analyzed using a Mixed Effect Model 
for longitudinal data with change from time-matched baseline in each 
analysis variable as dependent variable, and dose level, visit, and dose 
level-by-visit interaction as independent variables. LS means, the 
standard errors and the two-sided 90% and 95% confidence intervals 
will be provided for each dose level. The differences in the LS means 
between each TAK-925 group and the placebo group (each TAK-925 
group – the placebo group) and the two-sided confidence intervals will 
be provided.  
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.1 "Cohort 1~2" will be performed for 
the Cohort 3.  
Property of 
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TAK-925-1001 
Page 51 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.1 "Cohort 1~2" will be performed for 
the Cohort 4.  
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Temperature 
 
 
Systolic Blood Pressure in Sitting  
 
 
Diastolic Blood Pressure in Sitting  
 
 
Respiration Rate 
 
 
Pulse Rate 
 
Visit: 
Pulse Rate, Systolic Blood Pressure in Sitting, Diastolic Blood Pressure in 
Sitting: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 
24 Hours Postdose  
Respiration Rate, Temperature : Predose, 5 hours Postdose, 1 day Postdose 
 (For the period 1, data obtained at Day 2 will be used as the "1 day 
Postdose" visit. For the period 2, data obtained at Day 4 will be used as the 
"1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.1 "Cohort 1~2" will be performed for 
the Cohort 5~7.  
7.11.3.2 Systolic and Diastolic Blood Pressure in Standing Position
Cohort 1~2 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Systolic Blood Pressure (1 Minute 
after Standing) 
 
 
Diastolic Blood Pressure (1 Minute 
after Standing) 
 
Property of
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subject to the applicable Terms of Use


 
TAK-925-1001 
Page 52 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
 
Systolic Blood Pressure (5 Minutes 
after Standing) 
 
 
Diastolic Blood Pressure (5 Minutes 
after Standing) 
 
Visit: 
1, 2 and 4 Hours Postdose 
Analytical 
Method(s) : 
 
The following summary will be provided by dose level. 
(1)  Summary of Systolic and Diastolic Blood Pressure in Standing 
Position 
Descriptive statistics for observed values and changes from baseline 
(observed values of each analysis variable – observed values in sitting 
for each analysis variable) will be provided.
Cohort S1~S2 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort S1~S2. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Visit: 
1 Hour Postdose  
Property of
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Terms of Use


 
TAK-925-1001 
Page 53 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
7.11.4 12-Lead ECGs 
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QRS Interval 
 
 
QT Interval 
 
 
QTcF Interval 
 
 
Interpretation 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Visit: 
Predose, 2~9 Hours Postdose, Day 2 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
For each variable other than 12-lead ECG interpretations, summaries (1) 
and (2) will be provided by dose level. 
For 12-lead ECG interpretation, summary (3) will be provided by dose 
level. 
 
(1) Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of ECG Parameters 
Plots over time for each subject will be presented. 
 
(3) Summary of Shift of 12-lead ECG Interpretation 
Shift table showing the number of subjects in each category at 
"Predose" visit and each postdose visit will be provided. 
Property of Takeda: For 
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subject to the applicable Terms of Use


 
TAK-925-1001 
Page 54 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
Cohort S1~S2 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort S1~S2. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Visit: 
Predose, 2~9 Hours Postdose, 1 day Postdose 
(For the period 1, data obtained at Day -1 will be used as the "Predose" visit 
and data obtained at Day 2 will be used as the "1 day Postdose" visit. For 
the period 2, data obtained at Day 2 will be used as the "Predose" visit and 
data obtained at Day 4 will be used as the "1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort 5~7. 
7.11.5 Other Observations Related to Safety 
Not applicable. 
of Takeda: 
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TAK-925-1001 
Page 55 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
7.12 
Interim Analysis 
In this study, a sponsor's unblinded team will be organized. The sponsor's unblinded team 
must not directly be involved in the execution of the study at a study site or directly contact 
the site. After cohort 5, this team will review unblinded data on the safety, tolerability and 
pharmacodynamic effects (MWT) and available PK of TAK-925 obtained from cohort 5, and 
recommend a dose level for cohort 6 based on such data. After cohort 6, the dose and the 
number of subjects to be used in Cohort 7 will be recommended by the sponsor’s unblinded 
team on the basis of safety, tolerability, pharmacodynamic effects (MWT) and available PK 
data of TAK-925 obtained from Cohorts 5 and 6.  
7.13 
Changes in the Statistical Analysis Plan  
The changes from 1st version of the SAP were described in the Annex "Summary of Changes 
of TAK-925-1001 SAP".  
Property of Takeda: For non-commercial use only and subject to the
Sum
Sum
applicable 
inde
nde
lable PK
able P
mma
Terms 
d 
ed
of Use


 
TAK-925-1001 
Page 56 of 56 
Statistical Analysis Plan 2nd  
2 October 2018 
CONFIDENTIAL 
8.0 
REFERENCES 
No reference. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-925-1001 
A First-in-Human, Two-Part Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of TAK-925 in Healthy Adult and Elderly 
Volunteers and Patients with Narcolepsy
Phase 1 TAK-925 Study in Healthy Adult and Elderly Volunteers and Patients with 
Narcolepsy 
Version: 1st 
Date: 14 February 2018 
 
Prepared by: 
 
 
Based on: 
Protocol Version: Amendment1  
Protocol Date: 22 January 2018 
PPD
CCI
Property
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of
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Terms of Use


