Clinical trial NCT03522506
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2018-05-09; Completion date: 2018-11-07
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine the effect of TAK-925 after a single intravenous dose (compared to placebo) on promoting wakefulness as measured by sleep latency on the maintenance of wakefulness (MWT) in sleep-deprived healthy participants.

Detailed description:
The drug being tested in this study is called TAK-925. This study will assess the safety, tolerability, PK and PD of TAK-925 and will assess the effects of TAK-925 in sleep-deprived healthy adult participants.

The study will enroll approximately 20 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the 4 treatment sequences-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* TAK-925 Low Dose + Placebo + TAK-925 High Dose + Modafinil
* TAK-925 High Dose + TAK-925 Low Dose + Modafinil + Placebo
* Modafinil+ TAK-925 High Dose + Placebo + TAK-925 Low Dose
* Placebo + Modafinil + TAK-925 Low Dose + TAK-925 High Dose

TAK-925 will be administered as an intravenous infusion based on the availability of safety, tolerability and PK data from health Japanese participants in ongoing study TAK-925-1001.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 10 weeks. Participants will make a final visit 7 days after receiving their last dose of drug for a follow-up assessment.

Arms: arm 1: TAK-925 low dose milligram (mg), intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 1, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Intervention Period 2, followed by a minimum of 7-days washout period, further followed by TAK-925 high dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 3, followed by a minimum of 7-days washout period, further followed by Modafinil 300 mg, tablet, orally, once on Day 1 of Intervention Period 4. TAK-925 dose will be decided based on the availability of safety, tolerability and PK data from ongoing study TAK-925-1001. arm 2: TAK-925 high dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 1, followed by a minimum of 7-days washout period, further followed by TAK-925 low dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 2, followed by a minimum of 7-days washout period, further followed by Modafinil 300 mg, tablet, orally, once on Day 1 of Intervention Period 3, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Intervention Period 4. TAK-925 dose will be decided based on the availability of safety, tolerability and PK data from ongoing study TAK-925-1001. arm 3: Modafinil 300 mg, tablet, orally, once on Day 1 of Intervention Period 1, followed by a minimum of 7-days washout period, further followed by TAK-925 high dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 2, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Intervention Period 3, followed by a minimum of 7-days washout period, further followed by TAK-925 low dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 4. TAK-925 dose will be decided based on the availability of safety, tolerability and PK data from ongoing study TAK-925-1001. arm 4: Placebo, once on Day 1 of Intervention Period 1, followed by a minimum of 7-days washout period, further followed by Modafinil 300 mg, tablet, orally, once on Day 1 of Intervention Period 2, followed by a minimum of 7-days washout period, further followed by TAK-925 low dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 3, followed by a minimum of 7-days washout period, further followed by TAK-925 high dose mg, intravenously, administered as 9-hour infusion, once on Day 1 of Intervention Period 4. TAK-925 dose will be decided based on the availability of safety, tolerability and PK data from ongoing study TAK-925-1001.
Interventions: intervention 1: TAK-925 intervention 2: TAK-925 Placebo intervention 3: Modafinil intervention 4: Modafinil Placebo
Intervention descriptions: intervention 1: TAK-925 intravenous infusion. intervention 2: TAK-925 placebo-matching given as saline intravenous infusion. intervention 3: Modafinil tablets. intervention 4: Modafinil placebo-matching tablet.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, Single Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-925 in 
Sleep-Deprived Healthy Adults Utilizing Modafinil as an Active Comparator
NCT Number: NCT03522506
Protocol Approve Date: 08 May 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, Single Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-925 in 
Sleep-Deprived Healthy Adults Utilizing Modafinil as an Active Comparator
Study Identifier:
TAK-925-1002
Compound:
TAK-925
Date:
08 May 2018
Version/Amendment 
Number:
01
Date
Amendment Number
Region
08 March 2018
Initial Protocol
United States
08 May 2018
01
United States
Property of Taked
mercial use only and subject to the applicable Terms of Use


