Clinical trial NCT03748979
Conditions: Healthy Participants Narcolepsy
Sponsor: Takeda
Start date: 2018-11-21; Completion date: 2019-10-24
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-925 when administered to healthy participants and narcolepsy participants.

Detailed description:
The drug being tested in this study is called TAK-925. TAK-925 is being tested in healthy participants and participants with narcolepsy. This study will look at the safety, tolerability, pharmacokinetics, and efficacy of TAK-925.

This study will consist of three parts. Part A will be a randomized, double-blind, placebo-controlled, multiple rising dose (MRD) study in healthy participants. Part B is a randomized, double-blind, placebo-controlled MRD study in participants with narcolepsy. Part C is a randomized, double-blind, placebo-controlled, parallel group, multiple repeat dose study in participants with narcolepsy. Part A' is a single dose study in healthy participants.

The study will enroll approximately 96 participants planned as total. All participants except Part A' will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need):

Part A:

* TAK-925 (Dose Levels A1-A6)
* Placebo

Part B:

* TAK-925 (Dose Levels B1-B4)
* Placebo

Part C:

* TAK-925 (Dose Levels C1-C2)
* Placebo

Part A':

• TAK-925 (Dose Levels A'1-A'2)

All participants will be asked to take TAK-925 or Placebo at the same time each day from Day 1 to Day 7 in Parts A, B and C, and take TAK-925 on Day 1 in Part A'.

This multi-center trial will be conducted in Japan. The overall study period is approximately 15 days in Parts A, B and C, and approximately 7 days for Part A'. Participants will be partly admitted to a hospital during the study.

Arms: arm 1: TAK-925, Dose Level A, once daily for up to 7 days in healthy participants. arm 2: TAK-925, Dose Level A2, once daily for up to 7 days in healthy participants. Dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 3: TAK-925, Dose Level A3, once daily for up to 7 days in healthy participants. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 4: TAK-925, Dose Level A4, once daily for up to 7 days in healthy participants. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 5: TAK-925, Dose Level A5, once daily for up to 7 days in healthy participants. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 6: TAK-925, Dose Level A6, once daily for up to 7 days in healthy elderly participants. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 7: TAK-925 Placebo, once daily for up to 7 days in healthy participants. arm 8: TAK-925, Dose Level B1, once daily for up to 7 days in participants with narcolepsy. arm 9: TAK-925, Dose Level B2, once daily for up to 7 days in participants with narcolepsy. Dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 10: TAK-925, Dose Level B3, once daily for up to 7 days in participants with narcolepsy. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 11: TAK-925, Dose Level B4, once daily for up to 7 days in participants with narcolepsy. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 12: TAK-925 Placebo, once daily for up to 7 days in participants with narcolepsy. arm 13: TAK-925, Dose Level C1, once daily for up to 7 days in participants with narcolepsy. Dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 14: TAK-925, Dose Level C2, once daily for up to 7 days in participants with narcolepsy. This group is an additional optional cohort and dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts. arm 15: TAK-925 Placebo, once daily for up to 7 days in participants with narcolepsy. arm 16: TAK-925, Dose Level A'1, single dose in healthy participants. arm 17: TAK-925, Dose Level A'2, single dose in healthy participants. Dose level will be determined based on the data of safety, tolerability and PK data from previous cohorts.
Interventions: intervention 1: TAK-925 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-925 intervention 2: TAK-925 Placebo

Protocol documents:
Prot_001.pdf: 
Title: A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 
TAK-925 in Healthy Volunteers and Patients with Narcolepsy 
NCT Number: NCT03748979 
Protocol Approve Date: 12-JUN-2019 
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 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-925 in 
Healthy Volunteers and Patients with Narcolepsy
Study Identifier:
TAK-925-1003
Compound:
TAK-925 (Research Name: TAK-925 iv, TAK-925)
Date:
12 June 2019
Version/Amendment 
Number:
Amendment 3
Amendment History:
Date
Amendment Number
Region
10 Oct 2018
Initial Version
All sites
05 Nov 2018
Amendment 1
All sites
18 Jan 2019
Amendment 2
All sites
12 Jun 2019
Amendment 3
All sites
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TAK-925
Study ID TAK-925-1003
Page 2 of 128
Protocol
12 June 2019
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................13
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................14
4.0
INTRODUCTION.........................................................................................................26
4.1
Background .............................................................................................................26
4.1.1
Orexin..............................................................................................................26
4.1.2
TAK-925 .........................................................................................................27
4.2
Rationale for the Proposed Study.............................................................................29
4.3
Benefit/Risk Profile .................................................................................................29
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................31
5.1
Hypothesis...............................................................................................................31
5.1.1
Primary Hypothesis..........................................................................................31
5.1.2
Secondary Hypothesis......................................................................................31
5.2
Trial Objectives .......................................................................................................31
5.2.1
Trial Primary Objective....................................................................................31
5.2.2
Trial Secondary Objectives ..............................................................................31
5.2.3
32
5.3
Endpoints.................................................................................................................33
5.3.1
Primary Endpoint.............................................................................................33
5.3.2
Secondary Endpoints........................................................................................33
5.3.3
33
5.3.4
33
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................35
6.1
Trial Design.............................................................................................................35
6.2
Dose Escalation .......................................................................................................43
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................43
6.3.1
Rationale for Study Population.........................................................................43
6.3.2
Rationale of Trial Design .................................................................................44
6.3.3
Rationale for Dose ...........................................................................................46
6.3.4
Rationale for Endpoints....................................................................................50
6.3.5
Critical Procedures Based on Trial Objectives: Timing of Procedures..............50
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................51
6.5
Trial Beginning and End/Completion.......................................................................53
CCI
CCI
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TAK-925
Study ID TAK-925-1003
Page 3 of 128
Protocol
12 June 2019
6.5.1
Definition of Beginning of the Trial.................................................................53
6.5.2
Definition of End of the Trial...........................................................................53
6.5.3
Definition of Trial Completion.........................................................................53
6.5.4
Definition of Trial Discontinuation ..................................................................53
6.5.5
Criteria for Premature Termination or Suspension of the Trial .........................53
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............55
7.1
Inclusion Criteria .....................................................................................................55
7.2
Exclusion Criteria ....................................................................................................57
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products.........60
7.3.1
Concomitant Medications ................................................................................62
7.3.2
Fruit Juice........................................................................................................63
7.3.3
Alcohol............................................................................................................63
7.3.4
Caffeine ...........................................................................................................63
7.3.5
Smoking ..........................................................................................................63
7.4
Diet, Fluid, and Activity ..........................................................................................64
7.4.1
Diet and Fluids.................................................................................................64
7.4.2
Activity............................................................................................................64
7.5
Record of Discontinuation or Withdrawal of a Subject before Study Drug 
Administration.........................................................................................................65
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................65
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................67
7.8
Subject Replacement................................................................................................67
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................68
8.1
Clinical Study Drug .................................................................................................68
8.1.1
Clinical Study Drug Labeling...........................................................................68
8.1.2
Clinical Study Drug Inventory and Storage ......................................................69
8.1.3
Clinical Study Drug Blinding...........................................................................69
8.1.4
Randomization Code Creation and Storage ......................................................69
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ..................................69
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................69
8.2
Ancillary Supplies ...................................................................................................69
9.0
STUDY PROCEDURES...............................................................................................71
9.1
Administrative Procedures.......................................................................................71
9.1.1
Informed Consent Procedure............................................................................71
9.1.2
Inclusion and Exclusion ...................................................................................71
9.1.3
Medical History, Demographics, and Prior and Concomitant Medications .......72
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TAK-925
Study ID TAK-925-1003
Page 5 of 128
Protocol
12 June 2019
10.2.4
Start Date.........................................................................................................95
10.2.5
End Date..........................................................................................................95
10.2.6
Pattern of Adverse Event (Frequency)..............................................................95
10.2.7
Action Taken With Study Treatment................................................................95
10.2.8
Outcome ..........................................................................................................96
10.2.9
Collection and Reporting of AEs, SAEs and Abnormal LFTs...........................96
10.2.10 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...99
11.0
STATISTICAL METHODS........................................................................................100
11.1
Statistical and Analytical Plans ..............................................................................100
11.1.1
Analysis Sets .................................................................................................100
11.1.2
Analysis of Demography and Other Baseline Characteristics .........................100
11.1.3
PK Analysis...................................................................................................100
11.1.4
PD Analysis...................................................................................................101
11.1.5
Safety Analysis ..............................................................................................101
11.2
Interim Data Review..............................................................................................102
11.3
Determination of Sample Size................................................................................103
12.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................104
12.1
Study-Site Monitoring Visits .................................................................................104
12.2
Protocol Deviations................................................................................................104
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................104
13.0
ETHICAL ASPECTS OF THE STUDY......................................................................105
13.1
IRB and/or IEC Approval ......................................................................................105
13.2
Subject Information, Informed Consent, and Subject Authorization .......................106
13.3
Subject Confidentiality ..........................................................................................107
13.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................107
13.4.1
Publication and Disclosure.............................................................................107
13.4.2
Clinical Trial Registration..............................................................................108
13.4.3
Clinical Trial Results Disclosure....................................................................108
13.5
Insurance and Compensation for Injury..................................................................108
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.......................................109
14.1
Administrative Information....................................................................................109
14.1.1
Study Contact Information.............................................................................109
14.1.2
INVESTIGATOR AGREEMENT .................................................................109
14.1.3
Study-Related Responsibilities.......................................................................109
14.1.4
List of Abbreviations .....................................................................................109
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TAK-925
Study ID TAK-925-1003
Page 7 of 128
Protocol
12 June 2019
1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-925
Study Identifier: TAK-925-1003
Phase: 1
Protocol Title: A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-925 in Healthy Volunteers and Patients 
with Narcolepsy
Trial Design:
This study will consist of three parts. Part A is a randomized, double-blind, placebo-controlled, multiple rising dose 
(MRD) study to assess safety, tolerability, and pharmacokinetics (PK) of TAK-925 administered via intravenous (IV) 
infusion in healthy subjects. Part B is a randomized, double-blind, placebo-controlled MRD study to assess the safety, 
tolerability, PK and pharmacodynamics (PD) of TAK-925 administered via IV infusion in patients with narcolepsy 
type 1 (NT1). Part C is a randomized, double-blind, placebo-controlled, parallel group, multiple repeat dose study to 
assess the safety, tolerability, PK and PD of one or more dose levels of TAK-925 vs. placebo in patients with 
narcolepsy type 2 (NT2). Part A' is an open-label single oral dose study to assess PK, safety and tolerability of 
TAK-925 administered orally in healthy subjects. Parts A - A' may be conducted in parallel, rather than sequentially, 
depending on the doses administered and emerging safety/tolerability data.
In general, considering the completion times of the prior studies, TAK-925-1001 and TAK-925-1002, Part A, Part B 
and Part A' are expected to begin in parallel. Part A will test safety and tolerability in healthy volunteers (HV) starting 
from the dose level associated with that was found to be safe and tolerable based on the preliminary blinded safety 
adverse event (AE) profiles in TAK-925-1001 study. Part B will test safety, tolerability and PD in NT1 patients, who 
will be administered a lower dose than subjects in Part A. The initial dose in Part B was found to be safe and tolerable 
based on the preliminary blinded safety AE profiles in NT1 patients in the TAK-925-1001 study. The initial dose in 
Part B is more than 10 times lower than the highest dose level tested in TAK-925-1001 HV cohorts. Results from the 
TAK-925-1001 study will also be available at the time of initiation of Part A and Part B. Part A' will assess the safety, 
tolerability and PK after oral administration of TAK-925 in healthy volunteers at a dose level that was found to be safe 
and tolerable after IV administration in TAK-925-1001 study and is anticipated to result in lower exposure of 
TAK-925 after oral administration, due to high first-pass metabolism expected from available nonclinical data. For 
Part C, the NT2 patient doses are expected to be similar to that in Part A, although recruitment of these cohorts will be 
slower. Initiation of Part A and Part C may also occur at the same time if the similar doses are studied. The initiation of 
cohorts in parallel with each other is contingent on Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) approval, and if not approved, the cohorts will enroll as required, which may be sequentially or overlapping with 
each other. The NT1 and NT2 patients recruited are expected to be generally healthy other than having narcolepsy.
For more details, see Section 6.1.
Trial Primary Objective:
<All Parts>
To investigate the safety and tolerability of TAK-925 when administered to healthy subjects and NT1 and NT 2 
patients.
Secondary Objectives:
<All parts>
To investigate the pharmacokinetics of TAK-925 when administered to healthy volunteers or narcolepsy patients
<Parts B and C>
To investigate the PD of TAK-925 after multiple doses, primarily with evaluation of sleep latency on maintenance of 
wakefulness test (MWT) when TAK-925 is administered to NT1 or NT2 patients.
Trial Subject Population: Healthy adults, healthy elderly volunteers and patients with NT1 and NT2.
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TAK-925
Study ID TAK-925-1003
Page 8 of 128
Protocol
12 June 2019
Planned Number of Subjects:
(1) Part A Healthy adults
• Cohort A1: 8 subjects
• Cohort A2: 8 subjects
• Cohort A3 (optional): 8 subjects
• Cohort A4 (optional): 8 subjects
• Cohort A5 (optional): 8 subjects
• Cohort A6 (optional healthy elderly): 8 subjects.
(2) Part B NT1 patients
• Cohort B1: 6 subjects
• Cohort B2: 6 subjects
• Cohort B3 (optional): 4-6 subjects from B1 or B2, or
newly enrolled subjects.
• Cohort B4 (optional): 4-6 subjects from B1 or B2 or
newly enrolled subjects.
(3) Part C NT2 patients
• Cohort C1: 6 subjects
• Cohort C2 (optional): 6 subjects
Numbers for Part B and C show target number of 
subjects.
(4) Part A' Healthy adults
• Cohort A'1: 6 subjects
• Cohort A'2 (optional): 6 subjects
Planned Number of Sites:
3 sites
Dose Levels:
Dose Regimens:
Dosage:
<Part A>
Healthy adults and healthy elderly: TAK-925 or 
placebo is to be administered via IV infusion over 9 
hours once daily up to 7 days.
<Part B>
NT1 patients: TAK-925 or placebo is to be 
administered via IV infusion over 9 hours or longer 
once daily up to 7 days.
<Part C>
NT2 patients: TAK-925 or placebo is to be 
administered via IV infusion over 9 hours once daily up 
to 7 days.
<Part A'>
Healthy adults: TAK-925 is to be administered as a 
single oral dose
Administration:
<Part A, B and C>
Route of Administration:
<Part A, B and C>
intravenous (IV)
<Part A'>
Oral
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TAK-925
Study ID TAK-925-1003
Page 9 of 128
Protocol
12 June 2019
TAK-925 1.5 to 240 mg/9h is to be administered. The 
maximum dose cap in this study will be 240 mg/9h or 
dose levels which could be administered within 
equivalent infusion rate with 240 mg/9h when infusion 
time is longer.
<Part A'>
TAK-925 112 to 336 mg (given as oral solution) is to 
be administered in fasting condition.
Duration of Treatment:
<Part A, B and C>
7 days
<Part A'>
1 day
Planned Trial Duration:
<Part A>
Screening period: Day -28 to Day -3
Check-in: Day -2
Treatment Period: Day 1 to 7
Follow up visit: Day 15
<Part B and C>
Screening period: Day -42 to Day -3
Check-in: Day -2
Treatment Period: Day 1 to 7
Follow up visit: Day 15
Patients who will roll over from B1 or B2 to B3 or B4 could 
repeat the trial duration twice.
<Part A'>
Screening period: Day -28 to Day -2
Check-in: Day -1
Treatment Period: Day 1
Follow up phone call: Day 7
Main Criteria for Inclusion:
In order to be eligible for study participation, the following criteria must be satisfied:
1.
The subject must understand the study procedures and agree to participate by providing written informed
consent.
2.
The subject must be willing and able to comply with all study procedures and restrictions.
3.
The subject must be judged to be in good health by the investigator to participate in the study, based on clinical
evaluations including laboratory safety tests, medical history, physical examination, 12-lead electrocardiogram,
and vital sign measurements performed at the Screening Visit and prior to the first dose of study drug or first
invasive procedure.
4.
For a male subject who is nonsterilized and sexually active with a female partner of childbearing potential, the
subject must meet the following birth control requirements:
• Is a male subject who is sterile or agrees to use an appropriate method of contraception, including a condom
with or without spermicidal cream or jelly, from the first dose of study drug until 92 days after the last dose of
study drug. No restrictions are required for a vasectomized male subject provided the subject is at least 1 year
post bilateral vasectomy procedure prior to the first dose of study drug. A male subject whose vasectomy
procedure was performed less than 1 year prior to the first dose of study drug must follow the same restrictions
as a nonvasectomized man. Appropriate documentation of surgical procedure should be provided.
• Is a male subject who agrees to not donate sperm from the first dose of study drug until 92 days after the last
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TAK-925
Study ID TAK-925-1003
Page 13 of 128
Protocol
12 June 2019
2.0
STUDY SCHEMATIC
Table 2.a
Outline of the Study Parts and Planned Dosing Cohorts
Part
Cohort/Panel
Daily dose level 
(mg)
Dosing regimen
Randomization
Part A (Healthy 
adults)#
A1
44
IV infusion over 9 hours
up to 7 days. Start time 
of infusion could be 
changed in optional 
cohorts A3 to A5.
8 subjects randomized 6:2 to 
TAK-925 vs. placebo in each 
cohort, double-blind
A2
112 (TBD)
A3*
TBD
A4*
TBD
A5*
TBD
A6 (elderly)*
TBD
Part B (NT1 
patients)#
B1
11
IV infusion over 9 hours
up to 7 days
6 subjects randomized 4: 2 to
TAK-925 vs. placebo in each 
cohort, double-blind
B2
44 (TBD)
B3*
TBD
IV infusion with longer 
(TBD) hours up to 7 
days
4-6 subjects randomized (3:1,
4:1 or 5:1) to TAK-925 vs.
placebo in each cohort,
double-blind
B4*
TBD
IV infusion over 9 hours 
up to 7 days, different, 
increasing dose from 
Day 1 to Day 7
Part C (NT2 
patients)#
C1
44 (TBD)
IV infusion over 9 hours
up to 7 days
6 subjects randomized 4: 2 to 
TAK-925 vs. placebo in each 
cohort, double-blind
C2*
TBD
Part A' (Healthy 
adults)
A'1
112
Single oral 
administration
6 subjects per cohort 
(TAK-925 administration, 
open)
A'2*
TBD
Abbreviations: TBD, To Be Determined
Doses in subsequent cohorts in all parts will be determined based on the emerging safety/tolerability and PK (when 
available) and PD information and available safety/tolerability, and PK/PD data from previous cohorts as well as the 
ongoing TAK-925-1001 and TAK-925-1002 studies. Planned number of subjects in each cohort is shown.
# All doses given by IV infusion over 9 hours daily for 7 days except B3
* Optional cohorts
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TAK-925
Study ID TAK-925-1003
Page 26 of 128
Protocol
12 June 2019
CONFIDENTIAL
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 is greatly needed.
4.1.1
Orexin
Orexin is a neuropeptide and the orexinergic system is a major wake-promoting system of the 
brain. Two orexinergic neuropeptides, OX-A and OX-B, have been identified to date. The orexins 
exert effects via 2 types of receptors, the orexin type-1 receptor (OX1R) and the orexin type-2 
receptor (OX2R). OX-A has a high affinity to OX1R and OX2R, and OX-B has a high affinity to 
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TAK-925
Study ID TAK-925-1003
Page 28 of 128
Protocol
12 June 2019
The first-in-human (FIH) phase 1 study (TAK-925-1001), is currently being conducted in Japan. 
This study is designed to assess the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of single, ascending doses of TAK-925 when administered via a 9-hour 
IV infusion to healthy adult and elderly adult subjects (aged ≥65 years old) and patients with NT1. 
Based on preliminary blinded safety data, single doses ranging from 7 to 240mg in healthy 
subjects (approximately 8 subjects per cohort), and single doses of 11.2 and 44.8mg tested in NT1 
patients (4 subjects per cohort), have been safe and well tolerated with no severe or serious adverse 
events. All adverse events except influenza (considered as moderate) were mild in intensity. All 
cardiovascular related adverse events (blood pressure increased, pulse rate increased) were 
considered mild by the investigator. At dose levels less than 240mg, the BP and PR effects were 
not clearly present for any one individual. Some BP and/or PR increase adverse events related to 
orthostatic position were also reported at the dose level of 134.4mg or higher.
Following a single IV infusion, mean plasma systemic exposure of TAK-925 (Cmax, observed 
plasma concentration at the end of infusion [Ceoi], and area under the plasma concentration-time 
curve from time 0 to infinity [AUC∞]) increased approximately dose proportionally across dosing 
cohorts. On average, time to reach plateau was approximately 3 hours and the plasma terminal 
elimination t1/2ranged approximately from 3.8 to 5 hours across all doses. Further details can be 
found in the IB. TAK-925 exposure was increased by <30% in elderly subjects possibly due to 
decreased hepatic clearance.
In parallel with the FIH study described above, a proof of mechanism (POM)study in 
sleep-deprived healthy subjects is also ongoing in the US. This is a 4-period crossover study 
evaluating the PD effect on wakefulness, including maintenance of wakefulness test (MWT) sleep 
latency, of 2 single doses of TAK-925, 44mg and 112mg, each delivered as a 9-hour IV infusion, 
vs. modafinil 300mg as an active comparator, and placebo. Results from this study will inform 
potential therapeutic use of TAK-925 inother patient populations with sleep disorders not 
associated with orexin deficiency, including patients with narcolepsy type 2 (NT2). Hence in this 
proposed multiple rising dose (MRD) study, both orexin deficient (NT1 patients) and normal 
orexin conditions (NT2 patients) will be evaluated.
CCI
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TAK-925
Study ID TAK-925-1003
Page 29 of 128
Protocol
12 June 2019
4.2
Rationale for the Proposed Study
The primary objective of the current study is to evaluate the safety, tolerability, PK, efficacy and 
other PD of TAK-925 after repeated administration to
 