 
TAK-925-1001 
Page 2 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
TAK-925-1001 
Page 3 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.1 
Approval Signatures ....................................................................................... 2 
2.0 
TABLE OF CONTENTS ...................................................................................... 3 
List of In-Text Tables ................................................................................................. 4 
List of In-Text Figures................................................................................................ 4 
3.0 
LIST OF ABBREVIATIONS ............................................................................... 5 
4.0 
OBJECTIVES ...................................................................................................... 7 
4.1 
Primary Objectives ......................................................................................... 7 
4.2 
Secondary Objectives...................................................................................... 7 
4.3 
Additional Objectives ..................................................................................... 7 
4.4 
Study Design .................................................................................................. 7 
5.0 
ANALYSIS ENDPOINTS .................................................................................. 13 
5.1.1
Primary Endpoint .................................................................................... 13 
5.1.2
Secondary Endpoints ............................................................................... 13 
5.1.3
Exploratory Endpoints ............................................................................ 13 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................ 14 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ........................................ 15 
7.1 
General Principles ......................................................................................... 15 
7.1.1
Study Definitions .................................................................................... 15 
7.2 
Analysis Sets ................................................................................................ 16 
7.3 
Disposition of Subjects ................................................................................. 17 
7.3.1
Study Information ................................................................................... 17 
7.3.2
Screen Failures........................................................................................ 17 
7.3.3
Subject Eligibility ................................................................................... 17 
7.3.4
Disposition of Subjects ........................................................................... 18 
7.3.5
Protocol Deviations and Analysis Sets .................................................... 19 
7.4 
Demographic and Other Baseline Characteristics .......................................... 22 
7.4.1
Cohort 1~2 .............................................................................................. 22 
7.4.2
Cohort 3 .................................................................................................. 23 
7.4.3
Cohort 4 .................................................................................................. 23 
7.4.4
Cohort 5~7 .............................................................................................. 23 
7.5 
Medical History and Concurrent Medical Conditions .................................... 24 
7.5.1
Cohort 5~7 .............................................................................................. 24 
7.6 
Medication History and Concomitant Medications ........................................ 25 
7.6.1
Cohort 5~7 .............................................................................................. 25 
7.7 
Study Drug Exposure and Compliance .......................................................... 25 
7.7.1
Cohort 1~2 .............................................................................................. 25 
7.7.2
Cohort 5~7 .............................................................................................. 26 
Property of Takeda: 
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TAK-925-1001 
Page 4 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.8 
Efficacy Analysis .......................................................................................... 26 
7.8.1
Primary Efficacy Endpoint(s) .................................................................. 26 
7.8.2
Secondary Efficacy Endpoint(s) .............................................................. 26 
7.8.3
Additional Efficacy Endpoint(s) .............................................................. 26 
7.8.4
Statistical/Analytical Issues..................................................................... 26
7.9 
Pharmacokinetic/Pharmacodynamic Analysis ............................................... 28 
7.9.1
Pharmacokinetic Analysis ....................................................................... 28 
7.9.2
Pharmacodynamic Analysis .................................................................... 34 
7.10 
Other Outcomes ............................................................................................ 36 
7.11
Safety Analysis............................................................................................. 37
7.11.1 Adverse Events ....................................................................................... 37 
7.11.2 Clinical Laboratory Evaluations .............................................................. 41 
7.11.3 Vital Signs and Weight ........................................................................... 45 
7.11.4 12-Lead ECGs ........................................................................................ 48 
7.11.5 Other Observations Related to Safety ...................................................... 49 
7.12 
Interim Analysis ........................................................................................... 49 
7.13 
Changes in the Statistical Analysis Plan ........................................................ 49 
8.0 
REFERENCES ................................................................................................... 50 
LIST OF IN-TEXT TABLES 
Table 4.a  Summary of Cohorts ...................................................................................... 10 
LIST OF IN-TEXT FIGURES 
Figure 4.a  Summary of Cohort 1 and Cohort 2 .............................................................. 11 
Figure 4.b Summary of Cohort 3................................................................................ 11
Figure 4.c  Summary of Cohort S1~S4 (Healthy Adult Supplement Cohorts) .......... 11 
Figure 4.d  Summary of Cohort 5~7 ............................................................................... 12 
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8
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TAK-925-1001 
Page 5 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
Ae 
amount of drug excreted in urine 
ALT
alanine aminotransferase
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI
body mass index
CL R 
renal clearance 
Cmax 
maximum observed concentration 
CRF 
case report form 
CSF 
cerebrospinal fluid 
ECG 
electrocardiogram 
ESS 
epworth sleepiness scale 
fe 
fraction of administered dose of drug excreted in urine 
Ȗ-GTP 
gamma-glutamyl transferase 
KSS 
karolinska sleepiness scale 
LDH
lactate dehydrogenase 
Lambda z 
terminal disposition phase rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MWT 
maintenance of wakefulness test 
PD 
pharmacodynamics 
PK
pharmacokinetics
 
 
 
 
QTc 
corrected QT 
RBC 
red blood cell 
REM
rapid eye movement 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE
treatment-emergent adverse event 
tmax
time of first occurrence of Cmax
t1/2z 
half-life period 
ULN
upper limit of normal 
Vz 
volume of distribution 
CCI
CCI
CCI
CCI
Property of 
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subject to the applicable Terms of Use


 
TAK-925-1001 
Page 6 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
WBC 
white blood cell 
WHO Drug 
World Health Organization Drug Dictionary 
of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
TAK-925-1001 
Page 7 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
4.0 
OBJECTIVES 
4.1 
Primary Objectives 
x To evaluate the safety and tolerability of TAK-925 when a single dose of TAK-925 is 
administered to healthy adults, the healthy elderly and patients with type 1 narcolepsy. 
x To evaluate the PK of TAK-925 when a single dose of TAK-925 is administered to 
healthy adults, the healthy elderly and patients with type 1 narcolepsy. 
4.2 
Secondary Objectives 
x To evaluate the PD effects of TAK-925 (mainly, sleep latency in the MWT) when a 
single dose of TAK-925 is administered to patients with type 1 narcolepsy. 
4.3 
Additional Objectives 
4.4 
Study Design 
This study consists of two parts. 
Part 1 is an alternating panel, randomized, double-blind, placebo-controlled, crossover study 
to assess the safety, tolerability and PK of a single rising dose of TAK-925 in healthy adult 
and elderly volunteers. In Part 1, the safety and tolerability, and the PK including the 
concentration in the cerebrospinal fluid (CSF) at a single dose of TAK-925 in healthy adult 
volunteers will be also evaluated in an open cohort. 
Part 2 is a sequential panel, randomized, double-blind (unblinded for the sponsor), placebo-
controlled, 2-period crossover study to assess the safety, tolerability, PK and PD of one or 
more dose levels of TAK-925 vs. placebo in patients with type 1 narcolepsy. 
(1) Part 1 
Part 1 of the study will enroll 16 healthy adults into two separate cohorts of 8 subjects each, 
Cohort 1 and Cohort 2. In Cohort 3, 8 healthy elderly will be enrolled. In Cohorts 1 and 2 
consisting of 8 subjects each, 6 subjects will receive TAK-925 and 2 subjects will receive 
placebo, assigned randomly in each dosing period (each period is composed of a single dose 
level),and 2 subjects each in Cohorts 1 and 2 will be randomly assigned to Groups A to H. To 
CCI
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Terms of Use