TAK-925
Study ID TAK-925-1002
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
1.1
Protocol Amendment 01 Summary of Changes ........................................................11
2.0
STUDY SCHEMATIC..................................................................................................12
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................13
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................18
4.3
Benefit/Risk Profile .................................................................................................19
4.3.1
TAK-925 ...........................................................................................................19
4.3.2
Modafinil...........................................................................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.1.1
Primary Objective ..............................................................................................23
5.1.2
Secondary Objectives.........................................................................................23
5.1.3
Exploratory Objectives.......................................................................................23
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoint...............................................................................................24
5.2.2
Secondary Endpoints..........................................................................................24
5.2.3
Safety Endpoints................................................................................................25
5.2.4
Exploratory Endpoints .......................................................................................25
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design ...........................................................................................................26
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................27
6.2.1
Rationale of Study Design..................................................................................27
6.2.2
Rationale for Dose .............................................................................................28
6.2.3
Rationale for Endpoints......................................................................................29
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............31
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................31
6.4
Study Beginning and End/Completion .....................................................................32
6.4.1
Definition of Beginning of the Study..................................................................32
6.4.2
Definition of End of the Study ...........................................................................32
6.4.3
Definition of Study Discontinuation...................................................................32
6.4.4
Criteria for Premature Termination or Suspension of the Study..........................33
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Study ID TAK-925-1002
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............34
7.1
Inclusion Criteria .....................................................................................................34
7.2
Exclusion Criteria ....................................................................................................35
7.3
Excluded Medications, Supplements, Dietary Products............................................36
7.3.1
Concomitant Medications...................................................................................36
7.3.2
Fruit Juice ..........................................................................................................36
7.3.3
Alcohol..............................................................................................................36
7.3.4
Caffeine .............................................................................................................37
7.3.5
Smoking ............................................................................................................37
7.4
Diet, Fluids, and Activity.........................................................................................37
7.4.1
Diet and Fluids...................................................................................................37
7.4.2
Activity..............................................................................................................37
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................38
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................39
7.7
Subject Replacement................................................................................................39
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................40
8.1
Clinical Study Drug .................................................................................................40
8.1.1
Clinical Study Drug Labeling.............................................................................40
8.1.2
Clinical Study Drug Inventory and Storage ........................................................40
8.1.3
Clinical Study Drug Blinding.............................................................................40
8.1.4
Randomization Code Creation and Storage ........................................................40
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................40
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................41
9.0
STUDY PROCEDURES...............................................................................................42
9.1
Administrative Procedures.......................................................................................42
9.1.1
Informed Consent Procedure..............................................................................42
9.1.2
Inclusion and Exclusion .....................................................................................42
9.1.3
Medical History, Demographics, and Prior and Concomitant Medications .........42
9.2
Clinical Procedures and Assessments.......................................................................43
9.2.1
Full Physical Examination..................................................................................43
9.2.2
Height and Weight .............................................................................................43
9.2.3
BMI ...................................................................................................................43
9.2.4
Vital Signs .........................................................................................................43
9.2.5
Continuous Monitoring with Digital Technology ...............................................43
9.2.6
12-Lead ECG.....................................................................................................43
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Study ID TAK-925-1002
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9.2.7
Study Drug Administration ................................................................................44
9.2.8
C-SSRS..............................................................................................................44
9.2.9
Drug-Liking VAS ..............................................................................................45
9.2.10 Actigraphy.........................................................................................................45
9.2.11 Sleep Deprivation...............................................................................................45
9.2.12 AE Monitoring...................................................................................................45
9.2.13 Laboratory Procedures and Assessments ............................................................45
9.3
PK, Biomarker, PD, and Pharmacogenomic Samples...............................................47
9.3.1
PK, Biomarker, PD, and Pharmacogenomic Evaluations ....................................47
9.3.2
PK Measurements..............................................................................................47
9.3.3
Biomarker Measurements...................................................................................48
9.3.4
PD Measurements..............................................................................................49
9.3.5
PGx Measurements ............................................................................................50
9.3.6
Confinement ......................................................................................................51
10.0
ADVERSE EVENTS ....................................................................................................52
10.1
Definitions and Elements of AEs .............................................................................52
10.1.1 SAEs..................................................................................................................54
10.2
AE Procedures.........................................................................................................54
10.2.1 Assigning Severity/Intensity of AEs...................................................................54
10.2.2 Assigning Causality of AEs................................................................................55
10.2.3 Start Date...........................................................................................................55
10.2.4 End Date............................................................................................................55
10.2.5 Pattern of AE (Frequency) .................................................................................55
10.2.6 Action Taken With Study Treatment..................................................................55
10.2.7 Outcome ............................................................................................................56
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................56
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....58
11.0
STATISTICAL METHODS..........................................................................................59
11.1
Statistical and Analytical Plans ................................................................................59
11.1.1 Analysis Sets......................................................................................................59
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................59
11.1.3 PK Analysis .......................................................................................................59
11.1.4 PD Analysis .......................................................................................................60
11.1.5 Safety Analysis ..................................................................................................60
11.2
Interim Analysis and Criteria for Early Termination ................................................61
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Study ID TAK-925-1002
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11.3
Determination of Sample Size..................................................................................61
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................63
12.1
Study-Site Monitoring Visits ...................................................................................63
12.2
Protocol Deviations..................................................................................................63
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................63
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................64
13.1
IRB and/or IEC Approval ........................................................................................64
13.2
Subject Information, Informed Consent, and Subject Authorization .........................65
13.3
Subject Confidentiality ............................................................................................66
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................66