The available nonclinical 
pharmacology, PK, and toxicology data and the preliminary clinical data from the FIH trial 
(TAK-925-1001) and a POM trial (TAK-925-1002) support the current trial design. The safety, 
tolerability, PK, efficacy and PD data obtained from the proposed MRD study will inform the
design of and dosing regimen selection for subsequent studies with TAK-925.
4.3
Benefit/Risk Profile
TAK-925 is a first-in-class OX2R-selective agonist. Preclinical pharmacology studies 
demonstrated that TAK-925 had arousal effects in hypersomnolent states both in animals with 
orexin deficiency (mice) and animals without orexin deficiency (mice, cynomolgus monkeys and 
marmosets). To explore potential effects in human, the ongoing TAK-925-1001 (first-in-human, 
FIH) and TAK-925-1002 (POM) studies include, in addition to healthy subjects, narcolepsy 
patients with orexin deficiency (NT1) and sleep-deprived healthy subjects. In this proposed MRD 
study, NT1 patients (orexin deficient) and NT2 patients (normal to somewhat reduced orexin 
levels) will both be evaluated. The results may provide early clues on whether TAK-925 has 
sustained effects in both NT1 and NT2 patients.
Safety information is limited to the data from nonclinical studies and blinded single rising dose 
(SRD) (TAK-925-1001) clinical studies available in healthy subjects and small number of NT1 
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TAK-925
Study ID TAK-925-1003
Page 30 of 128
Protocol
12 June 2019
patients(data will be unblinded at the time of conduct of this study). 
 
 In current clinical 
studies, TAK-925 is infused at low rate over 9 hours. At dose levels up to 240mg, the Cmaxwas 
lower than that of monkey’s in which a 
 was observed. No 
 have occurred to 
date in the TAK-925-1001 and TAK-925 -1002 studies.
 
, would be expected to result in rapid 
resolution of increased blood pressure.
Clinical data from the ongoing SRD studies demonstrate TAK-925 is safe and well tolerated at 
dose levels up to 240mg (preliminary blinded data). Review of available nonclinical and clinical 
drug safety data, when viewed in context of the potential benefit for patients with narcolepsy, 
supports a favorable benefit/risk ratio for TAK-925.
To date, the observedsafety data for TAK-925, including mild and manageable adverse events, are 
acceptable considering the potential clinical benefit of TAK-925, and clinical study of TAK-925 
should continue.
In the protocol amendment 2 (which primarily adds Part A'for oral dosing), 
 
 
 
 No toxicity that modifies the clinical benefit/risk 
profiles of TAK-925 was found.
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TAK-925
Study ID TAK-925-1003
Page 31 of 128
Protocol
12 June 2019
5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designed based on the following hypothesis:
5.1.1
Primary Hypothesis
<Part A and C>
One or more safe and well-tolerated multiple IV infusion TAK-925 dose levels will achieve a Ceoi
(plasma concentration at the end of infusion) greater than or equal to the estimated concentration 
threshold required for efficacy in hypersomnia patients with normal CSF orexin level.
<Part B>
One or more safe and well-tolerated multiple IV infusion TAK-925 dose levels will achieve a Ceoi
(plasma concentration at the end of infusion) greater than or equal to the estimated concentration 
threshold required for efficacy in hypersomnia patients with low CSF orexin level.
5.1.2
Secondary Hypothesis
At least 1 dose of TAK-925 shows a clinically meaningful difference (expected to be at least 3 
minutes) from placebo for promoting wakefulness as measured by sleep latency using the MWT, 
after multiple dosing.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
<All Parts>
To investigate the safety and tolerability of TAK-925 when administered to healthy subjects and 
NT1 and NT2 patients.
5.2.2
Trial Secondary Objectives
<All parts>
To investigate the pharmacokinetics of TAK-925 when administered to healthy volunteers or 
narcolepsy patients
<Part B and C>
To investigate the PD of TAK-925 after multiple doses, primarily with evaluation of sleep latency 
on MWT when TAK-925 is administered to NT1 and NT2 patients.
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TAK-925
Study ID TAK-925-1003
Page 35 of 128
Protocol
12 June 2019
6.0
TRIALDESIGN AND DESCRIPTION
6.1
TrialDesign
This study will consist of 3parts. Part A is a randomized, double-blind, placebo-controlled, MRD 
study to assess safety, tolerability, and PK of TAK-925 administered via intravenous (IV) infusion 
in healthy subjects. Part B is a randomized, double-blind, placebo-controlled MRD study to assess 
the safety, tolerability, PK and PD of TAK-925 administered via IV infusion in patients with NT1. 
Part C is a randomized, double-blind, placebo-controlled, parallel group multiple repeat dose study 
to assess the safety, tolerability, PK and PD of one or more dose levels of TAK-925 vs. placebo in 
patients with NT2. Part A'is an open-label single oral dose study to assess PK, safety and 
tolerability of TAK-925 administered orally in healthy subjects. Parts A -A'may be conducted in 
parallel, rather than sequentially, depending on the doses administered and emerging 
safety/tolerability data.
In general, considering the completion times of the prior studies, TAK-925-1001 and 
TAK-925-1002, Part A, Part B and Part A'are expected to begin in parallel. Part A will test safety 
and tolerability in healthy volunteers (HV) starting from the dose level associated with that was 
found to be safe and tolerable based on the preliminary blinded safety adverse event (AE) profiles 
in TAK-925-1001 study. Part B will test safety, tolerability and PD in NT1 patients, who will be 
administered a lower dose than subjects in Part A. The initial dose in Part B was found to be safe 
and tolerable based on the preliminary blinded safety AE profiles in NT1 patients in the 
TAK-925-1001 study. The initial dose in Part B is more than 10 times lower than thehighest dose 
level tested in TAK-925-1001 HV cohorts. Results from the TAK-925-1001 study will also be 
available at the time of initiation of Part A and Part B. Part A'will assess the safety, tolerability and 
 TAK-925 
 to healthy volunteers at a dose level that was found to be 
safe and tolerable after IV administration in TAK-925-1001 study and is anticipated to result in 
lower exposure of TAK-925 after oral administration, 
 
 For Part C, the NT2 patient doses are expected to be similar to that 
in Part A, although recruitment of these cohorts will be slower. Initiation of Part A and Part Cmay 
also occur at the same time if the similar doses are studied. The initiation of cohorts in parallel with 
each other is contingent on Institutional Review Board(IRB)/Independent Ethics Committee 
(IEC) approval, and if not approved, the cohorts will enroll as required, which may be sequentially 
or overlapping with each other. The NT1 and NT2 patients recruited are expected to be generally 
healthy other than having narcolepsy.
Part A–MultipleRising Dose in Healthy Adults
Part A will have 2 dose cohorts as well as additional 4 optional cohorts. Each cohort of healthy 
adults will consist of 8 healthy subjects, randomized 6:2 active to placebo to TAK-925 vs. placebo 
(Table 6.a) in double-blinded fashion. The starting dose is selected based on the available 
preliminary safety, PK and PD data from the ongoing TAK-925-1001 study. Subsequent doses 
will be guided by safety, PK and PD data from previous cohorts as well as the TAK-925-1002 
study (which is ongoing at the time of this protocol writing). TAK-925 or placebo will be 
administered as an IV infusion over 9 hours once daily for 7 days. Following review of emerging 
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TAK-925
Study ID TAK-925-1003
Page 36 of 128
Protocol
12 June 2019
safety and PK data (when available) in Cohort A1, the dose in Cohort A2 will be determined. 
Healthy adultsmay be recruited for up to 3 additional cohorts (A3 to A5) with 8 subjects each 
(randomized 6:2 active to placebo). The dose may be higher, lower or the same as that of prior 
cohort dose levels. Shifting the start time of infusion while keeping the dose the same as that 
previously studied may be considered in these optional cohorts 
 
. The maximum dose and infusion rate in Part A shall not exceed the maximum 
dose or maximum infusion rate studied in healthy subjects in TAK-925-1001 study. The dose 
levels in subsequent cohorts will be optimized based on the recommendation of sponsor’s 
unblinded team. The unblinded team will review available unblinded data including 
 
The safety and tolerability of the same or a lower dose than that of previous healthy adults cohorts 
may be studied in an optional cohort of healthy elderly subjects (N=8 subjects aged 65-80 years 
old, randomized 6:2 to TAK-925 vs.placebo) in Cohort A6. The healthy elderly optional cohort 
will be included as there are expected to be a few older patients in the Part B or Part C. It is 
expected that the healthy elderly cohort will provide data that supports the evaluation of TAK-925 
in
 
Part B –MultipleRising Dose in Narcolepsy Type 1 (NT1)  Patients
Part B will be conducted in NT1 patients. Two cohorts are planned, with optional cohorts allowed. 
For CohortsB1 and B2, each cohort will consist of 6 subjects, randomized 4:2 to TAK-925 vs.
placebo (Table 6.a) in double blinded fashion. TAK-925 or placebo will be administered as an IV 
infusion over 9 hours once daily for 7 days. Exploratory PD assessments will include evaluation of 
potential efficacy with 
Thestartingdose level in Part Bwill be selected based on preliminary data from the ongoing 
TAK-925-1001 study utilizingdata regarding safety and tolerability, PK and results on the KSS 
and MWTin the NT1 cohorts, as well as the safety, tolerability and PK results in the healthy adult 
cohorts in TAK-925-1001 and Part A of this study (if available). The doses in the subsequent 
cohorts will be determined basedon safety, tolerability,PDand available PKdata from previous 
cohorts and/or from the prior studies with TAK-925. The dose level chosen in each of the 
subsequent cohorts will be determined by the sponsor’s unblinded team composed of personnel 
who do not have subject contact or involvement with execution of the protocol at the site. The 
unblinded team will review unblinded safety, tolerability, and available PK and PDresults from 
previous cohorts. The dose in the subsequent cohorts may be higher, the sameas or lower than that 
used inthe previous cohort(s).
Two additional cohorts (B3 and B4) may be evaluated, with 4-6 subjects in each. With the 
intention of sequential panel design, NT1 patients in Cohort B1 or B2 may participate in Cohort 
B3 or B4 if feasible operationally. Patients in cohort B1 and B2 may participate in B3 or B4 after a 
sufficient washout period if and allowed by regulatory authorities and IRB/IEC. The subject who 
directly move on to cohort B3 or B4 could skip the Day 8 some assessmentsand follow up visit 
and move into Day-2 in B3 orB4. Cohort B3 or B4 will essentially consist of newly enrolled NT1 
patients, but patients from B1/B2 who weigh over 50kg could be also enrolled. There should be 
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TAK-925
Study ID TAK-925-1003
Page 37 of 128
Protocol
12 June 2019
sufficient intervals between the last dose in Cohort B1 or B2 and the first dose in Cohort B3or B4
in order to make dose and dosing duration decisions for Cohorts B3 and B4. If there are fewer than 
4 Cohort B1 or B2 subjects enrolled to Cohort B3or B4, new patients with NT1 will be recruited. 
In Cohorts B3 and B4, TAK-925 will be administered in a blinded randomized manner (3:1, 4:1 or 
5:1). The primary purpose of Cohort B3 is to evaluate the safety and tolerability and PD of longer 
infusion time, as well as to
 
 
 Otherwise, the design and procedures 
for B3 will be the same as the design of B1. The primary purpose of Cohort B4 is to assess the 
within-subject exposure-response relationship for PD/efficacy and safety of TAK-925 in NT1 
patients. Patients in this cohort will receive different, increasing doses of TAK-925 daily over the 7 
day period, the sequence of doses will be identical across patients. All subjects will receive the 
same dosing schedule. One subject within B3 and B4, respectively, will be randomized to placebo.
Part C–Multiple DosesinNarcolepsy Type 2 (NT2)  patients
Narcolepsy type 2 patients will be evaluated in CohortsC1 and C2. This part will start once 
TAK-925-1002 study data is available and once safety/tolerability information for the dose level to 
be tested in Part C is available from Part A. Conduct of the C2 cohort is optional. C1 and C2 
cohorts will recruit 6 subjects each, randomized 4:2 to TAK-925 vs.placebo in double-blinded 
fashion, with study drug administered as a 9-hour intravenous infusion for 7 days (Table 6.a). The 
doses selected for Part C depend on the results from the TAK-925-1002 study, and data from other 
cohorts in this study may also be used. The same schedule of study assessments as in Part B will be 
executed 
Part A'–Single Oral Dosesin Healthy Adults
Part A'will investigate the pharmacokinetics of TAK-925 after oral administration in healthy 
subjects. Cohort A'1 will consist of 6 healthy subjects who will be administered a single dose of 
TAK-925 as anoral solution in an open-label fashion (Table 6.a). An oral dose of 112mg is 
selected based on the safety and tolerability profiles in TAK-925-1001 study and available 
nonclinical data as a potential starting dose. 
 