 
TAK-925-1001 
Page 8 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
assess the safety, tolerability, and PK of TAK-925 including CSF-PK of TAK-925, 4 healthy 
adults will be enrolled as Cohort 4. 
Administration of the study drug in Cohorts 1 and 2 will be performed alternately, with at 
least a 3-day interval between the cohorts and with a 7-day interval as well as more than 5 
times the terminal half-life (t1/2) of TAK-925 within the same cohort. Each subject will be 
given the study drug a maximum of three times. 
The first dose level cohort (Cohort 1, Dose Level 1) is designed to obtain the safety and 
tolerability information when a single dose of TAK-925 is administered as well as to obtain 
the information on pharmacokinetic parameters that will determine the dosing regimen 
(infusion rate) and doses in the subsequent periods in Part 1. For example, if the time required 
to achieve a steady state at a constant intravenous infusion rate is too long, if and the initial 
dose is safe and well tolerated, the infusion rate for the first 2 hours may be accelerated to 
achieve a steady state earlier in the subsequent periods. In Cohort 1 Dose Level 1, a small 
number of subjects will be given the study drug first as a sentinel group dosing. One subjects 
each in the sentinel group (two subjects) will receive either TAK-925 or placebo first prior to 
the remaining six subjects and those remaining 6 subjects will be dosed at least two hours 
after the sentinel group was dosed. In Cohort 2 Dose Level 2 and subsequent dose levels in 
Cohorts 1 and 2, Cohort 3 and Healthy Adult Supplemental receive TAK-925 or placebo 
simultaneously. (such that 4 subjects will be dosed at first, and if there are no safety issues, 
the remaining 4 subjects may be dosed about 1 hour later.) 
Doses following after Cohort 1 Dose Level 1 will be determined depending on the safety, 
tolerability and available PK of previous doses. After evaluating the safety, tolerability and 
PK in Cohort 1 Dose Level 1, dosing in Cohort 2 Dose Level 2 will be commenced. After 
evaluating the safety, tolerability and PK in Cohort 2 Dose Level 2, dosing in Cohort 1 Dose 
Level 3 will be commenced. After evaluation the safety, tolerability and available PK in 
Cohort 1 Dose Level 3, dosing in Cohort 2 Dose Level 4 will be commenced. In a similar 
fashion,, dosing in Cohort 1, Dose Level 5 and Cohort 2 Dose Level 6 in a similar fashion. 
Not all the Cohorts should be run necessarily, and the dose may be higher or lower than or 
the same to that of prior cohort dose levels, or intermediate dose between two prior doses. 
In the event that further investigation on the safety, tolerability and PK is needed after 
completion of Cohort 2 Dose Level 6, Healthy Adult Supplement Cohorts that will include 8 
healthy adults per cohort (up to 4 additional cohorts that include 32 healthy adults) may be 
commenced without amendment of the protocol. The cohort names of S1 to S4 will be 
assigned for Healthy Adult Supplement Cohort. Six subjects will be randomly assigned to the 
TAK-925 group and 2 subjects to the placebo group in a cohort, to evaluate the safety, 
tolerability and PK. In the Healthy Adult Supplement Cohort, the dose may be higher or 
lower than or the same to that of prior cohort dose levels, or an intermediate between two 
prior doses. 
In Cohort 3, 8 healthy elderly subjects will be enrolled. Of these 8 subjects, six will be 
randomly assigned to the TAK-925 group and 2 to the placebo group. This cohort will be 
initiated after started with the dose of which the safety and tolerability has been established in 
healthy adults. 
In Cohort 4, 4 healthy adults will be enrolled to evaluate the safety, tolerability and the CSF 
concentration of TAK-925 measured at one time point and the plasma concentration of TAK-
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Terms of Use


 
TAK-925-1001 
Page 9 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
925. In Cohort 4, subjects, study sites and the sponsor will not be blinded. This cohort will be 
initiated after the safety and tolerability of the dose to be evaluated in Cohort 4 has been 
established in healthy adults. 
Cohort 3 and 4 may be started at the discretion of the sponsor, considering the status of 
Cohorts 1, 2 and the Healthy Adult Supplement Cohort. (Cohorts 3 and 4 may be 
implemented in parallel with Cohorts 1 and 2. The doses to be used in Cohorts 3 and 4 will be 
determined based on the available safety, tolerability and PK data, and nonclinical study 
results.) 
(2) Part 2 
In Part 2, patients with type 1 narcolepsy will be enrolled in three cohorts: Cohorts 5 to 7. 
Part 2 is a 2-period crossover study to assess the safety, tolerability, PK and PD effects of a 
single dose of TAK-925. Part 2 may begin prior to the completion of Part 1. However, the 
dose to be used in Cohort 5 should be lower than the one used in Part 1 as well as be lower 
than 1/3 of the maximum dose of TAK-925 of which the safety and tolerability has been 
already confirmed. If Cohort 3 is not completed prior to starting Part 2, subjects aged 56 
years or older should not be enrolled in Cohorts 5, 6 and 7 until Cohort 3 is completed. 
In Cohorts 5 and 6, 4 subjects each will be enrolled, and TAK-925 or placebo will be 
intravenously infused for 9 hours on Day 1 and Day 3. Of 4 subjects in each cohort, 2 
subjects each will be randomly assigned to one of the defined sequences (Groups I to L, 
TAK-925 may be given at one dose level in each cohort). A maximum of 12 patients with 
type 1narcolepsy will be enrolled in Cohort 7. Of a maximum of 12 patients, 6 each will be 
randomly assigned to Group M or Group N. The dose level to be used in Cohort 5 will be 
determined based on the safety, tolerability and PK data obtained from Part 1. After the 
safety, tolerability, PD effects (MWT) in Cohort 5 and available PK have been investigated, 
dosing in Cohort 6 will be started using another 4 new subjects. The same trial design as 
Cohort 5 will be used in Cohort 6. The dose level to be used in Cohort 6 will be discussed by 
the sponsor's unblinded team. The sponsor's unblinded team must not directly be involved in 
the execution of the study at a study site or directly contact the site. This team will review 
unblinded data on the safety, tolerability, PD effects (MWT) and available PK of TAK-925, 
and recommend a dose based on those data. The dose level to be used in Cohort 6 may be 
higher or lower than the one used in Cohort 5. Cohort 7 will be composed of up to 12 
subjects. The dose and the number of subjects to be used in Cohort 7 will be recommended 
by the sponsor’s unblinded team on the basis of safety, tolerability, PD effects (MWT) 
obtained from Cohorts 5 and 6 and available PK data of TAK-925. The dose may be higher 
or lower than the doses used in Cohorts 5 and 6, or intermediate dose between these cohorts. 
See section 3.0 of protocol for the schedule of tests/observations /evaluations. Summary of 
Cohorts is shown in Table 4.a. 
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TAK-925-1001 
Page 10 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Table 4.a  Summary of Cohorts 
Part 
Cohort  
Subjects 
Sample Size 
Study Design 
Dosage 
Randomization 
11) 
12) 
Healthy adults 
n=8 
Double-blind,  
Cross-over 
TAK-925 7 mg (Dose 
Level 1) or placebo 
Each Cohort 
TAK-925: 6 subjects,  
Placebo: 2 subjects 
2 
TAK-925 TBD mg 
(Dose Level 2) 
or placebo 
1 
TAK-925 TBD mg  
(Dose Level 3)  
or placebo 
2 
TAK-925 TBD mg 
(Dose Level 4) 
or placebo 
1 
TAK-925 TBD mg 
(Dose Level 5) 
or placebo 
2 
TAK-925 TBD mg 
(Dose Level 6) 
or placebo 
S1 – S43)  
Healthy adults 
n=8 
Double-blind,  
parallel group 
TAK-925 TBD mg 
or placebo 
3 
Healthy elderly 
n=8 
Double-blind,  
parallel group 
TAK-925 TBD  mg 
or placebo 
4 
Healthy adults 
n=4 
Unblinded 
TAK-925 TBD  mg  
TAK-925: 4 subjects 
21) 
5 
Patients with type 1 
narcolepsy 
n=4 
Double-blind 
(the sponsor is unblinded) 
2 x 2 Cross-over 
TAK-925  TBD4) mg 
or placebo 
Each period 
TAK-925: 2 subjects,  
Placebo: 2 subjects 
6 
Patients with type 1 
narcolepsy 
n=4 
Double-blind 
(the sponsor is unblinded) 
2 x 2 Cross-over 
TAK-925 TBD mg or 
placebo 
7 
Patients with type 1 
narcolepsy 
N=12 
Double-blind 
(the sponsor is unblinded) 
2 x 2 Cross-over 
TAK-925 TBD  mg 
or placebo 
Each period 
TAK-925: max. 6 subjects,  
Placebo: max. 6 subjects 
1) In Part 1, the same subjects are used for Dose Levels 1, 3 and 5, and similaly, the same subjects are used for Dose Levels 
2, 4 and 6.  In Part 2, different subjects are used in each Cohort. The target plasma level totake into consideration as a standard is 
as follows. Dose Level 1: 20 ng/mL, Dose Level 2: 40 ng/mL, Dose Level 3: 80 ng/mL, Dose Level 4: 150 ng/mL, Dose Level 5: 300 
ng/mL, Dose Level 6: 600 ng/mL. The steady-state concentration (Css) of TAK-925 is estimated to be 21.3 ng/mL when 7 mg is 
administered as Dose level 1. 
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TAK-925-1001 
Page 11 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
2) In Cohort 1 Dose Level 1, 2 subjects are enrolled and each subject is assigned randomly to either the TAK-925 or placebo 
group to evaluate the safety, tolerability and pharmacokineticsof TAK-925.  Additional 6 subjects are enrolled, and 5 
subjects and 1 subject are assigned randomly to the TAK-925 and placebo groups, respectively, to evaluate the safety and 
tolerability of TAK-925.  
3) In the event that further investigation of the safety, tolerability and pharmacokinetics of TAK-025 is needed after 
completion of Cohorts 1 and 2, up to 4 additional cohorts that include 32 healthy adults can be commenced without 
amendment of the protocol.  
4) In Part 2, the dose to be used in Cohort 5 should be equal or less than one-third of the maximum dose of TAK-925 whose 
safety and tolerability were already confirmed. 
 