13.4.1 Publication and Disclosure.................................................................................66
13.4.2 Clinical Trial Registration..................................................................................67
13.4.3 Clinical Trial Results Disclosure ........................................................................67
13.5
Insurance and Compensation for Injury....................................................................67
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................68
14.1
Administrative Information......................................................................................68
14.1.1 Study Contact Information .................................................................................68
14.1.2 INVESTIGATOR AGREEMENT......................................................................69
14.1.3 Study-Related Responsibilities...........................................................................70
14.1.4 List of Abbreviations .........................................................................................70
15.0
DATA HANDLING AND RECORDKEEPING............................................................72
15.1
CRFs (Electronic and Paper)....................................................................................72
15.2
Record Retention .....................................................................................................72
16.0
REFERENCES..............................................................................................................74
17.0
APPENDICES...............................................................................................................77
LIST OF IN-TEXT TABLES
Table 4.a
Summary of Blinded TEAE Data From Study TAK-925-1001 
(Cohorts 1 and 2, Healthy Adult Subjects a) .......................................................21
Table 4.b
Summary of Blinded TEAE Data From Study TAK-925-1001 (Cohort 3, 
Healthy Elderly Adult Subjects a).......................................................................21
Table 6.a
Summary of Study Drug Assignment and Sequence (Double Dummy for 
Placebo).............................................................................................................26
Table 6.b
Dosing and Sampling Scheme............................................................................27
Table 9.a
Primary Specimen Collections ...........................................................................47
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Study ID TAK-925-1002
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LIST OF IN-TEXT FIGURES
Figure 4.a
Model of Diurnal Intrinsic OX Level in Brain Over Time ..................................19
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................77
Appendix B
Elements of the Subject Informed Consent.........................................................79
Appendix C
Investigator Consent to the Use of Personal Information ....................................82
Appendix D
Pregnancy and Contraception.............................................................................83
Appendix E
Detailed Description of Amendments to Text.....................................................86
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TAK-925
Study ID TAK-925-1002
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge MA 02139
USA
Compound:
TAK-925
Study Identifier: TAK-925-1002
Phase: 1b
Protocol Title: A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, Single Dose Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-925 in Sleep-Deprived Healthy Adults 
Utilizing Modafinil as an Active Comparator
Study Design:
Healthy adult male subjects aged 18 to 40 years, inclusive, who satisfy inclusion and exclusion criteria will be enrolled 
in the study. On Day 1 of treatment period 1, eligible participants will be equally randomized to 4 treatment sequence 
groups (sequence 1 to 4) which define the order of the treatment administration (TAK-925 44 mg [low dose, (LD)], 
TAK-925 112 mg [high dose (HD)] mg [both delivered as a 9-hour intravenous (IV) infusion], modafinil 300 mg, and 
placebo).
At the screening visit, subjects will complete medical examinations, an electrocardiogram (ECG), and clinical 
laboratory tests. After the screening visit, eligible participants will wear an actigraph from Day -6 until Day -1. After 
validation that actigraphy shows a normal sleep-wake cycle, and subjects have a negative drug screen, subjects will 
undergo an 8-hour nocturnal polysomnography to exclude any sleep disorders. Actigraphy results will also be 
collected for the 5-night period before Day-1 (Day -6 to Day -1) for every treatment period to ensure that sleep falls 
within normal nocturnal times (defined under Inclusion Criteria).
During the day before dosing on Day 1, subjects will be administered the Karolinska Sleepiness Scale (KSS) and 
Cambridge Cognition Computerized Battery of Tests (CCBT) at scheduled timepoints. A practice maintenance of 
wakefulness test (MWT) session, as well as a practice CCBT, will be performed on Day 1 of treatment period 1 (only 
once during the entire study) to familiarize subjects with the procedures. Study drug will be administered in the clinic 
in the evening on Day 1 of each treatment period. Subjects will undergo the MWT, KSS, and CCBT at specified time 
points after the start of the infusion. Subjects will be required to stay awake in between the MWT tests. Following 
completion of the IV infusion on Day 2, subjects will undergo an additional MWT test. When the final MWT test and 
cognitive testing has been completed, subjects will be allowed to sleep (recovery sleep) for approximately 6 hours. 
Polysomnography (PSG) recording will be collected during this time. Subjects may be discharged from the unit after 
completion on Day 2 with continuing actigraphy upon discharge (to begin on Day -6 before the next treatment period). 
The interval of each subsequent treatment period will be at least 7 days to ensure that the subject’s circadian rhythm 
has returned to a normal cycle. Subject’s vital signs, including blood pressure (BP), will be continuously monitored 
during the dosing and testing periods. Blood samples for determination of TAK-925 plasma concentrations will be 
collected at specified timepoints on Days 1 and 2 of each treatment period. Subjects will complete the Columbia–
Suicide Severity Rating Scale (C-SSRS) during screening, before study drug administration, and before discharge on 
Day 2 of each treatment period. Subjects will complete the Profile of Mood States (POMS) before and post study drug 
administration, and undergo a drug-liking Visual Analog Scale (VAS) following recovery sleep in each treatment 
period.
Primary Objective:
To determine the effect of TAK-925 after a single IV infusion (compared to placebo) on promoting wakefulness as 
measured by sleep latency on the MWT (performed at approximately 2, 4, 6, and 8 hours postdosing starting at 
approximately 1:00 AM and then at approximate times of 3:00, 5:00, and 7:00 AM) in sleep-deprived healthy 
volunteers.
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TAK-925
Study ID TAK-925-1002
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Secondary Objectives:
1.
To assess the safety/tolerability and pharmacokinetic (PK) parameters of a single IV infusion of TAK-925 in 
sleep-deprived healthy volunteers.
2.
To determine the effect of a single dose of modafinil (300 mg) on promoting wakefulness as measured by sleep 
latency on the MWT in order to confirm assay sensitivity.
3.
To evaluate the effect of TAK-925, LD and HD, on a measure of sleepiness, as compared to placebo.
Study Subject Population: Healthy male subjects, aged 18 to 40 years, inclusive.
Planned Number of Subjects:
Approximately 20 subjects randomized
Planned Number of Sites:
1 site in the US
Dose Levels:
Study Drug
TAK-925 112 mg (HD)
TAK-925 44 mg (LD)
Matching placebo
Modafinil
300 mg
Matching placebo
Route of Administration:
Study Drug
IV infusion
Modafinil
Oral (tablets)
Duration of Treatment:
1 dose of modafinil 300 mg or placebo followed by a 
continuous 9-hour IV infusion of study drug (TAK-925 
HD mg, TAK-925 LD mg, or placebo) beginning in the 
evening on Day 1 of each of 4 treatment periods
Planned Study Duration:
Up to approximately 12 weeks.
Main Criteria for Inclusion:
To be eligible for study participation, subjects must: 
1.
Understand the study procedures and agree to participate by providing written informed consent.
2.
Be willing and able to comply with all study procedures and restrictions.
3.
Be a healthy male, aged 18 to 40 years, inclusive, at the screening visit.
4.
Have a body mass index ≥18.5 and ≤30.0 (kg/m2) at the screening visit.
5.
Be a nonsmoker or have not used tobacco- or nicotine-containing products (eg, nicotine patch) for at least 
6 months before study drug administration of the initial dose of study drug.
6.
Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, 
medical history, physical examination, 12-lead ECG, and vital sign measurements performed at the screening 
visit and before administration of the initial dose of study drug/invasive procedure.
7.
Meet the specified birth control requirements.
8.
Is a male subject who agrees to not donate sperm from trial drug administration on the first day of the first dose 
until 5 half-lives plus 90 days after the last dose of study drug administration.
9.
Have regular sleep-wake habits (eg, routinely spending 6.5 to 8 hours sleeping nightly, not oversleeping by more 
than 3 hours on weekends, ie, total sleep not more than 11 hours) as determined by investigator interviews and 
confirmed in 5-day actigraphy records and whom regularly fall asleep between 9:30 PM and 12:00 AM.
10. Be willing to have actigraphy monitoring during the week before randomization and in each interval.
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Study ID TAK-925-1002
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Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
1.
Has a positive alcohol or drug screen.
2.
Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).
3.
Has excessive sleepiness defined by a self-reported Epworth Sleepiness Scale score at screening greater than 10; 
irregular work hours; or routine night-shift work within 1 month before randomization. 
4.
Currently experiencing or having a history of any known/suspected sleep disorder, any disorder associated with 
excessive daytime somnolence, or any diagnosis interfering with assessment of sleepiness.
5.
Abnormal findings on the initial PSG conducted on Day -1 (check-in), as specified in the study manual.
6.
Traveled across 2 or more time zones 2 weeks or less before screening; 
7.
Current or previous history of serious, severe, or unstable physical or psychiatric illness that may affect sleep or 
wakefulness; any medical disorder that may make the full completion of the study unlikely.
8.
Caffeine consumption of more than 400 mg/day for 2 weeks before screening (1 serving of coffee is 
approximately equivalent to 120 mg of caffeine).
9.
Hypertension or history of hypertension. Systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg is excluded.
10. Other significant cardiovascular risk factors including abnormal ECG QT interval findings and heart rate (HR).
11. Screening ECG reveals a QT interval with Frederica correction method >450 milliseconds.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:
1.
Latency for each MWT, defined as time to sleep onset.
Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. 
Trials are ended after 40 minutes if no sleep occurs, or after unequivocal sleep, defined as 3 consecutive epochs of 
stage 1 sleep, or 1 epoch of any other stage of sleep. If no sleep has been observed according to these rules, then 
the latency is defined as 40 minutes.
The secondary endpoints will be assessed through evaluation of the following parameters: 
1.
The following PK parameters calculated from plasma concentrations of TAK-925 and its metabolites M-I and 
M-II:

Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.

Area under the first moment plasma concentration-time curve from time 0 to infinity.

Maximum observed plasma concentration.

Plasma concentration observed at the end of infusion.

Time of first occurrence of Cmax.

Terminal disposition phase half-life.

Total clearance after intravenous administration (TAK-925 only).

Volume of distribution during the terminal disposition phase after intravenous administration (TAK-925 
only).

Volume of distribution at steady state after intravenous administration.
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Study ID TAK-925-1002
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2.
Sleepiness on the KSS.
Safety will be assessed through the following parameters:
1.
Treatment-emergent adverse events. Subjects will be monitored closely throughout the study for any adverse 
events.
2.
Physical examinations.
3.
Vital signs, including time-matched BP measurement and PK-BP relationships.
4.
12-lead ECGs.
5.
Clinical laboratory safety evaluations (hematology, blood chemistry, and urinalysis).
6.
Drug-liking VAS.
7.
POMS.
8.
Continuous monitoring of BP, HR (eg, Bodyconnect) at time points specified in the protocol, and sleep cycle from 
Day -5 to -1 by actigraphy with digital technology.
9.
C-SSRS.
Statistical Considerations:
The effect of TAK-925 on sleep latency on the MWT will be evaluated with a mixed effects model appropriate for a 
4-period crossover study. The response variable in the model will be the observed value of sleep latency. The model 
will contain fixed effects for sequence, period, treatment (TAK-925 LD, TAK-925 HD, modafinil, and placebo), time 
(as a categorical variable), and the treatment-by-time interaction, and a random effect for subject.
The estimated mean sleep latency for each treatment and the associated standard error and 95% CI will be extracted 
from the model at each time, along with all treatment differences and associated standard errors, 95% CIs, and 
p-values. The same quantities, averaged over all timepoints at which an MWT is performed, will also be extracted 
from the model using an appropriate contrast. The study objectives will be addressed using the results of the average 
treatment difference across all time points.
The change from time-matched baseline in HR and BP will be analyzed using a statistical model of the same form as 
for the primary endpoint. The estimated mean change from time-matched baseline for each treatment and the 
associated standard error and 95% CI will be extracted from the model at each time, along with all treatment 
differences and associated standard errors, 95% CIs, and p-values. The same quantities, averaged over all postdose 
timepoints, will also be extracted from the model using an appropriate contrast.
Sample Size Justification:
The sample size justification is based on a similar study to assess the alertness-promoting effects of MK-0249, a 
histamine subtype-3 receptor inverse agonist, and modafinil 200 mg, in healthy sleep-deprived males [1]. In that 
study, investigators observed a mean increase in sleep latency in the MWT of 
 with modafinil 200 mg 
compared with placebo at 6 hours postdose and a within-subject standard deviation of approximately 6.74 minutes. 
With similar variability, 16 completers will provide approximately 90% power for detecting a difference in sleep 
latency in the MWT between TAK-925 and placebo if the true increase over placebo is 
. This result is based 
on a 2-sided test with a 
.
To account for dropouts, approximately 20 subjects will be enrolled. 
CCI
CCI
CCI
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Study ID TAK-925-1002
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08 May 2018
1.1
Protocol Amendment 01 Summary of Changes
Rationale for Amendment 01
This document describes the changes in reference to the protocol incorporating Amendment 
No. 01. The primary reason for Protocol Amendment No. 1 is to update cognition rating scales and 
revise protocol text to align with the Inclusion/Exclusion Criteria. Minor grammatical, editorial, 
and formatting changes are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment 01:
1. Removed Sustained Attention to Response Task (SART) assessment throughout protocol and 
updated study schematic accordingly.
2. Replaced Cogstate Cognitive Computerized Battery of Tests with Cambridge Cognition 
Computerized Battery of Tests (CCBT).
3. Updated alcohol consumption restrictions.
4. Updated caffeine consumption restrictions.
5. Updated smoking restrictions.
6. Added dose levels selected for the low dose (LD) and high dose (HD).
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2.0
STUDY SCHEMATIC
Abbreviations: CCBT, Cambridge Cognition Computerized Battery of Tests; IV, intravenous; KSS, Karolinska 
Sleepiness Scale; MWT, maintenance of wakefulness test; NPSG, nocturnal polysomnography; PSG, 
polysomnogram.
*Performed once during the entire study.
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3.0
SCHEDULE OF STUDY PROCEDURES
Day
Each Treatment Period
Day
Day
Scheduled Time (Day 1 and 2)
Day
-28
to -2
-1
Hours
2 After 
Recovery 
Sleep
7
Screen-
ing d
Check
-in
Pre
dose
After Start of Infusion
After End of Infusion
Post
dose/
Early
Termina-t
ion
Follow
-up
Visit a
1
2
3
4
5
6
7
8
9
0.17
0.5
1
2
3
4
6
9
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history
X
X
Concomitant medication 
review
X---------------------------------------------------------------Continuous----------------------------------------------------------------------X
Clinic 
Procedures/Assessments
Full physical examination
X
X b
X
X
Height
X
Weight
X
X
X
X
Body mass index
X
Vital signs (BP, HR) c
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous monitoring with 
digital technology (BP, HR) d
X
X--------------------------------------------------------Continuous-------------------------------------------------------------X
Vital signs (respiratory rate, 
oral/tympanic temperature) e
X
X
X
12-lead ECG e
X
X
X
X
Study drug administration f
9-hour continuous IV infusion
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Day
Each Treatment Period
Day
Day
Scheduled Time (Day 1 and 2)
Day
-28 
to -2
-1
Hours
2 After 
Recovery 
Sleep
7
Screen-
ing d
Check
-in
Pre
dose
After Start of Infusion
After End of Infusion
Post
dose/
Early
Termina-t
ion
Follow
-up
Visit a
1
2
3
4
5
6
7
8
9
0.17
0.5
1
2
3
4
6
9
C-SSRS
X
X
X
Drug-liking VAS
X
Actigraphy g
X
Sleep deprivation
X
X-----------------------------------------------------------------------------------
X
Adverse events monitoring
X---------------------------------------------Continuous-------------------------------------------X
Pharmacodynamic 
Evaluations
Screening polysomnography 
(PSG)
X h
Maintenance Wakefulness Test 
(MWT), power spectrum EEG i
X
X
X
X
X
X
Karolinska Sleepiness Scale 
(KSS) j
X
X
X
X
X
X
CCBT j
X
X
X
X
X
X
POMS k
X
X
Recovery sleep PSG
X-----Continuous-----X
Laboratory 
Procedures/Assessments
Hematology
X
X
X
X
Urinalysis
X
X
X
X
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08 May 2018
Day
Each Treatment Period
Day
Day
Scheduled Time (Day 1 and 2)
Day
-28 
to -2
-1
Hours
2 After 
Recovery 
Sleep
7
Screen-
ing d
Check
-in
Pre
dose
After Start of Infusion
After End of Infusion
Post
dose/
Early
Termina-t
ion
Follow
-up
Visit a
1
2
3
4
5
6
7
8
9
0.17
0.5
1
2
3
4
6
9
Chemistry
X
X
X
X
Urine drug screen l
X
Hepatitis screen
X
HIV
X
Blood for retained samples and 
pharmacogenomics h
X
Pharmacokinetics 
Evaluations
Blood for plasma PK TAK-925 
and metabolites assay m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other
Confinement
X------------------------------------------------------------------Continuous----------------------------------------------------------------X
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Abbreviations: BP, blood pressure; CCBT, Cambridge Cognition Computerized Battery of Tests; C-SSRS, Columbia–Suicide Severity Rating Scale; EEG, electroencephalogram; 
HIV, human immunodeficiency virus; HR, heart rate; IV, intravenous; KSS, Karolinska Sleepiness Scale; MWT, Maintenance of Wakefulness; POMS, Profile of Mood States; PSG, 
polysomnography; PK, pharmacokinetics; VAS, visual analog scale.
a Follow-up visit will occur Day 7 (±2) after the last dose of study drugs.
b Can be performed within approximately 24 hours before study drug dosing.
c Vital signs (HR, BP) will be obtained as follows:
Day -1: will be obtained time matched with Day 1. Day -1 vital signs are to mirror the planned scheduled vital signs for Day 1 as it relates to predose and postdosing scheduled vital 
signs. Predose and postdose vital signs at the identical times allows for a time-matched comparison.
Day 1: predose, 1, 2, 4, 6, 9, 10, 11, 13 hours post IV dose
Follow-up visit
BP will be checked with the subject lying in a bed with the head of the bed at 30 degrees. See Section 6.2.4 for order of assessments.
d BP and HR will be continuously monitored during the confinement period, starting in the evening on Day -1.
e Vital signs (other than HR and BP) and 12-lead ECG will be performed within approximately 1 hour predose and 6 hour after start of infusion on Day 1 and at discharge on Day 2.
f Modafinil or matching placebo capsule will be administered at approximately an hour before start of IV dosing on Day 1. TAK-925 or matching placebo will be started infusing 
approximately at 11:00 PM on Day 1.
g Subjects will be monitored with actigraphy from Day -6 through Day -1.
h Will be performed only once in each subject before treatment period 1.
i MWT will be performed as following; approximately 2, 4, 6, 8, 10 hours after start of IV infusion. The MWT done at approximately 10 hours will be approximately 1 hour and 