 
(see Section 6.3.3). An optional Cohort A'2 is allowed based on the emerging information.
The study parts and planned dosing cohortsare outlined in Table 6.a.
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TAK-925
Study ID TAK-925-1003
Page 38 of 128
Protocol
12 June 2019
Table 6.a
Outline of the Study Parts and Planned Dosing Cohorts
Part
Cohort/Panel
Daily dose level
(mg)
Dosing regimen
Randomization
Part A
(Healthy adults)#
A1
44
IV infusion over 9 hours
up to 7 days. Start time of 
infusion could be changed 
in optional cohorts A3 to 
A5.
8 subjects randomized 6:2 
to TAK-925 vs. placebo in 
each cohort, double-blind
A2
112 (TBD)
A3*
TBD
A4*
TBD
A5*
TBD
A6 (elderly)*
TBD
Part B
(NT1 patients)#
B1
11
IV infusion over 9 hours
up to 7 days
6 subjects randomized 4: 2 
to TAK-925 vs. placebo in 
each cohort, double blind 
B2
44 (TBD)
B3*
TBD
IV infusion with longer 
(TBD) hours up to 7 days
4-6 subjects randomized
(3:1, 4:1 or 5:1 to
TAK-925 vs. placebo in
each cohort, double blind
B4*
TBD
IV infusion over 9 hours
up to 7 days, different, 
increasing dose from Day 
1 to Day 7
Part C
(NT2 patients)#
C1
44 (TBD)
IV infusion over 9 hours
up to 7 days
6 subjects randomized 4: 2 
to TAK-925 vs. placebo in 
each cohort, double blind
C2*
TBD
Part A' (Healthy 
adults)
A'1
112
Single oral administration
6 subjects per cohort 
(TAK-925 administration, 
open)
A'2*
TBD
Doses in subsequent cohorts in all parts will be determined based on the emerging safety/tolerability and PK (when 
available) and PD information and available safety/tolerability, and PK/PD data from previous cohorts as well as the 
ongoing TAK-925-1001 and TAK-925-1002 studies. Planned number of subjects in each cohort is shown.
# All doses given by IV infusion over 9 hours daily for 7 days except B3
* Optional cohorts
Study population
Healthy adults, healthy elderly volunteers and patients with NT1 and NT2.
Planned Number of Subjects:
(1) Part A Healthy adults

Cohort A1: 8 subjects

Cohort A2: 8 subjects

Cohort A3 (optional): 8 subjects

Cohort A4 (optional): 8 subjects

Cohort A5 (optional): 8 subjects
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TAK-925
Study ID TAK-925-1003
Page 43 of 128
Protocol
12 June 2019
6.2
Dose Escalation
Dose escalation in subsequent cohorts in all parts will be determined based on the available 
safety/tolerability and PK/PD data from previous cohorts as well as those from the ongoing 
TAK-925-1001 and TAK-925-1002 studies. Refer to the Section 6.3.3.1for Starting Dose, the 
Section 6.3.3.2for Maximum Dose and the Section 11.2for Interim Data Review in an unblinded 
manner. The dose escalation process will be concluded with the agreement between the sponsor's 
blinded team and the investigator(s) based on the dose recommendation of the sponsor's unblinded 
team. Please also refer to the Section 6.4for the situation when some cohorts might be run in 
sequential or in parallel without Interim Data Review by the sponsor.
Dose escalation will not occur in event the following criteria are met in any dosage level cohort:
A serious adverse events occurs for which causative relationships can not be denied:
Two cases or more of severe adverse events for which causative relationships can not be denied 
during the treatment with a singlecohort (from treatment initiation -to washout or at the time of 
completion of post-observation period)
Three or more cases of asymptomatic significantly increased blood pressure, as defined in Section 
7.6.
In Part B and C, elderly patient aged over 65 may be allowed to be enrolled in a cohort where daily 
dose is more than 112mg which the safety and tolerability was confirmed with elderly subjects in 
TAK-925-1001 study only after the safety and tolerability of TAK-925 in elderly subjects in Part 
A has been confirmed.
6.3
Rationale for TrialDesign, Dose, and Endpoints
6.3.1
Rationale for Study Population
(1) Part Aand A'(healthy subjects)
The subjects included in Part Aand Part A'will be healthy adultsand elderly(only Part A) who do
not have any significant diseases, cardiovascular or cerebrovascular health conditions. This will 
allow evaluation of the safety, tolerability and pharmacokinetic profiles of TAK-925 in a healthy 
population after repeated IV (Part A) or single oral (Part A') administration. Based on the 
observations in the single-rising dose study TAK-925-1001,
 
The healthy 
normal subjects in Part A are expected to be recruited quickly, before the NT2 cohorts are 
completed.
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Property of Takeda: For non-commercial use only and subject 
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TAK-925
Study ID TAK-925-1003
Page 45 of 128
Protocol
12 June 2019
essentiallyamedically healthy population other than having narcolepsy. Therefore, available data 
from TAK-925-1001 study supports starting this cohort in parallel with Part A. While typically 
healthy normal cohorts are dosed as a group, the NT1 patients would be enrolled individually and 
not as a cohort.  However, if regulatory and IRBs/IEC authorities disagree with conducting the 
cohorts in parallel, cohorts will be conducting in a sequential or overlapping manner.
The dose escalation process will be based on the safety and tolerability as well as PD effects of 
TAK-925 on sleep latency on the MWT. As such, it is critical that the data analysis will be done in 
a timely manner to ensure that this is available to the unblinded team. In order to preserve subject 
and site blinding and reduce any sponsor bias, a sponsor's unblinded team will be established that 
is composed of persons who do not have subject contact or involvement with execution of the 
protocol at the site. This team will review the safety, tolerability, available PK and results of the 
MWT and any other available data prior to determining the dosage in Cohort B2 and the necessity 
for any optional cohort, as well as the dose to be used in these cohorts. For cohorts B3, the daily 
dosing duration may be longer than in cohorts B1 or B2 and the doses may also be different. B3 
and B4 will be blinded and the same assessments conducted in B1 and B2 will be done, plus some 
additional assessments for B4. 
 
Patients in cohort B1 and B2 may participate in B3or B4after a sufficient washout period. The 
subject who directly move on to cohort B3 or B4 could skip Day 8 some assessment and follow up 
visit and move into Day-2 in B3 orB4. The Cohort B3 and B4 will be newly enrolled subjects or 
subjects from B1 or B2 over 50kg of weight.
Parallel group design was considered appropriate for narcolepsy patient part. Although cross over 
design is frequently used in Phase 1b study in order to keep sample size small and to be able to 
observe drug and placebo responses in the same subject, across over designwould require patients 
to be confined for over two weeksand this was not felt to be practical.
Typically, if G-protein coupled receptor (GPCR) desensitizationby receptor agonist occurs, this 
happenswithin ashort time frame of minutes (short reaction) or hours to days (longer reaction).
Based on this, seven days dosing should be sufficient to test the hypothesis.
A sample size of 6 subjects(4 active vs. 2 placebo) for B1 and B2 Cohorts was considered to be 
sufficient based on the fact that 4 subjectsin each NT1 cohort in TAK-925-1001 study gave 
sufficient information to decide the dose level in subsequent cohorts, whereas optional Cohorts B3 
and B4 are designed to randomize 4-6 subjects (3:1, 4:1 or 5:1 to TAK-925 vs. placebo). Part B
could be started once the appropriate dose level was determined based on TAK-925-1001 study 
resultsfrom the NT1 patient cohorts.
In cohort B4, a better understanding of within-subject exposure-response relationship for MWT
and 
will be obtained, along with an understanding of the variability of such relationship 
across individuals. This will help guide optimal dose selection in future studies. The dose will vary 
over the 7 days. Doses will be arranged in an increasing order over this period to minimize 
carry-over effects due to residual drug exposure from prior doses.
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Study ID TAK-925-1003
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(3) Part C
In Part C, a double-blind, placebo-controlled study design will be used. Results on the MWT will 
be compared between placebo and TAK-925.Whether an optional cohort C2 will be executed or 
not willbedecidedbased on the safety and tolerability as well as PD effects of TAK-925 on sleep 
latency on the MWTfrom cohort C1.Unblinded data review will be conducted to make this 
decision and to determine dose level in cohort C2. Parallel group design was considered 
appropriate for narcolepsy patient partwith the same reason described above for Part B. Number 
of subjects as 6 (4 active vs. 2 placebo) was again considered sufficient assuming the same effect 
size for NT2 with NT1 observed in TAK-925-1001 study.
 
 
Part C may be started once an appropriate dose level is determined based on either of 
TAK-925-1002 study resultsfrom the sleep deprived healthy population and/or resultsin Part A. 
In Part C, cohort C2 was not considered to beamandatory cohort and is optional.
(4) Part A'
Part A'is designed as an open-label single dose study to evaluate the safety, tolerability and 
 of 
TAK-925 after single oral administration in 6 healthy subjects. This is the first oral dosing in 
humans. Whether an optional cohort A'2 will be executed or not will be decided based on the 
emerging safety and 
 data from cohort A'1. 
 
.
6.3.3
Rationale for Dose
6.3.3.1 Starting Dose for This Trial
(1) Part A(healthy subjects)
Single doses from 7 to 240mg/day of TAK-925 were administered as an 9-hour intravenous (IV) 
infusion to healthy subjects in the TAK-925-1001 study in 5 cohorts (6 active and 2 placebo). 
Cohort 1 received 7, 28 and 112mg single doses and Cohort 2 received 14, 56 and 134.4mg single 
doses with a washout period of at least 7 days. Following data review in these 2 initial cohorts, 
6healthy elderly subjects (Cohort 3) received a single 112mg TAK-925, and 2 supplemental 
cohorts in healthy adult subjects (Cohorts 4 and 5) received 180 and 240mg single doses of 
TAK-925, respectively. It was considered that TAK-925 was generally safe and well-tolerated 
with no severe or serious adverse events (AEs) based on the blinded information in the dose range 
of ongoing TAK-925-1001 study.
 
 
 Preliminary PK findings showed approximate dose-proportional 
increases in plasma exposures of TAK-925 over the dose range studied. Mean TAK-925 plasma
exposure in elderly subjects was slightly greater (<30%) than that in younger healthy subjects, as a 
result of the reduced drug clearance. At the end of infusion, TAK-925 concentrations declined 
rapidly and in a biphasic manner with a mean terminal disposition phase half-life of about 3.8 to 5 
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hours across all doses. Additionally, single doses of 44 and 112mg/day of TAK-925 are being 
evaluated in sleep deprived healthy adults in the TAK-925-1002 study.
For PartA,44mg over a 9-hour IV infusion is considered to be safe as a starting dose in healthy 
subjects in order to support further characterization of the safety and tolerability profile of 
TAK-925 dosed daily for 7days, specifically any potential tolerance effects in BP after repeat dose 
administration. Considering the short elimination t1/2of TAK-925, little to no drug accumulation is 
expected following once daily dosing. Based on the preliminary PK results, mean AUC∞and Cmax
at 44.8mg were 972h*ng/mL and 98.3ng/mL, respectively. In comparison tothe exposures in 
 
(2) Part B (NT1 patients)
To date, single doses of 11.2 and 44.8mg/day of TAK-925 were administered as a 9-hour IV 
infusion to NT1patients in the TAK-925-1001 study. A third cohort is currently ongoing where 
patients will receive a single 5mg IV dose of TAK-925 over 9 hours. Both doses were safe and 
well-tolerated with no severe orserious adverse events. 
 
 Preliminary PK findings showed approximate 
dose-proportional increases in plasma exposures of TAK-925 and similarity in the TAK-925 PK 
profile between NT1 patients and healthy subjects. At 11.2mg dose level tested in NT1 patients, 
mean Ceoiwas 22.1ng/mL which was close to the estimated minimum effective exposure level 
from nonclinical studies (21.3ng/mL).
Therefore, 11mg is considered to be appropriate as a starting dose to examine safety, 
pharmacokinetics and pharmacodynamics profiles of TAK-925 dosed daily for 7 days, though 
5 mg which will be tested in TAK-925-1001 study as the 3rdNT1 cohort might be selected as an 
alternative starting dose depending on the result of the 3rdcohort of TAK-925-1001 study.
For Cohort B4, subjects will receive an increasing dose of TAK-925 over Days 1 to 7, although the 
dose on any one day may be the same as a prior day. The set of dose levels as well as the sequence 
of dose levels will be identical across subjects. The dose levels selected will target different parts 
of the anticipated dose-response curve: two dose levels in the plateau region, one in the bottom 
part and the remaining on the ascending part of the curve. Existing data from TAK-925-1001 study 
suggests 
 There is 
limited data to identify the lower end of the dose-response curve, an educated guess is that 
 
 Selection of final set of dose levels will be made once data from 
TAK-925-1001 all NT1 cohorts and TAK-925-1003 B1 and B2 cohorts become available.
(3) Part C(NT2 patients)
The starting dose in this part will be determined once results from the TAK-925-1002 study is 
available. Since levels of CSF orexin in NT2 patient may be mildly decreased or at normal levels, 
it is considered that the effective dose level may be similar to the healthy population as compared 
to orexin deficient NT1 population. In light of this, preliminary PD results fromstudy
TAK-925-1002 will guide dose selection for Part C.In addition,
 
 Therefore, the 
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TAK-925
Study ID TAK-925-1003
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in Adult HealthyVolunteers”[14], the calculated human 
 which 
is considered to be safe for oral administration.
6.3.3.2 Maximum Dose/Exposure for This Trial
For Parts A, B and C, the maximum dose cap in this study will be 240mg/9h or dose levels which 
could be administered within equivalent infusion rate with 240mg/9h when infusion time is longer. 
 
i.
Maximum dose/exposure based on NOAEL
Single doses up to 240mg/day of TAK-925 were administered as a 9-hour IVinfusion to healthy 
subjectsin TAK-925-1001 study. TAK-925wasgenerally safe andwell-toleratedwith no severe 
AEs or serious adverse events.
 