 
Dose Level 1 
 
Dose Level 2 
 
Dose Level 3 
A 
TAK-925 7 mg 
 
E 
TAK-925 TBD 
 
A 
TAK-925 TBD 
B 
TAK-925 7 mg 
ń 
F 
TAK-925 TBD 
ń 
B 
TAK-925 TBD 
C 
TAK-925 7 mg 
 
G 
TAK-925 TBD 
 
C 
Placebo 
D 
Placebo
 
H 
Placebo
 
D 
TAK-925 TBD 
 
Dose Level 4 
 
Dose Level 5 
 
Dose Level 6 
 
E 
TAK-925 TBD 
 
A 
TAK-925 TBD 
 
E 
TAK-925 TBD 
ń 
F 
TAK-925 TBD 
ń 
B 
Placebo 
ń 
F 
Placebo 
 
G 
Placebo 
 
C 
TAK-925 TBD 
 
G 
TAK-925 TBD 
 
H 
TAK-925 TBD 
 
D 
TAK-925 TBD 
 
H 
TAK-925 TBD 
TBD: To be determined 
1) 
Double-blind, crossover study. Each Cohort consists of 8 subjects, and each group consists of 2 subjects. Dose Levels 1, 
3 and 5 will be investigated in the same subjects (Groups A-D in Cohort 1). Similarly, Dose Levels 2, 4 and 6 will be 
investigated in the other same subjects (Groups E-H in Cohort 2). 
2) 
At Dose Level 1, firstly 2 subjects will be enrolled: one subject will be randomized to one of Groups A to C, and 
another subject to Group D. After confirming the safety and tolerability of TAK-925, 6 more subjects will be enrolled 2 
hours after the start of infusion, and each of these subjects will be randomly assigned to one of Groups A to D, to 
evaluate the safety, tolerability and PK of TAK-925. Finally, two subjects each will be assigned to Groups A to D. The 
doses after Dose Level 2 and subsequent doses will be determined based on the safety, tolerability and PK data obtained 
at previous dose levels. 
Figure 4.a  Summary of Cohort 1 and Cohort 2 
TAK-925 TBD
Placebo 
1) Double-blind study.  Cohort 3 consists of 8 subjects: 6 subjects in the TAK-925 group and 2 subjects in the placebo group. 
Figure 4.b  Summary of Cohort 3 
TAK-925 TBD 
Placebo 
1) In the event that further investigation of safety, tolerability and pharmacokinetics is needed after completion of Cohorts 1 and 2, up to 4 
additional cohorts that include 32 healthy adults can be commenced without amendment of the protocol. 
2) Double-blind study. Each Cohort consists of 8 subjects: 6 in the TAK-925 group and 2 in the placebo group. 
3) The dose can be determined for each Cohort.  
Figure 4.c  Summary of Cohort S1~S4 (Healthy Adult Supplement Cohorts) 
 
 
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TAK-925-1001 
Page 12 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
1. 
Cohort 5-7 (Patients with narcolepsy)1 
Cohort 5 
 
Cohort 6 
 
Period 1 
Period 2 
Cohort 
transfer 
 
Period 1 
Period 2 
I 
TAK-925 
TBD 
Placebo 
ń 
K 
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Placebo 
J 
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Cohort 7
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Period 1 
Period 2 
ń 
M 
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N 
Placebo 
TAK-925 TBD 
1)  Double-blind (the sponsor is unblinded), 2x2 crossover study.  
2) Cohorts 5 and 6 consist of 4 subjects. Two subjects are assigned to each group (Groups I-L).  Cohort 7 consists of a maximum of 12 subjects, 
and each group (Groups M and N) consists of a maximum 6 subjects. 
3) Each Cohort will be investigated in different subjects. 
Figure 4.d  Summary of Cohort 5~7 
Property of Takeda: For non-commercial use only and 
Co
Co
subject 
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con
the applicable Terms of Use