20 minutes after the end of the drug infusion. A practice MWT session will be performed on Day 1 of treatment period 1 (only once during the entire study) to familiarize subjects with 
the procedure.
k The POMS will be done predose to modafinil/placebo or IV drug administration and after the last MWT and KSS, and CCBT have been completed.
l Urine drug screen will be done at first period only, and not subsequent periods.
m Blood for TAK-925 PK will be collected: Pre, 1, 2, 4, 6, and 9 hours after start of infusion; 0.17, 0.5, 1, 2, 3, 4, 6, 9 hours after end of infusion; and at discharge. 
CCI
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4.0
INTRODUCTION
4.1
Background
Orexin (OX) is a neuropeptide that was discovered independently by research groups in Japan and 
the United States. The orexinergic system is a major wake-promoting system of the brain. 
OX-producing neurons are localized in a specific region of the lateral hypothalamus and have 
excitatory projections to wide areas of the neuraxis, including the cerebral cortex and other 
wake-promoting nuclei (cholinergic neurons of the basal forebrain, tuberomammillary nucleus, 
locus coeruleus, ventral tegmental area and dorsal raphe nucleus). The orexinergic system is also 
involved in several other functions, such as feeding, reward, and sympathetic activity. Two 
orexinergic neuropeptides, orexin-A and orexin-B, have been identified to date. The orexins exert 
effects via 2 types of receptors; orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). 
Orexin-A has a high affinity to OX1R and OX2R, and orexin-B has a high affinity to OX2R. The 2 
OX receptors have a distinct distribution in the arousal network–the locus coeruleus contains only 
OX1R, the tuberomammillary nucleus only OX2R, whereas both receptor types occur in the dorsal 
raphe nucleus and ventral tegmental area. The 2 OX receptors make distinct contributions to the 
regulation of arousal. OX2R in the tuberomammillary nucleus are essential for the maintenance of 
wakefulness (MWT), whereas both receptor types are required for the inhibition of rapid eye 
movement (REM) sleep [2].
The pathological loss of orexinergic neurons is associated with the development of narcolepsy [3]. 
The symptoms of narcolepsy can be divided into 2 groups: (i) symptoms caused by the intrusion of 
non-REM sleep into wakefulness (excessive daytime somnolence [EDS], sleep attacks) and (ii) 
symptoms caused by the intrusion of REM sleep into wakefulness (cataplexy, hypnagogic or 
hypnopompic hallucinations, sleep paralysis) [2]. The REM–sleep-related symptoms reflect 
physiological accompaniments of REM sleep: loss of muscle tone (cataplexy, sleep paralysis) and 
dreaming (visual hallucinations). 
Narcolepsy can also occur without cataplexy, termed narcolepsy type 2 (NT2); patients with this 
disorder may exhibit all clinical features of narcolepsy with the exception of cataplexy [4]. 
Narcolepsy with cataplexy, or narcolepsy type 1 (NT1), has been defined by International 
Classification of Sleep Disorders, 3rd edition (ICSD-3) criteria as having low levels of OX in 
cerebrospinal fluid (CSF) (<110 pg/mL; <30% of normal levels) and narcolepsy without cataplexy 
(NT2) with CSF OX levels >110 pg/mL (at least 30% of normal). 
The pathophysiology of NT1 has a presumed, though unproven, autoimmune basis in individuals 
with a specific genetic predisposition, the most common of which is the HLA DQB1*0602 (HLA 
DQB1 [major histocompatibility complex, class II, DQ beta 1]) [5,6]. The proposed etiology 
involves T-cell mediated destruction of OX-producing neurons in the hypothalamus 
[6-8]. Loss of OX-producing neurons are reflected by low CSF OX levels [9]. 
The presumed pathophysiology of NT2 is unclear. However, there are examples of patients 
initially classified as having NT2 who later develop cataplexy. In a few patients, CSF levels of OX 
have been demonstrated to decrease over time [10]. The dichotomy of the ICSD-3 criteria have 
also been subject to some criticism since measurement of OX in CSF is only performed as a 
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research tool and is not clinically available, and the symptoms of cataplexy may be quite subtle 
and unrecognized. As many as 30% of patients with NT2 are found to have CSF OX levels that are 
lower than normal [11]. African Americans are more likely to have low OX levels, even if 
cataplexy is absent [12]. It may be that there is a spectrum of narcolepsy such that some OX loss 
results in EDS without cataplexy, whereas greater loss results in cataplexy. This concept of a 
narcolepsy spectrum is supported by murine models of narcolepsy that show greater hypocretin 
loss in animals exhibiting cataplexy than in those exhibiting only sleep fragmentation/wakefulness
[11].
Mild to moderate loss of OX neurons has also been shown to occur in several neurodegenerative 
diseases (60% in Parkinson’s disease, 40% in Alzheimer’s disease, and 30% in Huntington’s 
disease, in contrast to 90% in narcolepsy) and this may contribute to the EDS observed in some 
patients with these diseases.
Currently available medications for EDS include modafinil, methylphenidate hydrochloride, 
dextroamphetamine sulfate, and/or sodium oxybate. These drugs have limited effectiveness and/or 
undesirable side effects such as nausea, headache, and dizziness [13]. The adverse effects from 
amphetamines also include irritability, hyperactivity, tremor, and mood changes [14]. Based on 
the data described above demonstrating that partial or complete OX deficiency plays an important 
role in the development of EDS, OX replacement therapy is expected to improve EDS through the 
pathophysiology-directed mechanism of action (MOA). A novel drug that acts to help address the 
deficiency of OX may address the spectrum of narcolepsy symptoms, and may have greater 
efficacy than currently approved drugs for treatment of EDS.
TAK-925 is a highly selective OX2R agonist being developed by Takeda for the treatment of 
narcolepsy. The OX receptor is a G protein-coupled receptor that has 2 subtypes, OX1R and 
OX2R. Upon activation, OX1R and OX2R couple with Gq protein to increase intracellular
calcium (Ca2+) concentration. In Chinese hamster ovary K1 cells expressing recombinant human 
OX2R, TAK-925 increased intracellular Ca2+ levels in a concentration dependent manner. In vivo 
pharmacology studies have demonstrated that TAK 925 increased wakefulness and decreased 
cataplexy-like events in the OX/ataxin-3 mouse model of NT1. TAK-925 significantly and 
dose-dependently enhanced wakefulness in wild type (WT) mice, common marmosets, and 
cynomolgus monkeys. Please refer to the TAK-925 Investigator’s Brochure for complete 
information on the investigational product.
4.2
Rationale for the Proposed Study
TAK-925 showed arousal effects in WT mice and monkeys as well as in OX/ataxin-3 mice, a 
narcolepsy mouse model with a loss of OX-producing neurons. This strongly suggests that 
TAK-925 can stimulate the OX wake promoting system, even if it is not deficient. It is important 
to note that the effects in the WT animals were found during their “sleep phase”. OX levels vary 
across the diurnal cycle [15,16], lowering midnight to early morning in the squirrel monkey, which 
has a pattern of wakefulness similar to that of humans [15]. As rigorous translation of animal 
models to the human condition is critical to our understanding of drug mechanisms in this study, 
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TAK-925 will be administered to sleep-deprived healthy subjects during nighttime to evaluate 
effects on wakefulness in sleep phase (see Figure 4.a) [15]. 
Figure 4.a
Model of Diurnal Intrinsic OX Level in Brain Over Time
4.3
Benefit/Risk Profile
As this study will be conducted in healthy subjects, there is no expected clinical benefit to study
participants other than receiving medical examinations and information about their overall health 
conditions. It is possible that the information obtained in the present study will become beneficial 
to patients with narcolepsy in the future.
This phase 1 study has been designed to mitigate the potential risks based on nonclinical findings. 
In addition, there is minimal risk associated with study noninvasive procedures including vital sign 
assessments and electrocardiograms (ECGs).
The principal mitigation for these risks includes appropriate selection of the study population, the 
clinical research unit setting, which permits close monitoring and rapid institution of appropriate 
care as needed, appropriate specified monitoring procedures, and utilization of experienced staff 
trained in study procedures. Overall, the risk:benefit profile is considered appropriate for this 
study.
4.3.1
TAK-925
TAK-925 safety information is derived from the data obtained from nonclinical studies and 
preliminary data from the ongoing first-in-human (FIH) study TAK-925-1001 in Japanese 
subjects.
Risks observed during the nonclinical studies included convulsions, vomiting, and blood pressure 
(BP) increase. Convulsions were observed in a single-dose intravenous (IV) escalating 
administration toxicity study in monkeys at a high infusion rate, but were not observed in 2-week 
Good Laboratory Practice toxicology studies with a slower infusion rate. Vomiting was seen in 
2-week toxicology studies in animals given higher doses. Nausea and vomiting are readily 
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monitored in subjects and managed as appropriate, including potentially stopping the study drug 