 
 
 
 
 
ii.
Part A(healthy volunteers) and Part C (NT2 patients)
The doses to be evaluated in healthy volunteers (Part A) and NT2 patients (Part C) in this MRD 
study are guided by the safety/tolerability profile obtained in study TAK-925-1001 and PD results 
from the TAK-925-1002 study in which 2 doses of TAK-925are currently studied in healthy 
subjects for effect on wakefulness during sleep deprivation. If these doses are ineffective in 
maintaining wakefulness under these conditions, doses greater than 112mg/day and up to 
240mg/daymay be studied in TAK-925-1003which is in the range of exposure (Cmax) tested in 
TAK-925-1001 single dose study.
iii.
Part B(NT1 patients)
In part B, NT1 patients will be administered doses up to and including approximately 44mg in 
cohort B1 and B2, which is the highest dose tested inthe single-rising dose study TAK-925 and 
considered to be safe in NT1 patients. Considering the short elimination t1/2of TAK-925, little to 
no drug accumulation is expected following once daily dosing. If attenuation in PD effect is 
observed after chronic dosing, the higher dose levels evaluated in Part A that did not have 
significant safety concerns or dose levels which could be administered by equivalent infusion 
speed may be also administered in Part B.
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Study ID TAK-925-1003
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In Part A', an additional optional cohort including 6 healthy subjects may be recruited, if further 
investigation of safety, tolerability and PK is deemed necessary. Again, the dose may be higher or 
the same to that of the prior cohort.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall study begins when the first subject signs the study informed consent form.
6.5.2
Definition of End of the Trial
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit, discontinues from the study, or is lost to follow-up 
(ie, the investigator is unable to contact the subject).
6.5.3
Definition of Trial Completion
The overall study is to be considered as completed as per the same definition as in Section 6.5.2.
6.5.4
Definition of Trial Discontinuation
Study discontinuation because of nonsafety reasons, such as the following:

A finding (eg, pharmacokinetic, pharmacodynamic, efficacy, biologic targets) from another
nonclinical or clinical study using the study treatment(s) results in the study being stopped for
a nonsafety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study
become available and results in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Study discontinuation because of safety reasons:

Early study termination because of unanticipated concerns of safety to the study subjects
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s)
of the same class, or methodology(ies) used in this study.
6.5.5
Criteria for Premature Termination or Suspension of the Trial
6.5.5.1 Criteria for Premature Termination or Suspension of Trial Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
or is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement.
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6.5.5.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Sites
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.
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Study ID TAK-925-1003
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including laboratory test results, need to be confirmed before the first dose of 
study drug.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
All subjects
1. The subject must understand the study procedures and agree to participate by providing written
informed consent.
2. The subject must be willing and able to comply with all study procedures and restrictions.
3. The subject must be judged to be in good health by the investigator to participate in the study,
based on clinical evaluations including laboratory safety tests, medical history, physical
examination, 12-lead electrocardiogram, and vital sign measurements performed at the
Screening Visit and prior to the first dose of study drug or first invasive procedure.
4. For a male subject who is nonsterilized and sexually active with a female partner of
childbearing potential, the subject must meet the following birth control requirements:
•
Is a male subject who is sterile or agrees to use an appropriate method of contraception,
including a condom with or without spermicidal cream or jelly, from the first dose of study
drug until 92 days after the last dose of study drug. No restrictions are required for a
vasectomized male subject provided the subject is at least 1 year post bilateral vasectomy
procedure prior to the first dose of study drug. A male subject whose vasectomy procedure
was performed less than 1 year prior to the first dose of study drug must follow the same
restrictions as a nonvasectomized man. Appropriate documentation of surgical procedure
should be provided.
•
Is a male subject who agrees to not donate sperm from the first dose of study drug until 92
days after the last dose of study drug.
Healthy adults (Parts A and A') and elderly (Part A)
5. The subject must be male or female.
6. The subject must have a body mass index (BMI) ≥18.5 to ≤30.0 kg/m2 at the Screening Visit.
7. The subject must be a current nonsmoker who has not used tobacco- or nicotine-containing
products (eg, nicotine patch) for at least 6 months prior to the first dose of study drug or first
invasive procedure.
8. The subject who is normotensive, with no history of hypertension or use of antihypertensive
medication. BP <140 systolic and <90 diastolic. BP measures should be obtained after the
patient has been resting a minimum of 10 minutes, and may be repeated 3 times in the event
that the BP is slightly elevated above these parameters. The average BP may be used based on
the investigator's or the subinvestigator's judgement.
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Study ID TAK-925-1003
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9. A female subject must meet one of the following birth control requirements:
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged >45 years
or 6 months of spontaneous amenorrhea in females aged >45 years with serum
follicle-stimulating hormone levels >40 mIU/mL). Appropriate documentation of
follicle-stimulating hormone levels is required.
Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate
documentation of surgical procedure.
Had a tubal ligation with appropriate documentation of surgical procedure.
Has a congenital condition resulting in no uterus.
Healthy adults (Parts A and A')
10. The subject must be aged 20 to 55 years, inclusive, at the Screening Visit.
11. The subject must have a body weight ≥50 kg inclusive at the Screening Visit.
Healthy elderly (Part A)
12. The subject must be aged 65 to 80 years, inclusive, at the time of informed consent.
13. The subject must have a body weight ≥40 kg inclusive at Screening.
NT1 and NT2 patients (Parts B and C)
14. The patient must be aged 18 to 80 years inclusive, at the time of informed consent.
15. The patient weighs at least 40 kg inclusive at the Screening Visit (≥50 kg is required for Cohort
B4).
16. The patient must have a diagnosis of narcolepsy of type 1 (Part B) or type 2 (Part C), as defined
by ICSD-3.
17. The patient’s ESS is ≥10 at baseline.
18. The patient must have blood pressure <140 systolic and <90 diastolic. The patient may have a
history of hypertension and be on antihypertensive medication treatment as long as the BP
meets these criteria. BP measures should be obtained after the patient has been resting a
minimum of 10 minutes, and may be repeated 3 times in the event that the BP is slightly
elevated above these parameters. The average BP may be used based on the investigator's or
the subinvestigator's judgement.
19. The patient must be willing to discontinue all medications used for the treatment of NT1 or
NT2 during the screening period (see Section 7.3).
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20. A female subject of childbearing potential who is sexually active with a nonsterilized* male
partner agrees to use a highly effective method of contraception from signing of informed
consent throughout the duration of the study.
* Definitions and procedures for adequate contraception and pregnancy avoidance, and
reporting responsibilities are defined in Appendix D of full protocol.
NT1 patients only (Part B)
21. HLA narcolepsy test positivity (HLA-DQB1*06:02)
22. Have ≥3 episodes of cataplexy/week reported during the Screening Period.
NT1 and NT2 patients (Parts B and C)
23. Average (of 4 sessions) Baseline MWT sleep latency is less than or equal to 20 minutes and no
single session has a sleep latency of greater than 30 minutes as determined by the site EEG
readers and investigators.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
All subjects
1. The subject has participated in another investigational study within 4 weeks (or based on local
regulations) prior to the Screening Visit. The 4-week window will be derived from the date of
the last study procedure and/or AE related to the study procedure in the previous study to the
Screening Visit of the current study. This criterion is not applicable to patients who will
participate in B3 or B4 after they completed B1 or B2.
2. The subject is an employee of the sponsor or study site or immediate family member (eg,
spouse, parent, child, sibling) of the sponsor or study site.
3. The subject has a history of cancer (malignancy).
4. The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex
allergy) or has had an anaphylactic reaction or significant intolerance to prescription or
nonprescription drugs or food.
5. The subject has a known hypersensitivity to any component of the formulation of TAK-925 or
related compounds.
6. The subject has a positive pregnancy test.
7. The subject is a lactating/nursing female.
8. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody,
or human immunodeficiency antibody/antigen, or serologic reactions for syphilis at the
Screening Visit. Note: Subjects with positive hepatitis B virus or hepatitis C virus serology
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Study ID TAK-925-1003
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may be enrolled if quantitative polymerase chain reaction for hepatitis B virus or hepatitis C 
virus ribonucleic acid is negative.
9. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL)
within 4 weeks prior to the Screening Visit.
10. The subject is unable to refrain from or anticipates using excluded medications (see Section
7.3) beginning approximately 7 days prior to administration of the first dose of study drug,
throughout the study including washout intervals between treatment periods, until the
Follow-up Visit.
11. The subject consumes excessive amounts, defined as greater than 6 servings (1 serving is
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other
caffeinated beverages per day.
12. The subject has a moderate to severe substance use disorder.
13. The subject’s renal creatinine clearance (CCR) ≤50 mL/min at the time of Screening and
Baseline.
14. The subject has poor peripheral venous access.
15. The subject has undergone whole blood draw prior to the start of study drug administration as
any of below:
For both male and female subjects,
•
≥200 mL within 4 weeks (28 days)
For male subjects,
•
≥400 mL within 12 weeks (84 days)
•
≥800 mL in total within 52 weeks (364 days)
For female subjects,
•
≥400 mL within 16 weeks (112 days)
•
≥400 mL in total within 52 weeks (364 days)
16. The subject has undergone blood component collection within 2 weeks (14 days) prior to the
start of study drug administration.
17. The subject has a risk of suicide according to endorsement of item 4 or 5 with
screening/baseline visit Columbia Suicide Severity Rating Scale (C-SSRS) or has made a
suicide attempt in the previous 6 months.
18. The subject has past or current epilepsy, seizure, tremor or the disorders of related symptoms.
19. The subject has a lifetime history of major psychiatric disorder, such as bipolar disorder or
schizophrenia. Subject who has history of major depressive disorder (MDD) may be include
but a subject who has current active major depressive disorder or who has had active major
depressive disorder in the past 6 months is excluded.
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20. The subject has a clinically significant history of head injury and trauma.
21. The subject has a history of cerebral ischemia, transient ischemic attack, intracranial
aneurysm, or arteriovenous malformation.
22. The subject has known coronary artery disease, a history of myocardial infarction (MI),
angina, cardiac rhythm abnormality, or heart failure.
23. The subject’s screening ECG reveals a QT interval with Frederica correction method (QTcF)
>450 milliseconds (men) or >470 milliseconds (women).
24. The subject has a resting PR outside of the range of 45 to 100 beats per minute, confirmed on
repeat testing within a maximum of 30 minutes, at the Screening Visit or Day -1.
25. The subject has medical condition (in case of Part B and C, narcolepsy is exceptional.) that
would preclude enrollment in the view of the investigators, such as medically significant
unstable cardiovascular, pulmonary, hepatic, renal, or Gastro-intestinal (GI) disease.
26. The subject has abnormal laboratory test values that suggest a clinically significant underlying
disease at the Screening Visit or baseline or any subject with transaminase (Alanine
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) >1.5 (Part A and A') or >2.0
(Part B and C)×upper limit of normal (ULN) at the Screening Visit (or baseline in Part A and
A').
27. Subjects experienced sleep wake cycle disturbance with external factors such as irregular work
hours; routine night-shift work or travel with significant jet lag within 7 days before
randomization.
28. The subject who, in the opinion of the investigator or sub-investigator, is unlikely to comply
with the protocol or is unsuitable for any other reason.
Healthy adults (Parts A and A') and elderly (Part A)
29. The subject administered TAK-925 in the past clinical trial.
30. The subject has a positive alcohol or drug screen.
31. The subject has a history of alcohol consumption exceeding 2 standard drinks per day on
average (1 glass is approximately equivalent to the following: beer [354 mL/12 oz], wine
[118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day).
32. The subject is unwilling to discontinue smoking while confined on the inpatient unit
33. If female, the subject is of childbearing potential (premenopausal and not sterilized).
34. The subject has clinically relevant sleep related disorders (including sleep apnea syndrome and
prior diagnosis of insomnia).
NT1 and NT2 patients (Part B and C)
35. The subject is unwilling to discontinue smoking no later than 40 minutes prior to the scheduled
MWT and 1 hour before sleep for Day 1 to Day 7.
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carefully and a washout period which is 5-folds or more of the disappearance 
half-life period of each drug is set up before baseline visit.
(5)
Mood stabilizers
-
(6)
Anticonvulsants
-
(7)
Sleeping pills
The Chinese medicine (Yokukansan, Yokukansankachinpihange) used for
insomnia is included.
(8)
Anti-Parkinson’s disease drugs
-
(9)
Adrenocorticosteroid
Only systemic administration.
(10) Interferon, interleukin-formulation
-
Footnotes are on last table page.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products (continued)
Prohibited drugs (a)
From 7 days or 5-half-lives period (longer one of either periods) 
before administration to completion of all tests planned on Day 8
(11) Muscle-relaxant drug
-
(12) Antihistamines
Only oral administration. A combination drug is also included.
(13) β-blockers which has a central-nerves action
-
(14) Antitussive which has a central-nerves action
-
(15) Antiemetic which has a central-nerves action
-
(16) Narcotic analgesic and non-narcotic analgesics
(Opioid system and Pregabalin only)
-
(17) St. John’s Wort, Health foods containing
melatonin
-
(18) Moderate to strong CYP3A inhibitors or
inducers
1) Strong CYP3A4 inhibitors: boceprevir,
clarithromycin, cobicistat, conivaptan,
danoprevir, ritonavir, elevitegravir, indinavir,
saquinavir, idelalisib, itraconazole, ketoconazole,
Lopinavir, netazodone, Nelfinavir, Paritaprevir,
Ombitasvir, Dasabuvir, posaconazole, Telaprevir,
tipranavir, troleandomycin, voriconazole
2) Moderate CYP3A4 inhibitors: Amprenavir,
Aprepitant, Atazanavir, casopitant, cimetidine,
ciprofloxacin, clotrimazole, Crizatinib,
cyclosporin, diltiazem, dronadarone,
erythromycin, fluconazole, Fosamprenavir,
fluvozamin, Miconazole, imatinib, istradefylline,
tofisopam, verapamil
3) Strong CYP3A4 inducers: Carbamazepine,
Enzalutamide, mitotane, phenobarbital,
phenytoin, rifabutin, rifampicin
4) Moderate CYP3A4 inducers: Bosentan,
Efavirenz, etravirine, Modafinil
-
(a) If medications are required to treat an AE, certain medications, including supplements, may be allowed after
discussion and agreement between the Sponsor and principal investigator, unless the investigator or designee
considers immediate administration is necessitated.
7.3.1
Concomitant Medications
In Part A and A', the use of concomitant medications (Prescribed drugs, OTC drugs, Supplements 
[St. John’s wort, ginseng, kava kava, Ginkao biloba and melatonin], Kampo medicines, 
Vaccination/vaccine) is not permitted throughout all study participation period. Subjects must be 
instructed not to take any medications without first consulting with the investigator. Any 
concomitant medication use must first be discussed with the sponsor, unless the investigator or 
designee considers immediate administration is necessitated. The occasional use of 
acetaminophen (approximately <1 g/day) is allowed.
In Part B or C, it is allowed for subjects to take any medication which is not banned in Section 7.3. 
The investigator or the subinvestigator will review the concomitant medication use at screening, 
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7.5
Record of Discontinuation or Withdrawal of a Subject before Study Drug 
Administration
The investigator or subinvestigator 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 investigator or subinvestigator 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>.