 
TAK-925-1001 
Page 13 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
5.0 
ANALYSIS ENDPOINTS 
5.1.1
Primary Endpoint 
x Safety and tolerability: adverse events, vital signs, body weight, 12-lead 
electrocardiogram (ECG) and clinical laboratory tests (hematology, serum chemistry and 
urinalysis) 
x Pharmacokinetics (PK): plasma concentrations and pharmacokinetic parameters, urine 
pharmacokinetic parameters, and cerebrospinal fluid (CSF) concentrations and 
pharmacokinetic parameters of TAK-925 and its metabolites (M-I and M-II). 
5.1.2 Secondary Endpoints 
z 
The average sleep latency in the MWT
5.1.3 Exploratory Endpoints 
CCI
Property of Takeda: For non-commercialal use only and 
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subject to the applicable 
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Terms of Use


 
TAK-925-1001 
Page 14 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
6.0 
DETERMINATION OF SAMPLE SIZE 
In Cohort 1-3 in Part 1, 8 subjects (6 in the TAK-925 group and 2 in the placebo group) was 
selected as the sample size to evaluate the safety, tolerability and PK of TAK-925 when a 
single dose of TAK-925 is administered intravenously to healthy adults and the healthy 
elderly. In the event that further investigation on the safety, tolerability and PK is needed 
after completion of Cohorts 1-2, a maximum of 4 additional cohorts (a total of 32 healthy 
adult subjects; 8 subjects [6 in TAK-925 group, 2 in placebo group] for each cohort) may be 
enrolled. 
For Cohort 4 in Part 1, 4 subjects will be enrolled to evaluate the safety, tolerability, PK of 
TAK-925 including the concentration of TAK-925 in the CSF when a single dose of TAK-
925 is administered intravenously to healthy adults. 
For Part 2, 4 patients each in Cohort 5, 6 and a maximum of 12 patients in Cohort 7 will be 
enrolled to evaluate the safety, tolerability, PK and PD effects of TAK-925 when a single 
dose of TAK-925 is administered to patients with type 1 narcolepsy. 
These sample sizes are not based on any effect size obtained by the MWT or statistical 
evidence. 
 
Property of Takeda: For non-commercial use only and subject
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TAK-925-1001 
Page 15 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1
Study Definitions 
The following definitions and calculation formulas will be used. 
x 
Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs 
on or after the start of study drug 
x 
Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to 
administration of study drug 
x 
Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles 
x 
Coefficient of variation (CV) (%): Standard deviation / mean * 100  
x 
QTcF interval (msec): QT interval (msec) / (RR interval (sec))0.33 (rounded to the nearest 
whole number) 
y 
Dose level
- 
Cohort 1~2 
 Placebo  
 TAK-925 xx mg 
- 
Cohort 3 
 Placebo 
 TAK-925 xx mg 
- 
Cohort 4 
 TAK-925 xx mg 
- 
Cohort 5~7 
 Placebo 
 TAK-925 xx mg 
y 
Group 
- 
Part1 (Healthy Adults or The Healthy Elderly) 
 Cohort 1 and Cohort 2: See Figure 4.a 
 Cohort 3: See Figure 4.b 
 Cohort 4: TAK-925 
 Cohort S1~S4: See Figure 4.c 
- 
Part2 (Patients with Narcolepsy) 
 Cohort 5~7: See Figure 4.d 
 
Property of Takeda: 
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TAK-925-1001 
Page 16 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.2 
Analysis Sets 
x 
Safety analysis set: All subjects who received at least one dose of study drug 
x 
Pharmacokinetic analysis set: All subjects who received at least one dose of study drug 
and whose plasma or CSF concentration can be measured at least once or whose 
cumulative urinary excretion can be calculated. 
x 
Pharmacodynamic analysis set: All subjects who received at least one dose of study drug. 
Property of Takeda: For non-commercial use only and subject to the applicable 
dy d
y
Terms 
drug
dru
of Use


 
TAK-925-1001 
Page 17 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
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 Receive Study Drug 
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 
7.3.3.1 Cohort 1~2 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Study Drug Administration Status 
 
[Treated, Not Treated] 
 
Primary Reason for Subject Not 
Being Treated 
[Adverse Event, Death, Lost to 
Follow-up, Pregnancy, Protocol 
Deviation, Sample Size Sufficient, 
Screen Failure, Study Terminated by 
Sponsor, Withdrawal by Subject, 
Other] 
 
Property of Takeda: 
ysis Set
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Analysis
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the applicable Terms of Use


 
TAK-925-1001 
Page 18 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
(1) Study Drug Administration Status 
Frequency distributions will be provided. When calculating percentages for 
the primary reasons for subject not being treated, the total number of not 
treated subjects will be used as the denominator. 
7.3.3.2 Cohort 3 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 3 
7.3.3.3 Cohort 4 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 4 
7.3.3.4 Cohort 5~7 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.3.1 will be performed for the Cohort 5~7 
7.3.4
Disposition of Subjects 
7.3.4.1 Cohort 1~2 
Analysis Set: All Subjects Who Received Study Drug 
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, Pregnancy, Protocol 
Deviation, Study Terminated by 
Sponsor, Withdrawal by Subject, 
Other] 
Property of Takeda:
is Set
is Set
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alysis
Variab
Variab
For
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and 
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applicable Terms of Use


 
TAK-925-1001 
Page 19 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
(1) Disposition of Subjects 
Frequency distributions will be provided by group and overall. 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. 
7.3.4.2 Cohort 3 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort 3 
7.3.4.3 Cohort 4 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort 4 
7.3.4.4 Cohort 5~7 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.4.1 will be performed for the Cohort 5~7 
7.3.5
Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Cohort 1~2 
Analysis Set: All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
 
Significant Protocol 
Deviation 
 
[Entry Criteria, Concomitant Medication, Procedure 
Not Performed Per Protocol, Study Medication, 
Withdrawal Criteria, Major GCP Violations] 
Property of 
7
Takeda: 
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of Use


 
TAK-925-1001 
Page 20 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Analytical 
Method(s) : 
 
(1) Protocol Deviations 
Frequency distribution will be provided by group and overall for each 
deviation category. 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. 
Cohort 3 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort 3 
Cohort 4 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort 4 
Cohort 5~7 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.1 "Cohort 1~2" will be performed for the 
Cohort 5~7 
Property of Takeda: 
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For 
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1~2
1~2" w
to the applicable Terms 
that
that
of Use


 
TAK-925-1001 
Page 21 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.3.5.2 Analysis Sets 
Cohort 1~2 
Analysis Set: All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
 
Handling of Subjects 
 
[Categories are based on the 
specifications in Subject Evaluability 
List] 
 
Analysis Sets 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
(1) Subjects Excluded from Analysis Sets 
(2) Analysis Sets 
Frequency distributions will be provided by group and overall. 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. 
Cohort 3 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort 3 
Cohort 4 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort 4 
Property of
S
Takeda: 
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Analy
Analy
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Terms of Use


 
TAK-925-1001 
Page 22 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Cohort 5~7 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
 