infusion. A mean systolic blood pressure (SBP) increase up to 19 mmHg was also noted in a 
monkey safety pharmacology study, and based on published literature this is considered a potential 
mechanism-based risk for OX2R agonists [17]. Therefore, frequent BP measurements will be 
obtained throughout the study. Detailed plans for management of BP increase are in Section 7.6. 
As the drug is expected to have a short half-life, stopping the infusion should result in rapid BP
lowering if toleration does not develop with continued study drug infusion.
The FIH phase 1 study of TAK-925, TAK-925-1001 is currently being conducted in Japan. It is 
assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single 
9-hour IV dose of TAK-925 when administered to healthy adult and elderly adult volunteers and 
patients with narcolepsy. This study consists of 2 parts: Part 1 and Part 2.
Part 1 is an alternating panel, randomized, double-blind, placebo-controlled, dose-escalation, 
crossover study to assess the safety, tolerability and PK of TAK-925 when administered as a 
single-dose to healthy adult and elderly adult volunteers. In Part 1, the safety, tolerability and the 
PK including the concentration of TAK-925 in the CSF when administered as a single dose to 
healthy adult volunteers will also be evaluated in a unblinded fashion.
Part 2 is a sequential panel, randomized, double-blind (sponsor unblinded), placebo-controlled, 
2-period crossover study to assess the safety, tolerability, PK, and PD of 1 or more doses of 
TAK-925 versus placebo in patients with NT1.
In Part 1, In the ongoing FIH study TAK-925-1001, single doses of TAK-925 or matching placebo 
given IV for 9 hours have been administered in Part 1 to 16 subjects (12 active and 4 placebo) in
2 cohorts in an alternating panel design. Cohort 1 received 7, 28, and 112 mg TAK-925/placebo as 
single doses and Cohort 2 received 14, 56, and 134.4 mg TAK-925/placebo as single doses in 2 
treatment periods, with a washout period of at least 7 days. Following review of the safety, 
tolerability, and PK in these cohorts, 6 healthy elderly adult subjects received a single IV dose of 
112 mg TAK-925 and 2 subjects received placebo. Cohort 4 will assess the safety and tolerability, 
and PK of TAK-925 including the concentration of TAK-925 in the CSF in 4 healthy adults.
TAK-925 was safe and tolerable in dose range tested between 7 mg and 134.4 mg (as of 
19 February 2018). PK parameters showed dose proportional increases with a relatively longer 
half-life (approximately 3 to 5 hours) in man than in animals.
A total of 16 subjects were initially dosed; however, in the first cohort (7 mg/placebo), 1 subject 
experienced a headache, and withdrew from the study. This subject was later diagnosed with 
influenza (headache included under symptom term). Subsequent cohorts that included that panel 
had 7 rather than 8 subjects. No other subject withdrawals have occurred. There have been no 
serious adverse events (SAEs) or severe adverse events (AEs).
All AEs except influenza (considered as moderate) were mild in severity. All cardiovascular 
effects related AEs (BP increased, pulse rate increased) were considered as mild.
A summary of blinded treatment-emergent adverse event (TEAE) data (verbatim terms) reported 
in Cohorts 1 and 2 (healthy adult subjects) and Cohort 3 (healthy elderly adult subjects) in 
Study TAK-925-1001 is provided in Table 4.a and Table 4.b, respectively.
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Table 4.a
Summary of Blinded TEAE Data From Study TAK-925-1001 
(Cohorts 1 and 2, Healthy Adult Subjects a)
Verbatim Term
Number of Events
Part 1 SRD Cohorts 1-2
TAK-925 or Placebo
(Healthy Adults a)
7 mg
n=8
14 mg
n=8
28 mg
n=7
56 mg
n=8
112 mg
n=7
134.4 mg
n=8
Any TEAE
2
0
1
3
1
7
Orthostatic hypotension
1
0
0
0
0
0
Influenza
1
0
0
0
0
0
Electrocardiogram PR prolongation
0
0
1
0
1
0
Pharyngodynia
0
0
0
1 b
0
0
White blood cell count increased
0
0
0
1
0
0
Triglyceride increased
0
0
0
1
0
0
Pulse rate increased
0
0
0
0
0
3
Blood pressure increased
0
0
0
0
0
2
Nausea
0
0
0
0
0
1
Feeling drunk
0
0
0
0
0
1
Abbreviations: SRD, single rising dose; TEAE, treatment-emergent adverse event.
a. Aged 20 to 55 years, inclusive.
b Predose.
Table 4.b
Summary of Blinded TEAE Data From Study TAK-925-1001 (Cohort 3, 
Healthy Elderly Adult Subjects a)
Verbatim Term
Number of Events
Part 1 SRD Cohort 3
TAK-925 or Placebo
112 mg
(Healthy Elderly Adults a)
n=8
Any TEAE
4
Blood pressure increased
4
a. Aged 65 to 80 years, inclusive.
Please refer to the TAK-925 Investigator’s Brochure for available clinical information on the 
investigational product.
4.3.2
Modafinil
Modafinil is approved in the United States as Provigil and name brand drug will be supplied for 
this study. The most serious risks noted in the prescribing information are noted below.
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There is a very low risk of serious rash, which may require hospitalization and discontinuation of 
treatment in adults in association with the use of modafinil. The risk is even lower with only 1 dose 
of the drug. The full prescribing information notes that no serious skin rashes have been reported 
in adult clinical studies (0 per 4264) of modafinil. Rare cases of serious or life-threatening rash, 
including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia 
and systemic symptoms have been reported in adults and children in worldwide postmarketing 
experience. The reporting rate of toxic epidermal necrolysis and Stevens-Johnson syndrome
associated with modafinil use, which is generally accepted to be an underestimate due to 
underreporting, exceeds the background incidence rate. 
There are no factors that are known to predict the risk of occurrence or the severity of rash
associated with modafinil. Nearly all cases of serious rash associated with modafinil occurred 
within 1 to 5 weeks after treatment initiation. Although benign rashes also occur with modafinil, it 
is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil 
should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not 
drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening 
or permanently disabling or disfiguring.
One serious case of angioedema and 1 case of hypersensitivity (with rash, dysphagia, and 
bronchospasm), were observed among 1595 patients treated with armodafinil, the R-enantiomer of 
modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical 
studies. However, angioedema has been reported in postmarketing experience with modafinil.
Multi-organ hypersensitivity reactions, including at least 1 fatality in postmarketing experience, 
have occurred in close temporal association (median time to detection 13 days: range 4-33) to the 
initiation of modafinil. Although there have been a limited number of reports, multi-organ 
hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors 
that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity 
reactions associated with modafinil. If a multi-organ hypersensitivity reaction is suspected, 
Provigil should be discontinued.
In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment
discontinuation (at a frequency >0.3%) and reported more often in patients treated with modafinil 
compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), 
confusion (<1%), agitation (<1%), and depression (<1%). Caution should be exercised when 
Provigil is given to patients with a history of psychosis, depression, or mania.
BP monitoring in short-term (<3 months) controlled trials showed no clinically significant changes 
in mean SBP and diastolic blood pressure (DBP) in patients receiving Provigil as compared to 
placebo.
Please refer to the current package labeling for modafinil for detailed information regarding the 
safety risks and risk mitigation measures for modafinil.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
1. To determine the effect of TAK-925 after a single IV dose (compared to placebo) on 
promoting wakefulness as measured by sleep latency on the MWT (performed at 
approximately 2, 4, 6, and 8 hours post-dosing starting at approximately 1:00 AM and then at 
approximate times of 3:00, 5:00, and 7:00 AM) in sleep-deprived healthy volunteers. 
Hypothesis: At least 1 of the tested doses of TAK-925 is superior to placebo for promoting 
wakefulness as measured by sleep latency on the MWT (a difference between TAK-925 and 
placebo of 9 minutes or greater is estimated).
5.1.2
Secondary Objectives
1. To assess the safety/tolerability and PK parameters of a single IV infusion of TAK-925 in 
sleep-deprived healthy volunteers.
Hypothesis: TAK-925 is generally well tolerated when administered as a single IV infusion, 
including effects on BP. (Overall mean difference in time-matched BP increase following 
administration of safe, tolerable, and effective dose of TAK-925 is less than or equal to 
10 mmHg over placebo.)
2. To determine the effect of a single dose of modafinil (300 mg) on promoting wakefulness as 
measured by sleep latency on the MWT in order to confirm assay sensitivity.
Hypothesis: Modafinil (300 mg) is superior to placebo on promoting wakefulness as measured
by sleep latency on the MWT (a difference between modafinil and placebo of 9 minutes is 
estimated [18].
3. To evaluate the effect of TAK-925, 44 mg (low dose [LD]) and 112 mg (high dose [HD]), on a 
measure of sleepiness, as compared to placebo.
Hypothesis: At least 1 dose of TAK-925 will be superior to placebo on the Karolinska 
Sleepiness Scale (KSS).
5.1.3
Exploratory Objectives
In sleep-deprived healthy volunteers: 
CCI
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5.2
Endpoints
5.2.1
Primary Endpoint
1. Latency for each MWT, defined as time to sleep onset.

Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 
30-second epoch. Trials are ended after 40 minutes if no sleep occurs, or after unequivocal 
sleep, defined as 3 consecutive epochs of stage 1 sleep, or 1 epoch of any other stage of 
sleep. If no sleep has been observed according to these rules, then the latency is defined as 
40 minutes.
5.2.2
Secondary Endpoints
Secondary endpoints will be assessed through the following parameters:
1. The following PK parameters calculated from plasma concentrations of TAK-925 and its 
metabolites M-I and M-II:

Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).

Area under the first moment plasma concentration-time curve from time 0 to infinity 
(AUC∞).

Maximum observed plasma concentration (Cmax).

Plasma concentration observed at the end of infusion (Ceoi).

Time of first occurrence of Cmax (tmax).

Terminal disposition phase half-life (t1/2z).

Total clearance after intravenous administration (CL) (TAK-925 only).

Volume of distribution during the terminal disposition phase after intravenous 
administration (Vz) (TAK-925 only).

Volume of distribution at steady state after intravenous administration (Vss).
2. Sleepiness on the KSS.
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5.2.3
Safety Endpoints
Safety will be assessed through the following parameters:
1. TEAEs. Subjects will be monitored closely throughout the study for any AEs.
2. Physical examinations.
3. Vital signs, including time-matched BP measurement and PK-BP relationships.
4. 12-lead ECGs.
5. Clinical laboratory safety evaluations (hematology, blood chemistry, and urinalysis).
6. Drug-liking visual analog scale (VAS).
7. Profile of Mood States (POMS).
8. Continuous monitoring of BP and heart rate (HR), eg, Bodyconnect, at time points specified in 
the protocol, and sleep cycle from Day -5 to -1 by actigraphy with digital technology.
9. Columbia-Suicide Severity Rating Scale (C-SSRS).
5.2.4
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters:
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, double-blind, double-dummy, placebo- and active-controlled, 4-period 
Williams design crossover study to evaluate the PK, PD, and safety of TAK-925 in sleep-deprived 
healthy volunteers. TAK-925 will be administered as an IV infusion over a 9-hour period based on 
the safety/tolerability and PK profiles established in healthy Japanese subjects in ongoing 
Study TAK-925-1001.
Healthy adult male subjects aged 18 to 40 years, inclusive, who satisfy inclusion and exclusion 
criteria will be enrolled in the trial. Approximately 20 subjects will be enrolled to ensure that at 
least 16 subjects complete the study. 
On Day 1 of treatment period 1, eligible subjects will be equally randomized to 4 treatment 
sequence groups (Sequence 1 to 4) which define the order of the treatment administration 
(TAK-925 LD mg, TAK-925 HD mg [both delivered as a 9-hour IV infusion], modafinil 300 mg, 
and placebo).
A summary of the study drug assignment and sequence in presented in Table 6.a.
Table 6.a
Summary of Study Drug Assignment and Sequence (Double Dummy for 
Placebo)
Sequence
N
Period 1
Period 2
Period 3
Period 4
1
5
TAK-925 LD mg
Placebo
TAK-925 HD mg
Modafinil 300 mg
2
5
TAK-925 HD mg
TAK-925 LD mg
Modafinil 300 mg
Placebo
3
5
Modafinil 300 mg
TAK-925 HD mg
Placebo
TAK-925 LD mg
4
5
Placebo
Modafinil 300 mg
TAK-925 LD mg
TAK-925 HD mg
Abbreviations: HD, high dose; LD, low dose.
At the screening visit, subjects will complete medical examinations, an electrocardiogram (ECG), 
and clinical laboratory tests. After the screening visit, eligible participants will wear an actigraph 
from Day -6 until Day -1. After validation that actigraphy a normal sleep-wake cycle, and subjects 
have a negative drug screen, subjects will undergo an 8-hour nocturnal polysomography (NPSG)
to exclude any sleep disorders. Actigraphy results will also be collected for the 5-night period 
before Day-1 (Day -6 to Day -1) for every treatment period to ensure that sleep falls within normal 
nocturnal times (defined under Inclusion Criteria).
During the day before dosing on Day 1, participants will be administered the KSS and CCBT at 
scheduled timepoints. A practice MWT session, as well as one practice CCBT, will be performed 
on Day 1 Treatment Period 1 (only once during the entire study) to familiarize subjects with the 
procedures. Study drug will be administered in the clinic in the evening on Day 1 of each treatment
period. Subjects will undergo the MWT, KSS, and CCBT at specified timepoints after the start of 
the infusion. Subjects will be required to stay awake in between the MWT tests. Following 
completion of the IV infusion on Day 2, subjects will undergo an additional MWT test. When the 
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final MWT test and cognitive testing have been completed, subjects will be allowed to sleep 
(recovery sleep) for approximately 6 hours. PSG recording will be collected during this time. 
Subjects may be discharged from the unit after completion on Day 2 with continuing actigraphy 
upon discharge (to begin on Day -6 before the next treatment period). The interval of each 
subsequent treatment period will be at least 7 days to assure that the subject’s circadian rhythm has 
returned to a normal cycle. Subject’s vital signs, including BP, will be continuously monitored 
during the dosing and testing period. Blood samples for determination of TAK-925 plasma 
concentrations will be collected at specified timepoints on Days 1 and 2 of each treatment period. 
Subjects will complete the C-SSRS during Screening, before study drug administration, and 
before discharge on Day 2 of each treatment period. Subjects will complete the POMS before and 
post study drug administration, and undergo a drug-liking VAS following recovery sleep in each 
treatment period.
An overview of the dosing and sampling scheme is provided in Table 6.b.
Table 6.b
Dosing and Sampling Scheme
Screening Period
Check-in and 
Baseline
Treatment Period
Time Interval 
Between 
Subsequent 
Treatment Period
Dose/Sample 
Collection
Sample Collection
Days -28 to -2
Day -1
NPSG/BP 
measurement a
Day 1
Sleep 
deprivation/study 
drug 
administration/study 
assessment
Day 2
Sleep 
deprivation/study 
drug continued 
infusion/study 
assessment/recovery 
sleep
Minimum of 7 days 
with actigraphy for 
5 days
X---------------------------Confinement----------------------------X
Abbreviations: BP, blood pressure; NPSG, nocturnal polysomnography.
a NPSG and time-matched BP only on Day -1 of treatment period 1. For Periods 2, 3, and 4, subjects will be admitted 
to the unit and allowed to sleep normally without NPSG or time-matched BP measurement. The time interval from the 
end of 1 period to the start of the next period will be at least 7 days.
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design
The study population chosen for this study consists of males aged 18 to 40 years who are generally 
in good health and normotensive (see inclusion/exclusion criteria for specifics). Healthy males
only are being used in this study to minimize any inter- and intra-individual variability related to 
between gender effects of the sleep cycle, as well as potential effects of the menstrual cycle on 
sleep. The age range specified is to again to mitigate against any effects of older age on sleep, as 
well as the higher likelihood of sleep abnormalities that rises with increasing age. This cohort is 
similar to that in other investigational drug studies with sleep deprivation in healthy normal 
subjects.
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This 4-period, Williams design crossover study is a design that has been previously used in other 
studies of drugs that have been evaluated for effects on wakefulness [18]. While there is a risk of 
dropouts during the study, a relatively short time between periods will aid in subject retention. A 
crossover design requires fewer subjects than a parallel group design, as treatment comparisons 
are based on intra-subject differences which are typically associated with smaller variability than 
between-subject differences. The study is directly translational from the data obtained in normal 
animals including 2 species of non-human primates. 
Nighttime is considered the most appropriate time period to evaluate the efficacy of TAK-925 in 
this sleep-deprived model study since there is evidence that OX levels are relatively lower during 
the nighttime compared to daytime. Considering the MOA of TAK-925, it is a reasonable 
assumption that the sensitivity to detect the efficacy of TAK-925 in healthy normal persons should 
be greater during nighttime.
Modafinil 300 mg, a standard treatment for EDS, will be included as an active reference 
compound. Modafinil is one of the most commonly used stimulants for narcolepsy, 
hypersomnolence associated with obstructive sleep apnea and shift-work disorder. Modafinil has 
previously been evaluated in both narcolepsy studies [19] and in sleep deprivation studies in 
healthy volunteers [20]. The tmax of modafinil is approximately 3 hours and in sleep-deprived 
healthy volunteers, MWT or efficacy on cognitive tests has been detected at approximately tmax
post administration. Compared with placebo, modafinil showed greater effects on wakefulness on 
the MWT sleep latency in both sleep-deprived healthy volunteers and in narcolepsy patients, with
9-minute and 6-minute increases in sleep latency, respectively [1,21]. Modafinil loses its PD 
effects at 10 hours post dosing, which is close to the same duration of the 9-hour TAK-925 
infusion. The timing of the dose of modafinil will be given so that tmax is achieved at the time of the 
first MWT. Modafinil will be given 1 hour before the start of the IV infusion. The study is not 
powered for use of modafinil as an actual comparator compound.
A double-dummy design will be used. Subjects receiving modafinil will receive IV normal saline. 
Those receiving TAK-925 will be given an oral (PO) placebo capsule.
6.2.2
Rationale for Dose
Based on the currently available information, this study will evaluate 2 dose levels of TAK-925, a 
low dose of 44 mg (LD) and high dose of 112 mg (HD). The HD of 112 mg was selected based on 
the safety and tolerability results in adult subjects from the ongoing FIH TAK-925-1001 study. 
Doses up to and including 134.4 mg, the maximum dose tested so far in healthy volunteers, were 
safe and well tolerated with no severe AEs or SAEs. All subjects dosed with 112 mg TAK-925 had 
acceptable safety and tolerability during the 9-hour IV infusion. The 44 mg LD was selected to 
evaluate a dose that may result in effects on wakefulness (as assessed by the MWT) that are greater 
than those of placebo, based on nonclinical studies, but are associated with systemic exposures of 
TAK-925 that are pharmacologically different those expected at the HD of 112 mg. Based on
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. Thus, the potential difference in the 
pharmacological response to TAK-925 has also been taken into consideration when choosing the 
LD and HD in sleep-deprived healthy subjects.
6.2.3
Rationale for Endpoints
6.2.3.1
Primary Endpoint
Effect on wakefulness as measured by sleep latency on the MWT was selected as the primary 
endpoint. The MWT is a validated objective measure that has been often used as a primary efficacy 
endpoint to measure EDS in clinical studies. An approximate 9-minute increase over placebo is 
considered as a benchmark PD effect size of TAK-925 in this study, based on the efficacy of 
modafinil 200 mg in a similar study in a sleep-deprived healthy population [18]. Note that the dose 
of modafinil used in this study will be 300 mg, which has been selected to demonstrate assay 
sensitivity.
6.2.3.2
Secondary Endpoints
KSS
The KSS is helpful in assessing the changes in response to the effects of drugs and is a measure of 
situational sleepiness. It is sensitive to fluctuations. It has been used in studies of shift work, jetlag, 
for driving abilities, attention and performance, and in clinical settings. It is helpful in assessing 
the changes in response to environmental factors, circadian rhythm, and effects of drugs. In a study 
conducted by [22,23] the authors investigated the validity of the KSS and found that it was highly 
correlated to EEG and behavioral variables. The results show that KSS has a high validity. 
CCBT
The CCBT has been used in studies on sleep deprivation and shift work-related cognitive 
impairment and the potential for detection of pharmacological remediation has also been evaluated
(internal data, Cambridge Cognition). Reaction time related batteries in the CCBT have shown
significant deterioration with sleep deprivation [24-26].
Wearable Devices
Wearable digital devices will be implemented in this study for monitoring biometric and physical 
activities associated with the sleep-wake cycle. An actigraphy device will capture data on the 
subject’s activity level, including intensity of movement, rest, and sleep. The primary purpose of 
this data is to confirm that the subject has maintained normal sleep/wake life habits before study 
drug administration. 
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BP data will be collected using a wrist- or finger-based device for measurement of radial arterial 
pressure or digital arterial pressure. BP data will be collected during PSG monitoring and 
continuous drug infusion to provide ample data for evaluation of PK-PD relationships between 
TAK-925 and BP versus placebo and BP. Outcome of these PK-PD analyses will help to inform 
assessment of the effects of TAK-925 on BP.
6.2.3.3
Exploratory Endpoints
6.2.3.4
Safety Endpoints
The safety endpoints of TEAEs, vital signs, 12-lead ECGs, and clinical laboratory evaluations 
(including hematology, chemistry, and urinalysis) are standard methods for assessing safety and 
tolerability of drugs in clinical studies.
The drug-liking VAS is a standard tool for assessing drug abuse potential. Many stimulant drugs 
are scheduled substances based on the potential for abuse. While TAK-925 is early in 
development, it is important to begin assessing the potential for abuse. An assessment of drug 
liking will be included. Since, TAK-925 has central nervous system (CNS) activity in animals and 
is expected to have CNS activity in humans, abuse potential will be assessed. TAK-925 is 
theorized to have a low potential for abuse probability based on its high selectivity for OX2R over 
OX1R [28]. Preliminary information relevant to the potential for abuse could be informative for 
further development of TAK-925.
The POMS is a well-validated self-report measure of mood states, and has high internal 
consistency as well as predictive and constructive validity. POMS is used in many clinical studies 
including research in narcolepsy populations [29].
Subjects will be monitored for any signs of suicidal ideation or behaviors using the C-SSRS.
BP increase is an identified risk from nonclinical safety studies. In the FIH study
(TAK-925-1001), mild BP increase or HR increase were reported in 2 healthy normal subjects out
of 8 subjects at the 134.4 mg dose level during study drug infusion. Continuous BP measurements
will be obtained in this study to further characterize PK-PD relationships with any BP increase that
may be observed after administration of TAK-925.
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6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures
For this study, the MWT is the critical procedure and should be performed as close to the 
scheduled time as possible.