Study termination 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 discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form using the following categories. For subjects
who withdrew from the study before the start of study drug administration, refer to Section 7.5.
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. Adverse event
The subject has experienced a pretreatment event or adverse event that requires early
termination because continued participation imposes an unacceptable risk to the subject’s
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4. Lost to follow-up.
The subject did not return to the clinic and attempts to contact the subject were unsuccessful.
Attempts to contact the subject must be documented in the subject’s source documents.
5. Withdrawal by subject.
The subject or subject’s legally acceptable representative wishes to withdraw from the study.
The reason for withdrawal, if provided, should be recorded in the electronic case report form.
Note: All attempts should be made to determine the underlying reason for the withdrawal and,
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an
adverse event should not be recorded in the “voluntary withdrawal” category.
6. Study terminated by sponsor.
The sponsor, institutional review board, or regulatory agency terminates the study.
7. Pregnancy.
The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the electronic case
report form.
7.7 
Procedures for Discontinuation or Withdrawal of a Subject
The investigator or subinvestigator may discontinue a subject’s study participation at any time 
during the study when the subject meets the study termination criteria described in Section 7.6. In 
addition, a subject may discontinue his or her participation without giving a reason at any time 
during the study. Should a subject’s participation be discontinued, the primary criterion for 
termination must be recorded by the investigator or subinvestigator. In addition, efforts should be 
made to perform all procedures scheduled for the Early Termination Visit.
7.8 
Subject Replacement
Due to the risk of screen failures and subject withdrawals, more subjects may be enrolled than 
planned/cohort. If a subject discontinues from the study, a replacement subject may be enrolled, if 
deemed appropriate by the investigator and sponsor. The study site should contact the sponsor for 
the replacement of subject’s treatment assignment and allocation number.
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the sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the 
sponsor or designee.
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9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the schedule of study procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or subinvestigator or site personnel whenever possible. Please 
note that it may become necessary to perform the following procedures at unscheduled time 
periods, per the discretion of the investigator or subinvestigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described
in Appendix B.
9.1.1.1
Assignment of Screening and Randomization Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only one screening number. Screening numbers must not be reused for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event.
For Parts A, B and C, all eligible subjects will be randomly allocated and will receive a 
randomization number. The randomization number identifies the subject for all procedures 
occurring after randomization. Once a randomization number is assigned to a subject, it can never 
be reassigned to another subject.
For Part A', all eligible subjects will be assigned a subject identification number, which identifies
the subject for all procedures after dosing. Once a subject identification number is assigned to a 
subject, it can never be reassigned to another subject.
9.1.1.2
Study Drug Assignment
In Parts A, B and C, on Day 1 of Treatment Period, subjects will be assigned a randomization 
number in ascending numerical order at each clinical site. The randomization number encodes the 
subject assignment to either TAK-925 or placebo, according to the randomization schedule 
generated before the study. Each subject will be dispensed blinded study drug, labeled with his/her 
unique randomization number, throughout the study.
In Part A', on Day 1 of Treatment Period, subjects will be assigned a subject identification number 
in ascending numerical order at clincal site.
9.1.2
Inclusion and Exclusion
Each subject will be assessed through randomization (Part A, B and C), or dosing (Part A')
according to the eligibility criteria provided in Section 7.0.
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9.2.15
Diagnostic Screening
The investigator will report the results of immunology and urine drug, urine, Alcohol screen, and if 
applicable Serum hCG and Serum follicle stimulating hormone (FSH) (Serum hCG is for 
childbearing potential only and Serum FSH is for nonchildbearing potential only), directly to 
subjects. The sponsor will confirm the overall test results (“Positive” or “All negative”), rather 
than detailed results, for subjects (including reserve subjects) to be administered the study drug. 
Regarding the result of a drug test in the part B and C, in the event that the medicine of "positive" 
is detected, the details are identified and eligibility is judged.
Serum
The serum diagnostic screening assessment will include the following tests:
HIV
Hepatitis screen (hepatitis B surface antigen, hepatitis C 
virus antibody)
Syphilis serum reaction test
Alcohol Screen
In Part A and A', subjects will undergo an alcohol breath test. A urine alcohol test may be
performed at the discretion of the investigator or subinvestigator.
Urine
The urine drug screening assessment will include the following tests:
Barbiturates
Morphines
Benzodiazepines
Phencyclidine
Cannabinoids
Stimulants
Cocaines
Tricyclic antidepressants
Cotinine (a)
(a)
Part A and A' only.
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 B and Part C. 
In almost all narcolepsy 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. The test 
will be skipped for patients who participated in B1 or B2 and rolled over to B3 or B4.
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Table 9.c
Sampling of blood samples for pharmacokinetic analysis (Part B and C)
Analyzed substances Samples
Study date
Blood sampling time
TAK-925 and its 
metabolites 
 
Plasma
Day 1-8
B1, B2, B4, C1 and C2
• Day 1 and 7: Predose, 1, 2, 4, 6, 9 hours after start of infusion,
0.17, 0.5, 2, 6, 10 and 15 hours after end of infusion.
B1, B2, C1 and C2
• Day 5 and 6: Predose, 9 hours after start of infusion
B3
• Day 1 and 7: Predose, 1, 2, 4, 6 after start of infusion, end of
infusion , 0.17 and 0.5 hour after end of infusion, bed time, just
after wake up and 24 hours after start of infusion.
• Day 5 and 6: Predose, end of infusion
B4
• Day 4: Predose, 1, 2, 4, 6, 9 hours after start of infusion, 0.17,
0.5, 2, 6, 10 and 15 hours after end of infusion
• Days 2, 3, 5 and 6: 2, 6 and 9 hour after start of infusion, 0.17,
0.5, 2 hours after end of infusion, bed time
In Cohort B3, samples will be taken at following time points in patients who participated in B1 or B2 as well.
Day 1: Predose, end of infusion
Day 2: Predose
Day 7: Predose, 2 hours after start of infusion, end of infusion, 0.17 and 0.5 hour after end of infusion, bed time, just 
after wake up and 24 hours after start of infusion.
Table 9.d
Sampling of blood samples for pharmacokinetic analysis (Part A')
Analyzed substances Samples
Study date
Blood sampling time
TAK-925 and its 
metabolites 
 
Plasma
Day 1
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours postdose
In the case when the subject prematurely discontinues the study between the first and the last 
scheduled PK sample blood draw, final blood samplesto be used for pharmacokinetic analysis are 
sampled from subjects during hospitalization. If the IV infusion is interruptedin PartsA, B and C, 
2 additional PK samples (1 sample drawn when the infusion is stopped and 1 sample drawn when 
the infusion is restarted)wouldbe collected so that the subject may be considered evaluable. The 
exact date and time of each sample should be recorded.
On the other hand, in the case of premature discontinuation during the period of follow-up after 
discharge, blood samples for pharmacokinetic analysis are not collected from the subjects who 
came to outpatient medical examination.
CCI
CCI
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times (approximately at 10:00, 12:00, 14:00, 16:00) on each of these days. Sleep latency of each 
session will be recorded. Subjects will be required to stay awake in between the MWT tests.
9.3.3.2
9.3.3.3
9.3.3.4
9.3.3.5
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Takeda: For non


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at a long-term storage vendor, or a comparable laboratory, with validated procedures in place, for 
up to but not longer than 15 years from the end of the study when the clinical study report is signed, 
or if less, the maximum period permitted under applicable law or until consent is withdrawn.
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the study will be stored securely with limited access, 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main study but using a code 
that is different from the code attached to the health information and other clinical test results 
collected in the study. The sample and data are linked to personal health information with code 
numbers; the samples are stripped of all personal identifying information but a key linking the 
samples to clinical analysis data exists. This link means that the subject may be identified but only 
indirectly. The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a pharmacogenomic sample for DNA analysis can withdraw 
their consent at any time and request disposal of a stored sample. Any remaining sample that can 
be identified as coming from the subject will be destroyed. The investigator and sponsor may 
continue to use and distribute any information and test results gathered before the request to 
withdraw.
9.4 
Confinement
Part A, B and C
Subjects will be admitted to a hospital during a period from Day -2 to Day 8 and discharged from 
the hospital if no clinically significant abnormalities were found at the physical examination and 
tests on Day 8, and confirmed by the investigator or subinvestigator.
In Part B and C
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 investigator or 
subinvestigator must be careful for frequent occurrence of cataplexy and ensure the subject safety 
in the most appropriate way.
Part A'
Subjects will be admitted to a hospital during a 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 investigator or subinvestigator.
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9.5
Childbearing Status and Methods of Contraception
9.5.1
Women of Childbearing Potential
9.5.1.1
Definition of Women of Childbearing Potential
A woman is considered of childbearing potential (ie, fertile) following menarche and until 
becoming postmenopausal, unless permanently sterile.
9.5.1.2
Acceptable Methods of Contraception for Women of Childbearing Potential
Refer to the Appendix D.
9.5.2
Women of Nonchildbearing Potential
9.5.2.1
Definition of Women of Nonchildbearing Potential
A female subject of nonchildbearing potential is defined as satisfying at least 1 of the following 
criteria:
1. Postmenopausal: At least 12 months of spontaneous amenorrhea and an FSH concentration
>40 mIU/mL.
2. Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate
documentation of surgical procedure.
3. Has no uterus as a result of a congenital condition.
9.5.2.2
Contraception for Women of Nonchildbearing Potential
No contraception is required for women of nonchildbearing potential.
9.6
Patient Interview
In order to obtain patients' point of views such as meaningfulness of narcolepsy treatment or its 
benefits, a post-clinical trial participation interview (questionnaires) may be conducted in the 
patient who gives consent. This interview will be done separately from the study.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment or the study participation.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug during 
participating the study, whether or not it is considered related to the drug or the study procedure.
An untoward finding generally may:

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 or subinvestigator 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 or
subinvestigator 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 worsening of laboratory values or abnormal 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. The first
evaluation (eg, laboratory test, ECG, X-ray, etc.) after obtaining the consent should NOT be
recorded as an AE unless related to a study procedure. However, if the subject experiences a
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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). Investigator or subinvestigators 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 investigators should ensure that the AE term recorded captures the
change from baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis),
worsening of the condition should only be captured as an AE if occurring to a greater extent to
that which would be expected. Again, 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. Investigators should ensure that the AE term recorded
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of
informed consent are not considered AEs. However, if a preplanned procedure is performed
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of
the condition should be captured appropriately as an AE. Complications resulting from any
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs but should be documented in the subject’s source documents.
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational
drug, to or by a study subject, at a dose above that which is assigned to that individual subject
according to the study protocol. It is up to the investigator or the subinvestigator to decide
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose
page of the eCRF, in order to capture this important safety information consistently in the
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database. AEs associated with an overdose will be documented on AE 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 on subjects who signed the informed 
consent forms as follows:
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at the
time of the event; it does not refer to an event that hypothetically might have caused death
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life
threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in the Takeda Medically Significant AE List
(Table 10.a).
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Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
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 or control 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 or control drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant medications 
and concurrent treatments.
10.2.3
Assigning Causality of AEs to Study Procedures
The causality of each AE to study procedures will be assessed.
The causality should be assessed as Related if the investigator or sub-investigator considers that 
there is reasonable possibility that an event is due to a study procedure. Otherwise, the causality 
should be assessed as Not Related.
10.2.4
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
the investigator or subinvestigator.
10.2.5
End Date
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.6
Pattern of Adverse Event (Frequency)
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.7
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.
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
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.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.8
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has
not returned to the normal range or to the baseline value; the subject died from a cause other
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed
study period has become worse than when it started; is an irreversible congenital anomaly; the
subject died from another cause with the particular AE state remaining “Not recovered/not
resolved.”

Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence
change at the end of the subject’s participation in the study.
10.2.9 
Collection and Reporting of AEs, SAEs and Abnormal LFTs
10.2.9.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Adverse Event related to Convulsion and Abnormal liver 
function tests [LFTs]) will commence at the time the subject signs the informed consent. Routine 
collection of AEs will continue until the follow-up period.
10.2.9.2 Reporting AEs
At each study visit, the investigator or subinvestigator will assess whether any subjective AEs have 
occurred. A neutral question, such as “How have you been feeling since your last visit?” may be 
asked. Subjects may report AEs occurring at any other time during the study. Subjects 
experiencing an SAE prior to the first exposure to study drug must be monitored until the 
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symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or there is a satisfactory explanation for the change. Nonserious AEs that begin prior to 
the first exposure to study drug, related or unrelated to the study procedure, need not be 
followed-up for the purposes of the protocol.
All subjects experiencing AEs after the first administration of the study medication, whether 
considered associated with the use of the study medication or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or until there is a satisfactory explanation for the changes observed. All AEs will be 
documented in the AE page of the eCRF, whether or not the investigator or subinvestigator
concludes that the event is related to the drug treatment. The following information will be 
documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Investigators’ opinion of the causal relationship between the event and administration of study
drug.

Investigators’ opinion of the causal relationship between the event and the study procedure(s)
(The details of study procedure(s) that may cause the event should also be provided).

Action taken with trial drug.

Outcome of event.

Seriousness.

Timing of occurrence (after administration of the study drug)
10.2.9.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
An SAE should be reported by the investigator or subinvestigator to the Sponsor (see Protocol 
Annex 1) within 1 business day of the first onset or notification of the SAE, along with any 
relevant information. The investigator should submit a detailed SAE Form to the Sponsor within 
10 calendar days. The information should be completed as fully as possible but contain, at a 
minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator or subinvestigator’s name.
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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/head of the study 
site and IRBs or IECs, as applicable, in accordance with national regulations in the countries where 
the study is conducted. Relative to the first awareness of the event by/or further provision to the 
Sponsor or Sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other events, 
unless otherwise required by national regulations. The Sponsor will also prepare an expedited 
report for other safety issues where these might materially alter the current benefit-risk assessment 
of study drug or that would be sufficient to consider changes in the study drug administration or in 
the overall conduct of the trial. The study site also will forward a copy of all expedited reports to 
his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized 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.
A blinded data review will be conducted before database lock. This review will assess the accuracy 
and completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
11.1.1
Analysis Sets
In this study, 3 analysis sets will be used: the safety set, the PK set, and the PD 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 Set
The safety set will be defined as all subjects who received at least one dose of study drug.
11.1.1.2PK Set
The PK set will be defined as all subjects who received at least one dose of study drug and 
providedsufficient PK measurements available to estimate PK parameters, at least 1 estimable PK 
parameter.
11.1.1.3 PD Set
The PD 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 set by 
treatment.
11.1.3
PK Analysis
(1)Endpoints and analysis methodologies
[Endpoints]
Plasma concentrations and pharmacokinetic parameters of TAK-925 and its metabolites 

M-
CCI
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composed of persons who do not have subject contact or involvement with execution of the 
protocol at the site, who will review unblinded data on safety, tolerability, available PK and PD 
results, and this dose may be higher, lower or the same than that used in the prior cohorts.
11.3
Determination of Sample Size
The sample size in Part A (8 subjects per cohort: 6 active and 2 placebo), Part B and C (6 patients 
per cohort: 4 active and 2 placebo) and Part A' (open label, 6 subjects per cohort) is assumed to be 
sufficient for investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
TAK-925 when multiple doses of TAK-925 are administered intravenously in healthy adults, 
healthy elderly, and narcolepsy patients, or when a single dose of TAK-925 is administered orally 
in healthy adults. The sample size is not based on considerations of statistical power.
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12.0 
QUALITY CONTROL AND QUALITY ASSURANCE
12.1 
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the study site guarantee access to source documents by the 
Sponsor or its designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, trial drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator or 
sub-investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
12.2 
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. The 
investigator should document all 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 designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and 
Medical Devices Agency of Japan [PMDA]). 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 access for quality assurance auditors to all study documents as described in 
Section 12.1.
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13.0 
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for 
GCP. Each investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of the 
Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through the 
protocol and through appendices containing requirements for informed consent and investigator 
responsibilities.
13.1 
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The Sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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13.2 
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator or subinvestigator to explain the detailed elements of the 
informed consent form, subject authorization form (if applicable), and subject information sheet 
(if applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the subject is not 
capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator or subinvestigator must also sign and date the 
informed consent form and subject authorization (if applicable) at the time of consent and prior to 
subject entering into the study; however, the Sponsor may allow a designee of the investigator to 
sign to the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator or subinvestigator must document the date the subject signs the informed consent in 
the subject’s medical record. Copies of the signed informed consent form, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be given to 
the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a pharmacogenomics (PGx) sample for DNA analysis can 
withdraw their consent and request disposal of a stored sample at any time prior to analysis. Notify 
Sponsor of consent withdrawal.
13.3 
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, MHRA, PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4 
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 
Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this Section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility name, investigator’s city, state (for Americans 
investigators), country, and 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 Takeda Policy/Standard, applicable laws and/or regulations.
13.5 
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.
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15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.0
REFERENCES
[1] 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
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[4] Sakurai T. New treatment of sleep disorders. Orexin and sleep-wake regulation system. Brain
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Research.
[6] Kornum BR, Knudsen S,Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, et al. Narcolepsy. Nat
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[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] Ohno K, Sakurai, T. Orexin neuronal circuitry: role in the regulation of sleep and wakefulness.
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[10]Scammell TE, Winrow CJ. (2011) Orexin receptors: pharmacology and therapeutic
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cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA
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[13]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
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[14]Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials
for Therapeutics in Adult Healthy Volunteers. US Department of Health and Human Services,
Food and Drug Administration, Center for Drug Evaluation and Research. 06 July 2005.
Publication No. 5541.
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[15]Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, et al. Pitolisant
versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial.
Lancet Neurol. 2013;12(11):1068-75.
[16]Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates
sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J
Clin Sleep Med. 2005;15;1(4):391-7.
[17]US Modafinil in Narcolepsy Multicenter Study Group Randomized trial of modafinil for the
treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88-97.
[18]Gast H, Schindler K, Rummel C, Herrmann US, Roth C, Hess CW, et al. EEG correlation and
power during maintenance of wakefulness test after sleep-deprivation. Clin Neurophysiol.
2011;122(10):2025-31.
[19]Blaivas AJ, Patel R, Hom D, Antigua K, Ashtyani H. Quantifying microsleep to help assess
subjective sleepiness. Sleep Med. 2007;8(2):156-9.
[20]Tirunahari VL, Zaidi SA, Sharma R, Skurnick J, Ashtyani H. Microsleep and sleepiness: a
comparison of multiple sleep latency test and scoring of microsleep as a diagnostic test for
excessive daytime sleepiness. Sleep Med. 2003;4(1):63-7.
[21]An H, Cho MH, Kim DH, Chung S, Yoon SY. Orexin Impairs the Phagocytosis and
Degradation of Amyloid-beta Fibrils by Microglial Cells. J Alzheimers Dis.
2017;58(1):253-61.
[22]Wei M, Zhao B, Huo K, Deng Y, Shang S, Liu J, et al. Sleep Deprivation Induced Plasma
Amyloid-beta Transport Disturbance in Healthy Young Adults. J Alzheimers Dis.
2017;57(3):899-906.
[23]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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TAK-925
Study ID TAK-925-1003
Page 127 of 128
Protocol
12 June 2019
Page 35, Section 6.1 Trial Design
Existing Text
(Omitted)
The initiation of cohorts in parallel with each other is contingent on regulatory and Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) approval, and if not approved, the 
cohorts will enroll as required, which may be sequentially or overlapping with each other.
(Omitted)
Revised Text
(Omitted)
The initiation of cohorts in parallel with each other is contingent on Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) approval, and if not approved, the cohorts will enroll 
as required, which may be sequentially or overlapping with each other.
(Omitted)
Rationale for Amendment
Editorial changes (This regulatory approval is not applicable in Japan)
Page 57, Section 7.1 Inclusion Criteria
Existing Text
No texts.
Revised Text
NT1 and NT2 patients (Parts B and C)
23. Average (of 4 sessions) Baseline MWT sleep latency is less than or equal to 20 minutes
and no single session has a sleep latency of greater than 30 minutes as determined by the
site EEG readers and investigators.
Rationale for Amendment
To exclude subjects who have too long MWT sleep latency to assess the PD of TAK-925.
Page 59, Section 7.2 Exclusion Criteria
Existing Text
26. The subject has abnormal laboratory test values that suggest a clinically significant underlying
disease or any subject with transaminase (Alanine aminotransferase [ALT] and/or aspartate
aminotransferase [AST]) >1.5 ×upper limit of normal (ULN) at the Screening Visit or
baseline.
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TAK-925
Study ID TAK-925-1003
Page 128 of 128
Protocol
12 June 2019
Revised Text
26. The subject has abnormal laboratory test values that suggest a clinically significant underlying
disease at the Screening Visit or baseline or any subject with transaminase (Alanine
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) >1.5 (Part A and A') or
>2.0 (Part B and C)×upper limit of normal (ULN) at the Screening Visit (or baseline in
Part A and A').
Rationale for Amendment
After the completion of healthy adults dose escalation part, preliminary blind safety and 
tolerability were confirmed and no concern was suggested for aggravation of liver function.
Generally, >2.0 × ULN for ALT/AST as an exclusion criterion is acceptable for patient study once 
clinical safety and tolerability was confirmed in healthy adults.
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SAP_000.pdf: 
 