Handling of Subjects 
 
[Categories are based on the 
specifications in Subject Evaluability 
List] 
 
Analysis Sets 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Pharmacodynamic Analysis Set 
 
[Included] 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort 1~2" will be performed for the 
Cohort 5~7 
7.4 
Demographic and Other Baseline Characteristics
7.4.1
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Pharmacokinetic 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 group and overall. 
Property of Takeda: For
W
non-commercial 
c Analy
Anal
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Height 
eight 
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use only 
aracte
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ort 1~2" 
rt 1~2
to the applicable
luabilit
uabil
Terms of Use


 
TAK-925-1001 
Page 23 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.4.2
Cohort 3 
Analysis 
Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analytical 
Method(s) : 
 
The same analysis as section 7.4.1 will be performed for the Cohort 3 
7.4.3
Cohort 4 
Analysis 
Set: 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
Analytical 
Method(s) : 
 
The same analysis as section 7.4.1 will be performed for the Cohort 4 
7.4.4
Cohort 5~7
Analysis Set: Safety Analysis Set
Pharmacokinetic Analysis Set 
Pharmacodynamic Analysis Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
[Min<= - <65, 65<= - <=Max]  
 
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] 
 
MWT (sleep latency) 
 
 
ESS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For
or
A
non-commercial 
)
(kg
kg)
(kg/m
kg/m
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the applicable Terms of Use


 
TAK-925-1001 
Page 24 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
 
 
 
 
 
 
 
Age of onset 
 
 
Period for diagnosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 group and overall. 
7.5 
Medical History and Concurrent Medical Conditions 
7.5.1
Cohort 5~7 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medical History 
 
Concurrent Medical Conditions 
Analytical 
Method(s) : 
 
(1) Medical History by System Organ Class and Preferred Term 
(2) Concurrent Medical Conditions by System Organ Class and Preferred 
Term 
Frequency distributions will be provided by group and overall. MedDRA 
dictionary will be used for coding. Summaries will be provided using SOC 
and PT, where SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency.  
A subject with multiple occurrences of medical history or concurrent 
medical condition within a SOC will be counted only once in that SOC. A 
subject with multiple occurrences of medical history or concurrent medical 
condition within a PT will be counted only once in that PT. 
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For
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(2
non-commercial 
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TAK-925-1001 
Page 25 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.6 
Medication History and Concomitant Medications 
7.6.1
Cohort 5~7 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medication History 
 
Concomitant Medications
Analytical 
Method(s) : 
 
(1) Medication History by Preferred Medication Name 
(2) Concomitant Medications That Started and Stopped Prior to Baseline 
by Preferred Medication Name 
(3) Concomitant Medications That Started Prior to and Were Ongoing at 
Baseline by Preferred Medication Name
(4) Concomitant Medications That Started After Baseline by Preferred 
Medication Name 
(5) Concomitant Medications That Started Prior to and Were Ongoing at  
Baseline as well as Those That Started After Baseline by Preferred 
Medication Name 
Frequency distributions will be provided by group and overall. WHO Drug 
dictionary will be used for coding. Summaries will be provided using 
preferred medication names and sorted in decreasing frequency based on the 
number of reports. A subject who has been administered several 
medications with the same preferred medication name will be counted only 
once for that preferred medication name. 
7.7 
Study Drug Exposure and Compliance
7.7.1
Cohort 1~2
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Number of Times the Study Drug was Taken 
 
[1, 2, 3] 
Analytical 
Method(s) : 
 
(1) Study Drug Exposure 
Frequency distributions will be provided by group. 
Property of
A
Takeda: 
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Coho
Analys
Analys
An
For 
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Terms of Use


 
TAK-925-1001 
Page 26 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.7.2
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Number of Times the Study Drug was Taken 
 
[1, 2] 
Analytical 
Method(s) : 
 
(1) Study Drug Exposure 
Frequency distributions will be provided by group. 
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 
Missing test results will not be used for hypothesis testing and estimations. 
For plasma and CSF concentrations and laboratory test results, values below the lower limit 
of quantification will be treated as zero. For laboratory test results, values above the upper 
limit of quantification will be treated as the upper limit value. 
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. 
Property of
No
N
Takeda:
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7.8.4.3
7.8.4.3
For 
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use only and subject to the applicable Terms of Use


 
TAK-925-1001 
Page 27 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
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. 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
TAK-925-1001 
Page 28 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
7.9.1.1 Plasma/CSF Concentrations 
Cohort 1~2 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Visit: 
Predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 Hours Postdose;  
0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 Hours after End of Infusion 
(10 Hours after End of Infusion is excluded for dose level 1 and 2 in Cohort 
1~2) 
Analytical 
Method(s) : 
 
The following summaries will be provided by dose level. Subjects 
administered placebo will be excluded from the analysis. 
 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided by visit.
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented. The vertical axis will 
be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable. 
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 for each analysis variable. 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. 
 
(5) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for dose level. 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. 
 
(6) Mean Plot of Plasma Concentrations 
Mean will be plotted for dose level. Visit will be plotted on the 
Property of Takeda: For non-commercial
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Terms of Use


 
TAK-925-1001 
Page 29 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
horizontal axis and each of the analysis variables will be plotted on the 
vertical axis. The vertical axis will be a common logarithmic scale. 
Cohort 3 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.1 "Cohort 1~2" will be conducted for the 
Cohort 3. For the results of (3) ~ (6) will be presented with the results of the 
cohort 1~2. 
Cohort 4 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s): 
 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
CSF Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Visit: 
Plasma Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
Predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 Hours Postdose;  
0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 Hours after End of 
Infusion
CSF Concentrations of TAK-925 and Its Metabolites (M-I and M-II) 
6 Hours Postdose 
Analytical 
Method(s): 
(1) For the plasma concentrations of TAK-925 and its metabolites (M-I and 
M-II), the same analysis as section 7.9.1.1 "Cohort 1~2" will be 
conducted. 
 
(2) For the CSF concentrations of TAK-925 and its metabolites (M-I and 
M-II), the same analysis as section 7.9.1.1 "Cohort 1~2" (1) will be 
conducted. 
Cohort 5~7 
Analysis Set: Pharmacokinetic Analysis Set 
Visit: 
Predose; 1, 2, 4, 6 and 9 Hours Postdose; 0.17, 0.5, and 2 Hours after End of 
Infusion; Bedtime; Wake up time; 15 Hours after End of Infusion 
Property of Takeda: For non-commercial
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Terms of Use


 
TAK-925-1001 
Page 30 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.1 "Cohort 1~2" will be conducted for the 
Cohort 5~7. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


 
TAK-925-1001 
Page 31 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.9.1.2 Pharmacokinetic Parameters 
Cohort 1~2 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Pharmacokinetic Parameters of TAK-925 and Its Metabolites (M-I and M-
II) 
 
AUClast 
AUCinf 
Cmax 
 
Ceoi 
tmax 
t1/2z 
 
Lambda z 
Vss (for TAK-925) 
Vz (for TAK-925) 
 
CL (for TAK-925) 
AUCinf D 
Cmax D 
Analytical 
Method(s) : 
 
The following summary will be provided by dose level. Subjects 
administered placebo will be excluded from the analysis. 
 