 
Title: A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 
TAK-925 in Healthy Volunteers and Patients with Narcolepsy 
 
NCT Number: NCT03748979 
Statistical analysis plan Approve Date: 28-OCT-2019 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable 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-925-1003 
A 3-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Dose Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-
925 in Healthy Volunteers and Patients with Narcolepsy 
Version: 2nd 
Date: 28 October 2019 
Prepared by: 
Based on: 
Protocol Version: Amendment 3 
Protocol Date: 12 June 2019 
 
PPD
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Rising
ising
Terms of Use


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TAK-925-1003 
Page 3 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
2.0 
TABLE OF CONTENTS 
1.1 
 ....................................................................................... 2 
2.0 
TABLE OF CONTENTS ...................................................................................... 3 
3.0 
LIST OF ABBREVIATIONS ............................................................................... 5 
4.0 
TRIAL OBJECTIVES .......................................................................................... 7 
4.1 
Trial Primary Objectives ................................................................................. 7 
4.2 
Trial Secondary Objectives ............................................................................. 7 
4.3 
Trial Exploratory Objectives........................................................................... 7 
4.4 
Trial Design .................................................................................................... 8 
5.0 
ANALYSIS ENDPOINTS .................................................................................. 12 
5.1.1
Primary Endpoint .................................................................................... 12 
5.1.2
Secondary Endpoints ............................................................................... 12 
5.1.3
 12 
5.1.4
 12 
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 A1~A3 ........................................................................................ 22 
7.4.2
Cohort B1~B2 ......................................................................................... 23 
7.4.3
Cohort C1~C2 ......................................................................................... 24 
7.4.4
Cohort A'1 .............................................................................................. 24 
7.5 
Medical History and Concurrent Medical Conditions .................................... 24 
7.5.1
Cohort B1~B2 ......................................................................................... 24 
7.5.2
Cohort C1~C2 ......................................................................................... 25 
7.6 
Medication History and Concomitant Medications ........................................ 25 
7.6.1
Cohort B1~B2 ......................................................................................... 25 
7.6.2
Cohort C1~C2 ......................................................................................... 26 
7.7 
Study Drug Exposure and Compliance .......................................................... 26 
7.7.1
Cohort A1~A3 ........................................................................................ 26 
CCI
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TAK-925-1003 
Page 5 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA
analysis of covariance
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
BP 
blood pressure 
Ceoi
plasma concentration at the end of infusion
CL 
total clearance after intravenous administration 
Cmax 
maximum observed concentration 
CV 
coefficient of variation 
ECG 
electrocardiogram 
EEG 
electroencephalography 
ESS 
epworth sleepiness scale 
GGT
gamma-glutamyl transferase 
GCP 
Good Clinical Practice 
HV 
healthy volunteer 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV
intravenous 
KSS 
karolinska sleepiness scale 
LDH
lactate dehydrogenase 
LS
least square
MAV 
markedly abnormal value 
MCH 
mean cell hemoglobin 
MCHC 
mean cell hemoglobin concentration 
MCV 
mean cell volume 
MedDRA
medical dictionary for regulatory activities
MR
metabolic ratio 
MRD 
multiple rising dose 
MWT 
maintenance of wakefulness test 
 
NT1
narcolepsy type 1
NT2 
narcolepsy type 2 
PD 
pharmacodynamics 
PGI-C 
patient global impression of change 
CCI
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TAK-925-1003 
Page 6 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
PK 
pharmacokinetics 
 
 
 
 
PT 
preferred term 
PTE
pretreatment event
PTR 
peak trough ratio during a dosing interval, at steady state 
PVT 
psychomotor vigilance task 
QTcB 
QT interval corrected for heart rate by the Bazett method 
QTcF 
QT interval corrected for heart rate by the Fridericia method 
RBC
red blood cell
Rac AUC 
accumulation ratio based on AUC during a dosing interval 
Rac Cmax 
accumulation ratio based on Cmax 
REM 
rapid eye movement 
RT 
reaction time 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE
treatment-emergent adverse event 
tmax 
time of first occurrence of Cmax 
t1/2z 
half-life period 
Vss 
volume of distribution at state after intravenous administration 
Vz 
volume of distribution 
WBC 
white blood cell 
WHO Drug
World Health Organization Drug Dictionary
CCI
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TAK-925-1003 
Page 7 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
4.0 
TRIAL OBJECTIVES 
4.1 
Trial Primary Objectives 
<All Parts> 
To investigate the safety and tolerability of TAK-925 when administered to healthy subjects 
and NT1 and NT2 patients. 
4.2 
Trial Secondary Objectives 
<All parts> 
To investigate the pharmacokinetics of TAK-925 when administered to healthy volunteers or 
narcolepsy patients 
<Part B and C> 
To investigate the PD of TAK-925 after multiple doses, primarily with evaluation of sleep 
latency on MWT when TAK-925 is administered to NT1 and NT2 patients. 
4.3 
Trial Exploratory Objectives 
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ts
of Use


TAK-925-1003 
Page 8 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
4.4 
Trial Design 
This study will consist of 3 parts. Part A is a randomized, double-blind, placebo-controlled, 
MRD study to assess safety, tolerability, and PK of TAK-925 administered via intravenous 
(IV)infusion in healthy subjects. Part B is a randomized, double-blind, placebo-controlled
MRD study to assess the safety, tolerability, PK and PD of TAK-925 administered via IV
infusion in patients with NT1. Part C is a randomized, double-blind, placebo-controlled,
parallel group multiple repeat dose study to assess the safety, tolerability, PK and PD of one
or more dose levels of TAK-925 vs. placebo in patients with NT2. Part A' is an open-label
single oral dose study to assess PK, safety and tolerability of TAK-925 administered orally in
healthy subjects. Parts A - A' may be conducted in parallel, rather than sequentially,
depending on the doses administered and emerging safety/tolerability data.
In general, considering the completion times of the prior studies, TAK-925-1001 and TAK-
925-1002, Part A, Part B and Part A' are expected to begin in parallel. Part A will test safety
and tolerability in healthy volunteers (HV) starting from the dose level associated with that
was found to be safe and tolerable based on the preliminary blinded safety adverse event
(AE) profiles in TAK-925-1001 study. Part B will test safety, tolerability and PD in NT1
patients, who will be administered a lower dose than subjects in Part A. The initial dose in
Part B was found to be safe and tolerable based on the preliminary blinded safety AE profiles
in NT1 patients in the TAK-925-1001 study. The initial dose in Part B is more than 10 times
lower than the highest dose level tested in TAK-925-1001 HV cohorts. Results from the
TAK-925-1001 study will also be available at the time of initiation of Part A and Part B. Part
A' will assess the safety, tolerability and 
 TAK-925 
 to healthy
volunteers at a dose level that was found to be safe and tolerable after IV administration in
TAK-925-1001 study and is anticipated to result in lower exposure of TAK-925 after oral
administration, 
.
For Part C, the NT2 patient doses are expected to be similar to that in Part A, although
recruitment of these cohorts will be slower. Initiation of Part A and Part C may also occur at
the same time if the similar doses are studied. The initiation of cohorts in parallel with each
other is contingent on Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
approval, and if not approved, the cohorts will enroll as required, which may be sequentially
or overlapping with each other. The NT1 and NT2 patients recruited are expected to be
generally healthy other than having narcolepsy.
Part A – Multiple Rising Dose in Healthy Adults 
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TAK-925-1003 
Page 9 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Part A will have 2 dose cohorts as well as additional 4 optional cohorts. Each cohort of 
healthy adults will consist of 8 healthy subjects, randomized 6:2 active to placebo to TAK-
925 vs. placebo (Table 4.a) in double-blinded fashion. The starting dose is selected based on 
the available preliminary safety, PK and PD data from the ongoing TAK-925-1001 study. 
Subsequent doses will be guided by safety, PK and PD data from previous cohorts as well as 
the TAK-925-1002 study (which is ongoing at the time of this protocol writing). TAK-925 or 
placebo will be administered as an IV infusion over 9 hours once daily for 7 days. Following 
review of emerging safety and PK data (when available) in Cohort A1, the dose in Cohort A2 
will be determined. Healthy adults may be recruited for up to 3 additional cohorts (A3 to A5) 
with 8 subjects each (randomized 6:2 active to placebo). The dose may be higher, lower or 
the same as that of prior cohort dose levels. Shifting the start time of infusion while keeping 
the dose the same as that previously studied may be considered in these optional cohorts  
. The maximum dose and infusion rate in Part 
A shall not exceed the maximum dose or maximum infusion rate studied in healthy subjects 
in TAK-925-1001 study. The dose levels in subsequent cohorts will be optimized based on 
the recommendation of sponsor’s unblinded team. The unblinded team will review available 
unblinded data including 
 
 
The safety and tolerability of the same or a lower dose than that of previous healthy adults 
cohorts may be studied in an optional cohort of healthy elderly subjects (N=8 subjects aged 
65-80 years old, randomized 6:2 to TAK-925 vs. placebo) in Cohort A6. The healthy elderly
optional cohort will be included as there are expected to be a few older patients in the Part B
or Part C. It is expected that the healthy elderly cohort will provide data that supports the
evaluation of TAK-925 in

Part B – Multiple Rising Dose in Narcolepsy Type 1 (NT1) Patients 
Part B will be conducted in NT1 patients. Two cohorts are planned, with optional cohorts 
allowed. For Cohorts B1 and B2, each cohort will consist of 6 subjects, randomized 4:2 to 
TAK-925 vs. placebo (Table 4.a) in double blinded fashion. TAK-925 or placebo will be 
administered as an IV infusion over 9 hours once daily for 7 days. Exploratory PD 
assessments will include evaluation of potential efficacy with 
 
. 
The starting dose level in Part B will be selected based on preliminary data from the ongoing 
TAK-925-1001 study utilizing data regarding safety and tolerability, PK and results on the 
KSS and MWT in the NT1 cohorts, as well as the safety, tolerability and PK results in the 
healthy adult cohorts in TAK-925-1001 and Part A of this study (if available). The doses in 
the subsequent cohorts will be determined based on safety, tolerability, PD and available PK 
data from previous cohorts and/or from the prior studies with TAK-925. The dose level 
chosen in each of the subsequent cohorts will be determined by the sponsor’s unblinded team 
composed of personnel who do not have subject contact or involvement with execution of the 
protocol at the site. The unblinded team will review unblinded safety, tolerability, and 
available PK and PD results from previous cohorts. The dose in the subsequent cohorts may 
be higher, the same as or lower than that used in the previous cohort(s). 
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TAK-925-1003 
Page 10 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Two additional cohorts (B3 and B4) may be evaluated, with 4-6 subjects in each. With the 
intention of sequential panel design, NT1 patients in Cohort B1 or B2 may participate in 
Cohort B3 or B4 if feasible operationally. Patients in cohort B1 and B2 may participate in B3 
or B4 after a sufficient washout period if and allowed by regulatory authorities and IRB/IEC. 
The subject who directly move on to cohort B3 or B4 could skip the Day 8 some assessments 
and follow up visit and move into Day-2 in B3 or B4. Cohort B3 or B4 will essentially 
consist of newly enrolled NT1 patients, but patients from B1/B2 who weigh over 50 kg could 
be also enrolled. There should be sufficient intervals between the last dose in Cohort B1 or 
B2 and the first dose in Cohort B3 or B4 in order to make dose and dosing duration decisions 
for Cohorts B3 and B4. If there are fewer than 4 Cohort B1 or B2 subjects enrolled to Cohort 
B3 or B4, new patients with NT1 will be recruited. In Cohorts B3 and B4, TAK-925 will be 
administered in a blinded randomized manner (3:1, 4:1 or 5:1). The primary purpose of 
Cohort B3 is to evaluate the safety and tolerability and PD of longer infusion time, as well as 
to 
 
Otherwise, the design and procedures for B3 will be the same 
as the design of B1. The primary purpose of Cohort B4 is to assess the within-subject 
exposure-response relationship for PD/efficacy and safety of TAK-925 in NT1 patients. 
Patients in this cohort will receive different, increasing doses of TAK-925 daily over the 7 
day period, the sequence of doses will be identical across patients. All subjects will receive 
the same dosing schedule. One subject within B3 and B4, respectively, will be randomized to 
placebo. 
Part C – Multiple Doses in Narcolepsy Type 2 (NT2) patients 
Narcolepsy type 2 patients will be evaluated in Cohorts C1 and C2. This part will start once 
TAK-925-1002 study data is available and once safety/tolerability information for the dose 
level to be tested in Part C is available from Part A. Conduct of the C2 cohort is optional. C1 
and C2 cohorts will recruit 6 subjects each, randomized 4:2 to TAK-925 vs. placebo in 
double-blinded fashion, with study drug administered as a 9-hour intravenous infusion for 7 
days (Table 4.a). The doses selected for Part C depend on the results from the TAK-925-1002 
study, and data from other cohorts in this study may also be used. The same schedule of study 
assessments as in Part B will be executed 
 
Part A' – Single Oral Doses in Healthy Adults 
Part A' will investigate the pharmacokinetics of TAK-925 after oral administration in healthy 
subjects. Cohort A'1 will consist of 6 healthy subjects who will be administered a single dose 
of TAK-925 as an oral solution in an open-label fashion (Table 4.a). An oral dose of 112 mg 
is selected based on the safety and tolerability profiles in TAK-925-1001 study and available 
nonclinical data as a potential starting dose.
 