(1) Summary of Pharmacokinetic Parameters 
For AUClast, AUCinf, Cmax and Ceoi, descriptive statistics, geometric 
mean, and CV will be provided. For tmax, descriptive statistics will be 
provided. For all other variables, descriptive statistics and CV will be 
provided. 
Cohort 3 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.2 "Cohort 1~2" will be conducted for the 
Cohort 3. 
Cohort 4 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Pharmacokinetic and CSF Parameters of TAK-925 and Its Metabolites (M-I 
and M-II) 
 
AUClast 
AUCinf 
Cmax 
 
Ceoi 
tmax 
t1/2z 
 
Lambda z 
Vss (for TAK-925) 
Vz (for TAK-925) 
 
CL (for TAK-925) 
R CSF/Plasma,SS 
AUCinf D 
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TAK-925-1001 
Page 32 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
 
Cmax D 
 
 
Analytical 
Method(s) : 
 
The following summaries will be provided by dose level. Subjects 
administered placebo will be excluded from the analysis. 
 
(1) Summary of Pharmacokinetic Parameters 
For AUClast, AUCinf, Cmax and Ceoi, descriptive statistics, geometric 
mean, and CV will be provided. For tmax, descriptive statistics will be 
provided. For all other variables, descriptive statistics and CV will be 
provided. 
Cohort 5~7 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.2 "Cohort 1~2" will be conducted for the 
Cohort 5~7. 
7.9.1.3 Urine Pharmacokinetic Parameter 
Cohort 1~2 
Analysis Set: Pharmacokinetic Analysis Set 
 
 
 
 
Analysis 
Variable(s) : 
 
Urine Pharmacokinetic Parameters of TAK-925 and its metabolites (M-I 
and M-II) 
 
Ae24 
fe24 
CL R 
Analytical 
Method(s) : 
 
The following summary will be provided by dose level. Subjects 
administered placebo will be excluded from the analysis. 
 
(1) Summary of Urine Pharmacokinetic Parameter 
Descriptive statistics and CV will be provided. 
Property of Takeda: 
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Terms 
i
of Use


 
TAK-925-1001 
Page 33 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Cohort 3 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.3 "Cohort 1~2" will be conducted for the 
Cohort 3. 
Cohort 4 
Analysis Set: Pharmacokinetic Analysis Set 
Analytical 
Method(s): 
 
The same analysis as section 7.9.1.3 "Cohort 1~2" will be conducted for the 
Cohort 4. 
 
Property of Takeda: For non-commercial use only and subject to 
wi
the 
ill be
ll be
applicable Terms of Use


 
TAK-925-1001 
Page 34 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.9.2
Pharmacodynamic Analysis 
7.9.2.1 Average Sleep Latency in MWT/Sleep Related Parameters in MWT 
Cohort 5~7 
Analysis Set: Pharmacodynamic Analysis Set 
Analysis 
Variable(s): 
 
Average Sleep Latency in MWT, 
 
 
 
Visit: 
: 
10㸸00, 12㸸00, 14㸸00, 16㸸00 
Analytical 
Method(s): 
 
The following summaries will be provided. 
 
(1) For the average sleep latency in MWT, descriptive statistics for the 
observed values will be provided by dose level. An analysis of variance 
(ANOVA) for crossover design with the observed value as a response, 
the dose level, the group and the period as factors, the subject as a 
random effect will be conducted. Least square (LS) means, the standard 
errors, and the two-sided 90% and 95% confidence intervals will be 
provided for each dose level. The difference in the LS means between 
each dose level of TAK-925 and the placebo (each dose level of TAK-
925 - the placebo), the standard error of the difference, and the two-
sided confidence intervals and p-value will be provided. 
 
 
 
 
 
   
 
(2) 
 
 
 
 
 
 
 
 
CCI
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Terms of Use


 
TAK-925-1001 
Page 35 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
 
 
7.9.2.2 
 
 
 
 
7.9.2.3 
 
CCI
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Property of Takeda: : For non-commercial use only and subject to the 
able 
applicab
Terms of Use


 
TAK-925-1001 
Page 36 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.9.2.4 
 
7.10 
Other Outcomes 
Not applicable.
CCI
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Term of Use


 
TAK-925-1001 
Page 37 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.11 
Safety Analysis 
In this study, safety will be evaluated as the primary endpoint. 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Cohort 1~2
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 level. 
 
(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 for each 
dose level will be based on the number of subjects who were treated by that 
dose level in the safety analysis set. 
Property of Takeda: For non-commercial
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TAK-925-1001 
Page 38 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
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. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.1 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
Property of
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Terms of Use


 
TAK-925-1001 
Page 39 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.11.1.2 Displays of Treatment-Emergent Adverse events 
Cohort 1~2 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution by 
dose level. 
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 
 
(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 
 
The frequency distribution will be provided according to the rules below. 
Percentages for each dose level will be based on the number of subjects 
who were treated by that dose level in the safety analysis set. 
Number of subjects 
• Summary tables other than (5) and (6) 
Property of Takeda: For 
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Terms of Use


 
TAK-925-1001 
Page 40 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
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. 
 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.1.2 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
PTE 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution. 
Property of 
A
Takeda: 
7.11.1
7.11.1
For 
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of Use


 
TAK-925-1001 
Page 41 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
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 Clinical Laboratory Evaluations 
7.11.2.1 Hematology and Serum Chemistry 
Cohort 1~2 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Hematology 
 
 
 
 
 
Serum Chemistry 
 
 
 
 
 
 
 
CCI
CCI
Property of Takeda: For 
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non-commercia use only and subject to the
rences 
rences
applicable 
es below
below
will be
will be
Terms of Use


 
TAK-925-1001 
Page 42 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Visit: 
Predose, Day 2, Day7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
 
The following summaries will be provided by dose level.
 
(1) Summary of Laboratory Test Results and Change from Baseline by 
Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. 
For each laboratory test, the laboratory values will be classified as 
"Low", "Normal" or "High" relative to the normal reference range. The 
shift tables will be based on these classifications. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Visit: 
Predose, 1 day Postdose 
(For the period 1, data obtained at Day -1 will be used as the "Predose" visit 
and data obtained at Day 2 will be used as the "1 day Postdose" visit. For 
of Takeda: 
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Terms of Use


 
TAK-925-1001 
Page 43 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
the period 2, data obtained at Day 3 will be used as the "Predose" visit and 
data obtained at Day 4 will be used as the "1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.1 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
7.11.2.2 Urinalysis 
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
 
 
 
 
 
 
 
 
 
 
 
Visit: 
Predose, Day 2, Day 7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
For specific gravity, summaries (1) , (2) and (4) will be provided by dose 
level. 
For Microscopy (RBC, WBC, Squamous Epithelial Cell), summary (3) will 
be provided by dose level. 
CCI
Property of 
V
Takeda: Fo
For non-commercial use only and subject to 
to the applicable Terms of Use


 
TAK-925-1001 
Page 44 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
For each variable other than specific gravity and Microscopy, summaries 
(3) and (4) will be provided by dose level.
 