925-
An optional Cohort A'2 is allowed based on the emerging information.
The study parts and planned dosing cohorts are outlined in Table 4.a.
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TAK-925-1003 
Page 11 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Table 4.a 
Outline of the Study Parts and Planned Dosing Cohorts 
Part 
Cohort/Panel 
Daily dose level 
(mg) 
Dosing regimen 
Randomization 
Part A 
(Healthy adults)# 
A1 
44
IV infusion over 9 hours 
up to 7 days. Start time of 
infusion could be changed 
in optional cohorts A3 to 
A5. 
8 subjects randomized 6:2 
to TAK-925 vs. placebo 
in each cohort, double-
blind 
A2 
112 (TBD) 
A3* 
TBD 
A4* 
TBD 
A5* 
TBD 
A6 (elderly)* 
TBD 
Part B 
(NT1 patients)# 
B1 
11
IV infusion over 9 hours 
up to 7 days 
6 subjects randomized 4: 
2 to TAK-925 vs. placebo 
in each cohort, double 
blind  
B2 
44 (TBD) 
B3* 
TBD 
IV infusion with longer 
(TBD) hours up to 7 days 
4-6 subjects randomized
(3:1, 4:1 or 5:1 to TAK-
925 vs. placebo in each
cohort, double blind
B4* 
TBD 
IV infusion over 9 hours 
up to 7 days, different, 
increasing dose from Day 
1 to Day 7 
Part C 
(NT2 patients)# 
C1 
44 (TBD) 
IV infusion over 9 hours 
up to 7 days 
6 subjects randomized 4: 
2 to TAK-925 vs. placebo 
in each cohort, double 
blind 
C2* 
TBD 
Part A' (Healthy 
adults) 
A'1
112 
Single oral administration 
6 subjects per cohort 
(TAK-925 administration, 
open) 
A'2* 
TBD 
Doses in subsequent cohorts in all parts will be determined based on the emerging safety/tolerability and PK 
(when available) and PD information and available safety/tolerability, and PK/PD data from previous cohorts as 
well as the ongoing TAK-925-1001 and TAK-925-1002 studies. Planned number of subjects in each cohort is 
shown. 
# All doses given by IV infusion over 9 hours daily for 7 days except B3 
* Optional cohorts
Property of Takeda: For non-commercial 
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TAK-925-1003 
Page 12 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
5.0 
ANALYSIS ENDPOINTS 
5.1.1
Primary Endpoint 
<All Parts> 
x
Safety and tolerability: number of subjects with AEs
5.1.2 Secondary Endpoints 
< Parts A, B and C> 
x
Pharmacokinetic parameters (Ceoi, AUCȫ, Rac(AUC)) of TAK-925
<Part B and C>
x
Change from baseline in Sleep latency in the MWT to Days 1 and 7
5.1.3
 
5.1.4
 
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Property of Takeda: For non-commercial use only and 
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applicable Terms of Use


TAK-925-1003 
Page 13 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-925-1003 
Page 14 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
6.0 
DETERMINATION OF SAMPLE SIZE 
The sample size in Part A (8 subjects per cohort: 6 active and 2 placebo), Part B and C (6 
patients per cohort: 4 active and 2 placebo) and Part A' (open label, 6 subjects per cohort) is 
assumed to be sufficient for investigating the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of TAK-925 when multiple doses of TAK-925 are administered 
intravenously in healthy adults, healthy elderly, and narcolepsy patients, or when a single 
dose of TAK-925 is administered orally in healthy adults. The sample size is not based on 
considerations of statistical power. 
Property of Takeda: For non-commercial use only and subject to the applicable 
d on
on
Terms of Use


TAK-925-1003 
Page 15 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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 that occurs on or after the
start of study drug administration.
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
Average Sleep Latency in MWT: Average of four MWTs measured on the same day
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 -1 subtracted from values of Day 1
and 7 in the matching column in the table below for each subject
¾
MWT
Day 
Time (Time postdose㸦hour㸧) 
Day -1 
10:00 
12:00 
14:00 
16:00 
Day 
1,7 
10:00 (2 hr) 
12:00 (4 hr) 
14:00 (6 hr) 
16:00 (8 hr) 
¾
¾
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Property of Takeda: For non-commercial 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-925-1003 
Page 17 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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 Were Not Randomized 
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 A1~A3 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
Study Drug Administration Status 
[Rnadomized, Not Randomized] 
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
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For 
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the applicable Terms of Use


TAK-925-1003 
Page 18 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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 B1~B2 
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 
B1~B2 
7.3.3.3 Cohort C1~C2 
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 
C1~C2 
7.3.3.4 Cohort A'1 
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 A'1 
7.3.4
Disposition of Subjects 
7.3.4.1 Cohort A1~A3 
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 
Property of
A
Takeda: 
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1
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Analys
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Page 19 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Sponsor, Withdrawal by Subject, 
Other] 
Analytical 
Method(s) : 
(1) Disposition of Subjects 
Frequency distributions will be provided by treatment 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 B1~B2 
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 B1~B2 
7.3.4.3 Cohort C1~C2 
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 C1~C2 
7.3.4.4 Cohort A'1
Analysis Set: All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
The same analysis as section 7.3.4.1 will be per ormed for the Cohort A'1 
7.3.5
Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Cohort A1~A3 
Analysis Set: All Subjects Who Received Study Drug 
Analysis 
Variable(s) : 
Significant Protocol 
Deviation 
C
C
Property of 
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Takeda: 
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7.3.5
7.3.5
For 
A
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TAK-925-1003 
Page 20 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
[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 treatment 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 B1~B2 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
The same analysis as section 7.3.5.1 "Cohort A1~A3" will be performed for 
the Cohort B1~B2 
Cohort C1~C2 
Analysis 
Set: 
All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
The same analysis as section 7.3.5.1 "Cohort A1~A3" will be performed for 
the Cohort C1~C2 
Property of Takeda: For
the
th
non-commercial 
Who
ho R
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use only
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3.5.1
and subject to the applicable 
all 
all fo
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Terms of Use


TAK-925-1003 
Page 21 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Cohort A'1 
Analysis Set: All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
The same analysis as section 7.3.5.1 "Cohort A1~A3" will be performed for 
the Cohort A'1 
7.3.5.2 Analysis Sets 
Cohort A1~A3 
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 Set 
PK Set 
[Included] 
[Included] 
Analytical 
Method(s) : 
(1) Subjects Excluded from Analysis Sets 
(2) Analysis Sets
Frequency distributions will be provided by treatment 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 B1~B2 
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 Set 
[Included] 
Property of
S
Takeda: 
rt t B1
B1~B
ed
Analy
Analy
For
on
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non-commercial 
ded 
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to the applicable Terms of Use


TAK-925-1003 
Page 22 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
PK Set 
PD Set 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort A1~A3" will be performed for 
the Cohort B1~B2 
Cohort C1~C2 
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 Set 
PK Set 
PD Set 
[Included] 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
The same analysis as section 7.3.5.2 "Cohort A1~A3" will be performed for 
the Cohort C1~C2 
Cohort A'1 
Analysis Set: All Subjects Who Received Study Drug 
Analytical 
Method(s) : 
The same analysis as section 7.3.5.2 "Cohort A1~A3" will be performed for 
the Cohort A'1 
7.4 
Demographic and Other Baseline Characteristics
7.4.1
Cohort A1~A3 
Analysis Set: Safety Set 
Analysis 
Variable(s) : 
Age (years) 
Gender 
[Male, Female] 
Height (cm)
Property of 
7
Takeda: 
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7.4
For non-commercial
as sec
as sec
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C2
All Sub
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TAK-925-1003 
Page 23 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Weight (kg)
BMI (kg/m2) 
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 treatment group and overall. 
7.4.2
Cohort B1~B2 
Analysis Set: Safety 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] 
average MWT (sleep latency) 
 
 
 
 
 
 
 
 
 
Age of onset (year) 
CCI
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Property of Takeda: For
C
or
or 
a
mercial 
mme
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TAK-925-1003 
Page 24 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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 treatment group and overall. 
7.4.3
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.4.2 will be performed for the Cohort C1~C2 
7.4.4
Cohort A'1 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.4.1 will be performed for the Cohort A'1 
7.5 
Medical History and Concurrent Medical Conditions 
7.5.1
Cohort B1~B2 
Analysis Set: Safety 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 for each treatment group and 
overall. MedDRA dictionary will be used for coding. Summaries will be 
CCI
CCI
CCI
Property of 
A
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Se
ysis 
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For 
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TAK-925-1003 
Page 25 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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. 
7.5.2
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.5.1 will be performed for the Cohort C1~C2 
7.6 
Medication History and Concomitant Medications 
7.6.1
Cohort B1~B2 
Analysis Set: Safety 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 for each treatment group and 
overall. A summary of (2) ~ (5) will also be provided for concomitant 
medications whose primary purpose was "primary diagnosis". 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 
(4
(
non-commercial 
t
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His
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ca
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TAK-925-1003 
Page 26 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
medications with the same preferred medication name will be counted only 
once for that preferred medication name. 
7.6.2
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.6.1 will be performed for the Cohort C1~C2 
7.7 
Study Drug Exposure and Compliance
7.7.1
Cohort A1~A3 
Analysis Set: Safety Set 
Analysis 
Variable(s) : 
Number of Times the Study Drug was Taken 
[1, 2, 3, 4, 5, 6, 7] 
Analytical 
Method(s) : 
(1) Study Drug Exposure
Frequency distributions will be provided by treatment group. 
7.7.2
Cohort B1~B2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.7.1 will be performed for the Cohort B1~B2 
7.7.3
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.7.1 will be performed for the Cohort C1~C2 
7.8 
Efficacy Analysis 
Not applicable. 
7.8.1 Primary Efficacy Endpoint(s) 
Not applicable. 
7.8.2 Secondary Efficacy Endpoint(s) 
Not applicable. 
Property of 
7
N
Takeda: 
al
od(s) :
) :
7.8
For
Sa
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non-commercial 
analysi
nalys
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C2
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aken
to the applicable 
ort C1
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Terms of Use


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


TAK-925-1003 
Page 28 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1
Pharmacokinetic Analysis 
7.9.1.1 
 
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of Takeda: For non-commercial use only and subject to the applicable erms 
Term of Use


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Statistical Analysis Plan 2nd 
28 October 2019 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable 
ms 
Terms of Use


TAK-925-1003 
Page 30 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable 
ms 
Term of Use


TAK-925-1003 
Page 31 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.9.1.2 Pharmacokinetic Parameters 
Cohort A1~A3 
Analysis Set: PK Set 
Analysis 
Variable(s) : 
Pharmacokinetic Parameters of TAK-925 and 
 
 
 AUCtau  
 
 
Ceoi 
 
Rac AUC(only Day 7) 
 
 
 
 
 
 
 
 
 
 
Visit: 
Day 1, Day 7
Analytical 
Method(s) : 
The following summaries will be provided by treatment group. Subjects 
administered placebo will be excluded from the analysis. 
(1) Summary of Pharmacokinetic Parameters
For 
, 
, AUCtau, 
, 
 Ceoi, descriptive
statistics, geometric mean, and CV will be provided. 
(2)
Cohort B1~B2 
Analysis Set: PK Set 
Analytical 
Method(s): 
The same analysis as section 7.9.1.2 "Cohort A1~A3" will be conducted for 
the Cohort B1~B2. 
Cohort C1~C2 
Analysis Set: PK Set 
CCI
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Property of 
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Anal
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TAK-925-1003 
Page 32 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Analytical 
Method(s): 
The same analysis as section 7.9.1.2 "Cohort A1~A3" will be conducted for 
the Cohort C1~C2. 
 
7.9.2
Pharmacodynamic Analysis 
7.9.2.1
Average Sleep Latency in MWT/Sleep Latency in Each Session in MWT
Cohort B1~B2 
Analysis Set: PD Set 
Analysis 
Variable(s): 
Average Sleep Latency in MWT, Sleep Latency in Each Session in MWT 
Visit: 
Average Sleep Latency in MWT: Day -1, Day 1, Day 7 
Sleep Latency in Each Session in MWT: 
Day -1: 10㸸00, 12㸸00, 14㸸00, 16㸸00 
Day 1 and Day 7: 10:00 (2hr), 12㸸00 (4hr), 14㸸00 (6hr), 16㸸00 (8hr) 
Analytical 
Method(s): 
The following summaries will be provided. 
(1) For the average sleep latency in MWT, descriptive statistics for the
, changes from baseline and 
CCI
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Property of Takeda: 
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TAK-925-1003 
Page 33 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
will be provided by visit by treatment group. The effect of TAK-925 
will be evaluated with a linear mixed effects model. The response 
variable in the model will be the change from baseline in the average 
sleep latency in the MWT. The model will include treatment (each 
treatment of TAK-925 and placebo), day (as a categorical variable), the 
treatment-by-day as fixed effects, baseline average sleep latency in the 
MWT as a covariate, and subjects as a random effect. Least square (LS) 
means, the standard errors, and the two-sided 95% confidence intervals 
will be provided for each treatment group. For each day, the difference 
in the LS means between each treatment of TAK-925 and the placebo 
(each treatment of TAK-925 - the placebo), the standard error of the 
difference and the two-sided confidence intervals will be provided.
 
 
 
The differences in the LS means 
between each treatment of TAK-925 group and the placebo group (each 
treatment of TAK-925 group - placebo group), the standard error and 
the two-sided 95% confidence intervals will be provided. 
 
 
  
 
 
 
 
 
  
If there is a missing value of sleep latency in MWT at Day -1, it will be 
imputed by the predicted value of the same subject and the same 
session based on a model with sleep latency in MWT at Day -1 as a 
response, session as a fixed effect, and a subject as a random effect. 
After conducting imputation, the average sleep latency in MWT will be 
recalculated and the model analysis as above will be conducted as 
reference. 
C
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of Use


TAK-925-1003 
Page 34 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
(2)
Cohort C1~C2 
Analysis Set: PD Set 
Analytical 
Method(s): 
The same analysis as section 7.9.2.1 "Cohort B1~B2" will be conducted. 
7.9.2.2 
 
CCI
CCI
CCI
Property of
of 
CCI
Takeda: 
od(s):
d(s):
7.9.2.
7.9.2.
For 
P
non-co
PD S
commercial use only and subject to the applicable 
rms 
Term of Use


TAK-925-1003 
Page 35 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.9.2.3 
 
CCI
CCI
CCI
Property of
of Takeda: 
r
For non-co
commercial 
non
n
use only and subject to the applicable 
rms 
Term of Use


TAK-925-1003 
Page 36 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.9.2.4 
 
CCI
CCI
CCI
Property of
of Takeda: For non-commercial 
e
use only and subject to the applicable erms 
Ter
of Use


TAK-925-1003 
Page 37 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.9.2.5 
 
7.9.2.6 
 
CCI
CCI
CCI
CCI
CCI
Property y of Takeda: For 
omm
mmercial 
n-co
on-
non
use only and subject to the 
able 
applica
Terms 
Term of Use


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


TAK-925-1003 
Page 39 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.9.2.8 
 
CCI
CCI
CCI
Property of Takeda: For 
mercialal 
non-comm
use only and subject to the applicable 
rms 
Term of Use


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


TAK-925-1003 
Page 41 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.10.1.2 
 
7.10.1.3 
 
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rms 
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Statistical Analysis Plan 2nd 
28 October 2019 
CCI
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Term of Use


TAK-925-1003 
Page 43 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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 A1~A3 
Analysis Set: Safety 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 for each treatment group. 
(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 
treatment group will be based on the number of subjects in the safety set. 
Number of subjects 
of Takeda: For non-commercial
of Tre
of Tre
s, num
, num
reatme
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TAK-925-1003 
Page 44 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
•
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 B1~B2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.1.1 "Cohort A1~A3" will be performed 
for the Cohort B1~B2. 
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.1.1 "Cohort A1~A3" will be performed 
for the Cohort C1~C2. 
Cohort A'1 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.1.1 "Cohort A1~A3" will be performed 
for the Cohort A'1 
7.11.1.2 Displays of Treatment-Emergent Adverse events 
Cohort A1~A3 
Analysis Set: Safety Set 
of Takeda:
is Set
is Set
alytical
alytica
Metho
Metho
For non-commercial 
me analy
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Coh
use only 
1
and 
1.1 "C
1.1 "
subject to the
calcul
calcu
applicable 
nted only
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Terms 
or
or
of Use


TAK-925-1003 
Page 45 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Analysis 
Variable(s) : 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Time of Onset (day) 
[Day 1, Day 2, Day 3, Day 4, Day5, 
Day 6, Day 7, Day8 - Max] 
Analytical 
Method(s) : 
The following summaries will be provided using frequency distribution for 
each treatment group. 
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
(9) Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term Over Time
(10) Treatment-Emergent Adverse Events Occurred during Infusion by
System Organ Class and Preferred Term
(11) Treatment-Emergent Adverse Events Occurred after Infusion by
System Organ Class and Preferred Term
Property of Takeda: For
(7
(7
non-commercial 
rerea
referre
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of Tr
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Terms of Use