(1) Summary of Urine Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Urine Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Number of Subjects in Categories of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. 
 
(4) Summary of Shifts of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. The laboratory value for 
specific gravity will be classified as "Low", "Normal" or "High" 
relative to the normal reference range. If applicable, the laboratory 
value for each urine laboratory test other than specific gravity will be 
classified as "Normal" or "Abnormal" relative to the normal reference 
range. The shift tables will be based on these classifications. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort 3 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort 4 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Property of 
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Terms of Use


 
TAK-925-1001 
Page 45 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Visit: 
Predose, 1 day Postdose 
(For the period 1, data obtained at Day -1 will be used as the "Predose" visit 
and data obtained at Day 2 will be used as the "1 day Postdose" visit. For 
the period 2, data obtained at Day 3 will be used as the "Predose" visit and 
data obtained at Day 4 will be used as the "1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.2.2 "Cohort 1~2" will be performed for 
the Cohort 5~7 
7.11.3 Vital Signs and Weight 
7.11.3.1 Body Temperature, Respiratory Rate, Systolic and Diastolic Blood Pressure in 
Sitting Position, Pulse Rate and Weight 
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Temperature 
 
 
Systolic Blood Pressure 
 
 
Diastolic Blood Pressure 
 
 
Respiration Rate 
 
 
Pulse Rate 
 
 
Weight 
 
Visit: 
Pulse Rate, Systolic Blood Pressure, Diastolic Blood Pressure: Predose, 
0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 Hours 
Postdose, Day 7 
Respiration Rate, Temperature : Predose, 5 Hours Postdose, Day 2 
Weight: Predose, Day 2, Day 7 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
The following summaries will be provided by dose level. 
 
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Vital Signs Parameters and Weight 
Plots over time for each subject will be presented. 
Property of 
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Terms of Use


 
TAK-925-1001 
Page 46 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.1 "Cohort 1~2" will be performed for 
the Cohort 3.  
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.1 "Cohort 1~2" will be performed for 
the Cohort 4.  
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : 
 
Temperature 
 
 
Systolic Blood Pressure 
 
 
Diastolic Blood Pressure 
 
 
Respiration Rate 
 
 
Pulse Rate 
 
Visit: 
Pulse Rate, Systolic Blood Pressure, Diastolic Blood Pressure: Predose, 
0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 Hours Postdose  
Respiration Rate, Temperature : Predose, 5 hours Postdose, 1 day Postdose 
 (For the period 1, data obtained at Day 2 will be used as the "1 day 
Postdose" visit. For the period 2, data obtained at Day 4 will be used as the 
"1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.1 "Cohort 1~2" will be performed for 
the Cohort 5~7.  
7.11.3.2 Systolic and Diastolic Blood Pressure in Standing Position 
Cohort 1~2 
Analysis Set: Safety Analysis Set
Property of Takeda: 
Analytic
Analytic
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TAK-925-1001 
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Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Analysis 
Variable(s) : 
 
Systolic Blood Pressure (1 minute 
after standing) 
 
 
Diastolic Blood Pressure (1 minute 
after standing) 
 
 
Systolic Blood Pressure (5 minutes 
after standing) 
 
 
Diastolic Blood Pressure (5 minutes 
after standing) 
 
Visit: 
1 Hour Postdose 
Analytical 
Method(s) : 
 
The following summary will be provided by dose level. 
(1)  Summary of Systolic and Diastolic Blood Pressure in Standing 
Position 
Descriptive statistics for observed values will be provided. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort 3. 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.3.2 "Cohort 1~2" will be performed for 
the Cohort 5~7. 
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to the applicable Terms of Use


 
TAK-925-1001 
Page 48 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
7.11.4 12-Lead ECGs 
Cohort 1~2 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QRS Interval 
 
 
QT Interval 
 
 
QTcF Interval 
 
 
Interpretation 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Visit: 
Predose, 2~9 Hours Postdose, Day 2 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
For each variable other than 12-lead ECG interpretations, summaries (1) 
and (2) will be provided by dose level. 
For 12-lead ECG interpretation, summary (3) will be provided by dose 
level. 
 
(1) Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of ECG Parameters 
Plots over time for each subject will be presented. 
 
(3) Summary of Shift of 12-lead ECG Interpretation 
Shift table showing the number of subjects in each category at 
"Predose" visit and each postdose visit will be provided. 
Cohort 3 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort 3. 
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the applicable Terms of Use


 
TAK-925-1001 
Page 49 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
Cohort 4 
Analysis Set: Safety Analysis Set
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort 4. 
Cohort 5~7 
Analysis Set: Safety Analysis Set
Visit: 
Predose, 2~9 Hours Postdose, 1 day Postdose 
(For the period 1, data obtained at Day -1 will be used as the "Predose" visit 
and data obtained at Day 2 will be used as the "1 day Postdose" visit. For 
the period 2, data obtained at Day 2 will be used as the "Predose" visit and 
data obtained at Day 4 will be used as the "1 day Postdose" visit.)  
Analytical 
Method(s) : 
 
The same analysis as section 7.11.4 "Cohort 1~2" will be performed for the 
Cohort 5~7. 
7.11.5 Other Observations Related to Safety
Not applicable. 
7.12 
Interim Analysis 
In this study, a sponsor's unblinded team will be organized. The sponsor's unblinded team 
must not directly be involved in the execution of the study at a study site or directly contact 
the site. After cohort 5, this team will review unblinded data on the safety, tolerability and 
pharmacodynamic effects (MWT) and available PK of TAK-925 obtained from cohort 5, and 
recommend a dose level for cohort 6 based on such data. After cohort 6, the dose and the 
number of subjects to be used in Cohort 7 will be recommended by the sponsor’s unblinded 
team on the basis of safety, tolerability, pharmacodynamic effects (MWT) and available PK 
data of TAK-925 obtained from Cohorts 5 and 6. 
7.13 
Changes in the Statistical Analysis Plan  
The analyses in the statistical analysis plan do not differ from the analyses specified in the 
protocol.  
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TAK-925-1001 
Page 50 of 50 
Statistical Analysis Plan 1st 
14 February 2018 
CONFIDENTIAL 
8.0 
REFERENCES 
No reference. 
of Takeda: For non-commercial use only and subject to the applicable Terms of Use