TAK-925-1003 
Page 46 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
The frequency distribution will be provided according to the rules below. 
Percentages for each treatment group will be based on the number of 
subjects 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.
•
Summary table for (9)
A subject with a TEAE that occurs in more than one interval is counted
in all the intervals that the TEAE occurs. For each time interval, a subject
with multiple occurrences of TEAE within a SOC or a PT will be
counted only once in that SOC or PT.
When calculating percentages for each time interval, the number of
subjects at risk (i.e., subjects who either have an exposure or have an
occurrence of TEAE, during or after the corresponding time interval)
will be used as the denominator. The number of subjects whose onset of
any one of the TEAEs is within the time interval will be used as the
numerator.
Cohort B1~B2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.1.2 "Cohort A1~A3" will be performed 
for the Cohort B1~B2. 
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.1.2 "Cohort A1~A3" will be performed 
for the Cohort C1~C2. 
Property of Takeda: 
ical
ical
thod
od(s(s)
For 
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non-commercial 
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Terms of Use


TAK-925-1003 
Page 47 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Cohort A'1 
Analysis Set: Safety Set 
Analysis 
Variable(s) : 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s) : 
The following summaries will be provided using frequency distribution.
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
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 
7
Takeda: 
7.11
11
For non-commercial 
rred
re
Treatm
Treatm
nd Pref
Pre
ensity o
nsity o
System
System
(7)
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tion
arized us
ized u
Terms of Use


TAK-925-1003 
Page 48 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
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 A1~A3 
Analysis Set: Safety Set 
Analysis 
Variable(s) : 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
Platelet 
WBC 
WBC Differentials (Neutrophils, Eosinophils, Basophils, Lymphocytes, 
Monocytes)  
MCH 
MCHC 
MCV 
Serum Chemistry 
Albumin  
Alkaline Phosphatase 
ALT  
AST  
Total Bilirubin 
Blood Urea Nitrogen 
Calcium  
Chloride 
Creatinine  
GGT 
Glucose 
Potassium 
Total Protein  
Sodium 
C-reactive Protein
Total Cholesterol 
LDH 
Magnesium
Phosphorus 
Triglycerides 
Uric acid
Visit: 
Predose, Day 4, Day 8, Day 15 
(Data obtained at Day 1 will be used as the "Predose" visit) 
Property of Takeda: For
Se
S
non-commercial 
Differ
Differ
Monocyt
onocyt
MCH
MCH
use only and subject to the
rences 
rences
applicable 
es below
below
will be
will be
Terms of Use


TAK-925-1003 
Page 49 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Analytical 
Method(s) : 
The following summaries will be provided by treatment group. 
Cohort B1~B2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.2.1 "Cohort A1~A3" will be performed 
for the Cohort B1~B2. 
Cohort C1~C2 
Analysis Set: Safety Set 
Analytical 
Method(s) : 
The same analysis as section 7.11.2.1 "Cohort A1~A3" will be performed 
for the Cohort C1~C2. 
Cohort A'1 
Analysis Set: Safety Set 
Visit: 
Predose, Day 2 
(Data obtained at Day 1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
The same analysis as section 7.11.2.1 "Cohort A1~A3" will be performed 
for the Cohort A'1 
CCI
Property of 
C
Takeda: 
s) :
)
Coho
oh
For non-commercial
s as se
as se
B1~
1~B
Safety S
afety S
use only and 
d subject to the applicable 
rms 
Term of Use


TAK-925-1003 
Page 50 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.11.2.2 Urinalysis 
Cohort A1~A3 
Analysis Set: Safety Set 
Analysis 
Variable(s) : 
Protein 
[-,  +-,  +,  2+,  3+] 
Glucose 
[-,  +,  2+,  3+,  4+] 
Occult Blood
[-,  +-,  +,  2+,  3+] 
Nitrite 
[-,  +] 
Ketone Bodies 
[-,  +-,  +,  2+,  3+] 
pH 
[5.0<= - <=7.5, 8.0<= - <=9.0] 
Specific Gravity 
Urobilinogen 
[+-,  +,  2+,  3+]
Visit: 
Predose, Day 4, Day 8, Day 15 
(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 
treatment group. 
For each variable other than Specific Gravity, summaries (3) and (4) will be 
provided by treatment group. 
CCI
Property of Takeda: For 
mercial 
le other
other
treatm
reatm
non-comm
use
mmar
mma
only
e used
use
ie
and 
ed a
ed a
subject 
9.0.0] ] 
to the applicable Terms of Use


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


TAK-925-1003 
Page 52 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable 
ms 
Terms of Use


TAK-925-1003 
Page 53 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of 
of
C
Ta
Takeda: For non-co
commercial 
no
se 
use only and subject to the applicable 
s 
Terms of Use


TAK-925-1003 
Page 54 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.11.4
 
CCI
CCI
CCI
Property of
of 
da:
a: 
Takeda For 
or
Fo non-commercial use only and subject to the applicable 
ms 
Terms of Use


TAK-925-1003 
Page 55 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
CCI
Property of Takeda: For non-commercial use only and subject to the applicable 
s 
Terms of 
o Use


TAK-925-1003 
Page 56 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.11.5
 
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the 
plicable 
e
appli
erms 
Term of Use


TAK-925-1003 
Page 57 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.11.6
 
CCI
CCI
CCI
Property of Takeda: For non-commercial use only 
on
and su
subject to the applicable 
rms 
Term of Use


TAK-925-1003 
Page 58 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
7.11.7
 
7.11.8 Other Observations Related to Safety 
Not applicable.
7.12 
Interim Data Review 
The dose level chosen for Cohorts in Part A, B, C after the first cohort in each group and 
whether to proceed to next cohort or stop the part may be evaluated by the sponsor’s 
unblinded team composed of persons who do not have subject contact or involvement with 
execution of the protocol at the site, who will review unblinded data on safety, tolerability, 
available PK and PD results, and this dose may be higher, lower or the same than that used in 
the prior cohorts.  
7.13 
Changes in the Statistical Analysis Plan 
From the SAP version 1.0, the following parts were updated. Cohort A3, C2 and A’1 were 
added in each section. Other main modified parts are as below.
Before the change 
Cover 
Prepared by: 
Based on: 
PPD
CCI
CCI
CCI
Property of 
B
C
Takeda:
Chan
han
m the SA
the SA
ded in 
ded in 
Befo
efo
For 
rts.s.
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ng
non-commercial 
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orts i
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sed of p
ed of 
tocol a
ocol a
PD res
PD res
use 
fe
only 
ety
ty
ly and subject to the 
le 
applicable Terms 
erms of Use


TAK-925-1003 
Page 59 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Protocol Version: Initial Version 
Protocol Date: 10 October 2018 
After the change 
Cover 
Prepared by:
Based on: 
Protocol Version: Amendment 3 
Protocol Date: 12 June 2019 
Reason for the change 
Department name changed and protocol was amended. 
Before the change 
7.1.1 Study Definitions 
y
Treatment Group
-
Cohort A1~A2

Placebo (pooled Cohort A1 and A2)

TAK-925 44mg, TBD
-
Cohort B1~B2

Placebo (pooled Cohort B1 and B2)

TAK-925 11mg, TBD
-
Cohort C1

Placebo

TAK-925 TBD
After the change 
7.1.1 Study Definitions 
y
Treatment Group
-
Cohort A1~A3

Placebo (pooled Cohort A1, A2 and A3)

TAK-925 44mg, 112mg, 180mg
-
Cohort B1~B2

Placebo (pooled Cohort B1 and B2)
PPD
Property of
7.7.
Takeda: 
o


After t
After t
For 
TAK
AK
hort C
hort C
non-commercial 
d Cohor
Coho
4mg,
mg, T
B2
ebo (po
(po
9
use only and 
d.
subject to the applicable Terms of Use


TAK-925-1003 
Page 60 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 

TAK-925 11mg, 44mg
-
Cohort C1~C2

Placebo

TAK-925 44mg, 112mg
-
Cohort A'1

TAK-925 112mg
Reason for the change 
The conducting cohorts and each dose level were determined. 
Before the change 
7.9.1.1 
 
After the change 
CCI
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CCI
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t
subject to 
t
the applicable Terms of Use


TAK-925-1003 
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Statistical Analysis Plan 2nd 
28 October 2019 
CCI
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ms 
Term of Use


TAK-925-1003 
Page 62 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
 
Before the change 
Cohort A1~A2 
Analysis Set: PK Set 
Analysis 
Variable(s) : 
Pharmacokinetic Parameters of TAK-925 and 
 
 
 
 
Ceoi 
 
 
 
 
 
 
 
 
 
RAUC(only Day 7) 
 
Visit: 
Day 1, Day 7
Analytical 
Method(s) : 
The following summaries will be provided by treatment group. Subjects 
administered placebo will be excluded from the analysis. 
(3) Summary of Pharmacokinetic Parameters
For 
, 
, 
 and Ceoi, descriptive statistics, geometric
mean, and CV will be provided. 
After the change 
Cohort A1~A3 
Analysis Set: PK Set 
Analysis 
Variable(s) : 
Pharmacokinetic Parameters of TAK-925 and 
 
 
 AUCtau 
 
 
Ceoi 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of 
C
Takeda: 
After the
After the
Coh
For non-commercial 
wing su
ing su
istered 
stered 
Summ
Summ
F
use
RA
RA
se on
on y
only and subjec
d d
ct 
bject
CCI
to the applicable Terms 
r
of Use


TAK-925-1003 
Page 63 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
 
Rac AUC(only Day 7) 
 
 
 
 
 
 
 
 
 
Visit: 
Day 1, Day 7
Analytical 
Method(s) : 
The following summaries will be provided by treatment group. Subjects 
administered placebo will be excluded from the analysis. 
(1) Summary of Pharmacokinetic Parameters
For 
, 
 AUCtau, 
, 
 Ceoi, descriptive
statistics, geometric mean, and CV will be provided. 
(2)
Reason for the change 
Pharmacokinetic parameters were added. 
Before the change 
7.9.2.1 Average Sleep Latency in MWT/Sleep Latency in Each Session in MWT
Cohort B1~B2 
Analytical 
Method(s): 
The following summaries will be provided. 
(1) For the average sleep latency in MWT, descriptive statistics for the
, changes from baseline and 
will be provided by visit by treatment group. The effect of TAK-925
will be evaluated with a linear mixed effects model. The response
variable in the model will be the observed value of the average sleep
latency in the MWT. The model will include treatment (each treatment
of TAK-925 and placebo), day (as a categorical variable), the
treatment-by-day as fixed effects, baseline average sleep latency in the
MWT as a covariate, and subjects as a random effect. Least square (LS)
means, the standard errors, and the two-sided 95% confidence intervals
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For 
T
non-commercial 
dded
de
atency 
tency 
use 
d.d.
onlyly and
and 
an
subject
ect 
ubjec
sub
to
ovide
ovide
to the
Ceoi
Ceo
ed
t
applicable 
Subjects 
ubject
d
Terms of Use


TAK-925-1003 
Page 64 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
will be provided for each treatment group. For each day, the difference 
in the LS means between each treatment of TAK-925 and the placebo 
(each treatment of TAK-925 - the placebo), the standard error of the 
difference and the two-sided confidence intervals will be provided. 
 
 
 
 The differences in the LS means 
between each treatment of TAK-925 group and the placebo group (each 
treatment of TAK-925 group - placebo group), the standard error and 
the two-sided 95% confidence intervals will be provided. 
 
 
  
 
 
 
 
 
   
(2)
CCI
CCI
CCI
CCI
Property of Takeda: For non-commercialal 
rcia
rc
on-commerc
use
use 
us
onlyly 
only
o
and
and 
an
subject
ect 
sub
to
to 
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TAK-925-1003 
Page 65 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
After the change 
7.9.2.1 Average Sleep Latency in MWT/Sleep Latency in Each Session in MWT 
Cohort B1~B2 
Analytical 
Method(s): 
The following summaries will be provided. 
(1) For the average sleep latency in MWT, descriptive statistics for the
, changes from baseline and 
will be provided by visit by treatment group. The effect of TAK-925
will be evaluated with a linear mixed effects model. The response
variable in the model will be the change from baseline in the average
sleep latency in the MWT. The model will include treatment (each
treatment of TAK-925 and placebo), day (as a categorical variable), the
treatment-by-day as fixed effects, baseline average sleep latency in the
MWT as a covariate, and subjects as a random effect. Least square (LS)
means, the standard errors, and the two-sided 95% confidence intervals
will be provided for each treatment group. For each day, the difference
in the LS means between each treatment of TAK-925 and the placebo
(each treatment of TAK-925 - the placebo), the standard error of the
difference and the two-sided confidence intervals will be provided. 
 The differences in the LS means
between each treatment of TAK-925 group and the placebo group (each
treatment of TAK-925 group - placebo group), the standard error and
the two-sided 95% confidence intervals will be provided.
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TAK-925-1003 
Page 66 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
 
 
 
 
 
  
If there is a missing value of sleep latency in MWT at Day -1, it will be 
imputed by the predicted value of the same subject and the same 
session based on a model with sleep latency in MWT at Day -1 as a 
response, session as a fixed effect, and a subject as a random effect. 
After conducting imputation, the average sleep latency in MWT will be 
recalculated and the model analysis as above will be conducted as 
reference. 
(2)
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TAK-925-1003 
Page 67 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
The response variable for model analysis was changed for better assessment. Because 
missing value was occurred at Day -1 of MWT value, the analysis using imputation method 
was added for reference. 
Before the change 
7.9.2.2 
 
After the change 
7.9.2.2 
 
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TAK-925-1003 
Page 68 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
 
Before the change 
7.9.2.3 
 
After the change 
7.9.2.3 
 
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TAK-925-1003 
Page 69 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
Error correction. 
Before the change 
7.9.2.4 
 
After the change 
7.9.2.4 
 
Reason for the change 
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TAK-925-1003 
Page 70 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
To meet another department request. 
Before the change 
7.9.2.5 
 
Reason for the change 
Error correction. 
Before the change 
7.9.2.6 
 
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TAK-925-1003 
Page 71 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
After the change 
7.9.2.6 
 
Reason for the change 
To meet another department request.
Before the change 
7.9.2.7 
 
 
 
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TAK-925-1003 
Page 73 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
To meet another department request. 
Before the change 
7.9.2.8
After the change 
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TAK-925-1003 
Page 77 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Error correction and to clarify the description. 
Before the change 
7.11.2.2 Urinalysis 
Cohort A1~A2 
Analysis 
Variable(s) : 
Protein 
[-,  +-,  +,  2+,  3+]  
Glucose 
[-,  +,  2+,  3+,  4+] 
Occult Blood
[-,  +-,  +,  2+,  3+] 
Nitrite 
[-,  +] 
Ketone Bodies 
[-,  +-,  +,  2+,  3+] 
pH 
[5.0<= - <=7.5, 8.0<= - <=9.0] 
Specific Gravity 
Urobilinogen 
[+-,  +,  2+,  3+]
Microscopy  
RBC 
[below 1/HPF, 1-4/HPF, 5-9/HPF, 10-19/HPF, 
20-29/HPF, 30-49/HPF, 50-99/HPF, above or equal to
100/HPF] 
WBC 
[below 1/HPF, 1-4/HPF, 5-9/HPF, 10-19/HPF, 
20-29/HPF, 30-49/HPF, 50-99/HPF, above or equal to
100/HPF] 
Casts 
[below 1/HPF, 1-4/HPF, 5-9/HPF, 10-19/HPF, 
20-29/HPF, 30-49/HPF, 50-99/HPF, above or equal to
100/HPF] 
Visit: 
Predose, Day 4, Day 8, Day 15 
(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 
treatment group. 
For Microscopy (Erythrocytes (RBC), Leukocytes (WBC), Squamous 
Cells), summaries (3) will be provided by treatment group. 
For each variable other than Specific Gravity and Microscopy, summaries 
(3) and (4) will be provided by treatment group.
After the change 
7.11.2.2 Urinalysis 
Property of Takeda: 
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TAK-925-1003 
Page 80 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
Error correction and to clarify the description. 
Before the change 
7.11.4 
 
After the change 
7.11.4 
 
Reason for the change 
Error correction. 
Before the change 
7.11.5 
 
After the change 
7.11.5 
 
 
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TAK-925-1003 
Page 81 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
Reason for the change 
To make the definitions more appropriate and the analysis for change from time-matched day 
1 to day 7 was added 
7.14
REFERENCES
No reference.
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TAK-925-1003 
Page 82 of 82 
Statistical Analysis Plan 2nd 
28 October 2019 
APPENDIX A 
 
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