Blood samples for PK evaluations must be drawn as close as possible to the specified time.

ECG and vital sign measurements should be completed before blood sampling if the timing of 
these assessments overlap.

All other procedures should be performed as close as possible (either before or after) the 
scheduled times.

The suggested order of the PD assessments of each treatment period is as follows:
–
MWT.
–
KSS.
–
CCBT.
–
POMS.

The order of priority can be changed during the study with joint agreement of the investigator 
and the sponsor.

Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined below may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study subjects.
Some alterations from the currently outlined dose and/or dosing regimen may be permitted based 
on newly available data.
The following may occur:

Changes in the dose of the study drug administered may occur.

The interval between doses may be lengthened if supported by safety, PD, and PK evidence. 

The PK/PD sampling scheme may be modified during the study based on newly available PK 
or PD data (eg, to obtain data closer to the tmax). If indicated, these collected samples may also 
be assayed in an exploratory manner for metabolites and/or additional PD markers.

For PK blood draw, the timing of sampling collection may be changed without changing the 
total number of samples which will be taken based on TAK-925-1001 study PK data.
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
Additional MWT, neuropsychological tests (CCBT), and KSS evaluations could be added to 
characterize PK-PD relationships of TAK-925 based on TAK-925-1001 study results.

Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This blood 
volume may include repeat samples or modified PK/PD time points based on emerging data. 
The total blood volume withdrawn from any single subject will not exceed the maximum 
allowable volume during his/her participation in the entire study.

The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, 
safety laboratory tests) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, PK, or PD/biomarker data (eg, to obtain data 
closer to the time of peak plasma concentrations). These changes will not increase the number 
of study procedures for a given subject during his/her participation in the entire study.

Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatine kinase to serum chemistry panel that was 
already drawn). 
It is understood that the current study may employ some or none of the alterations described above. 
Any alterations described above made to this protocol to meet the study objectives must be 
detailed by the sponsor in a letter to the Trial Master File and forwarded to the investigator for 
retention. The letter will be forwarded to the institutional review board (IRB)/independent ethics 
committee (IEC) at the discretion of the investigator.
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.4.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
study, or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.4.3
Definition of Study Discontinuation
Study discontinuation because of nonsafety reasons, such as the following:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical study 
using the study treatment(s) results in the study being stopped for a nonsafety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a nonsafety-related reason.

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Study discontinuation because of safety reasons:
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
Early study termination because of unanticipated concerns of safety to the study subjects 
arising from clinical or nonclinical trials with the trial treatment(s), comparator(s), drug(s) of 
the same class, or methodology(ies) used in this study.
6.4.4
Criteria for Premature Termination or Suspension of the Study
6.4.4.1
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
or is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement.
6.4.4.2
Procedures for Premature Termination or Suspension of the Study or the Participation of 
the Study Sites
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
1. Understand the study procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all study procedures and restrictions.
3. Be a healthy male, aged 18 to 40 years, inclusive, at the screening visit.
4. Have a body mass index (BMI) ≥18.5 and ≤30.0 (kg/m2) at the screening visit.
5. Be a nonsmoker or have not used tobacco- or nicotine-containing products (eg, nicotine patch, 
chew, e-cigarettes, etc.) for at least 6 months before study drug administration of the initial 
dose of study drug.
6. Be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign 
measurements performed at the screening visit and before administration of the initial dose of 
study drug/invasive procedure.
7. 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 <5 half-lives plus 90 days> after the last dose of study drug. No restrictions are 
required for a vasectomized male subject provided the subject is at least 1 year 
postbilateral vasectomy procedure before the first dose of study drug. A male subject 
whose vasectomy procedure was performed less than 1 year before 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 study drug administration on the 
first day of the first dose until 5 half-lives plus 90 days after the last dose of study drug 
administration.
8. Have regular sleep-wake habits (eg, routinely spending 6.5 to 8 hours sleeping nightly, not 
oversleeping by more than 3 hours, ie, total sleep not more than 11 hours) as determined by 
investigator interviews and confirmed in 5-day actigraphy records and whom regularly fall 
asleep between 9:30 PM and 12:00 AM.
9. Be willing to have actigraphy monitoring during the week before randomization and in each 
interval.
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7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. Has participated in another investigational study within 4 weeks (or based on local 
recommendations) before the pretrial (screening) visit. The 4-week window will be derived 
from the date of the last study procedure and/or AE related to the study procedure in the 
previous study to the screening visit of the current study. 
2. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the clinical 
research unit or of the sponsor.
3. Has a history of cancer (malignancy).
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
5. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), or 
HIV antibody/antigen, at Screening. Note: Subjects with positive hepatitis B virus (HBV) or 
HCV serology may be enrolled if quantitative polymerase chain reaction for HBV or HCV 
viral RNA is negative.
6. Has a positive alcohol or drug screen at screening.
7. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks 
before the pretrial (screening) visit. 
8. Is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies beginning approximately 7 days before 
administration of the initial dose of study drug, throughout the study (including washout 
intervals between treatment periods), until the poststudy visit. Excluded food substances and 
medications are listed in Appendix 4.
9. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass 
is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce] per day).
10. Has excessive sleepiness defined by a self-reported Epworth Sleepiness Scale score at 
screening greater than 10; irregular work hours; or routine night-shift work within 1 month 
before randomization. 
11. Currently experiencing or having a history of any known/suspected sleep disorder, any 
disorder associated with EDS, or any diagnosis interfering with assessment of sleepiness.
12. Abnormal findings on the initial PSG conducted on Day -1 (check-in), as specified in the study 
manual.
13. Traveled across 2 or more time zones 2 weeks or less before screening or any time during study 
participation. 
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14. Current or previous history of serious, severe, or unstable physical or psychiatric illness that 
may affect sleep or wakefulness; current or past history of epilepsy or convulsion; or any 
medical disorder that may make the full completion of the study unlikely.
15. Caffeine consumption of more than 400 mg/day for 2 weeks before screening (1 serving of 
coffee is approximately equivalent to 120 mg of caffeine).
16. Participants treated with medications with CNS effects within 14 days of check-in including 
sedating antihistamines, decongestant sympathomimetics, and/or monoamine oxidase 
inhibitors. Participants need to comply with conventional phase 1 pharmacology study 
prohibited/excluded medications specified in protocol.
17. Hypertension or history of hypertension. SBP ≥140 mmHg or DBP ≥90 mmHg is excluded.
18. Other significant cardiovascular risk factors including abnormal ECG QT interval findings and 
HR.
19. Screening ECG reveals a QT interval with Frederica correction method (QTcF) 
>450 milliseconds.
7.3
Excluded Medications, Supplements, Dietary Products
7.3.1
Concomitant Medications
The use of concomitant medications (see Section 9.1.3) 7 days before administration of the first 
dose of study drug, throughout the study (including the washout interval between treatment 
periods), and until the follow-up visit is not permitted. Subjects must be instructed not to take any 
medications without first consulting with the investigator. Any concomitant medication use must 
first be discussed with the sponsor, unless the investigator or designee considers immediate 
administration is necessitated.
The occasional use of acetaminophen (approximately <1 g/day) is allowed.
7.3.2
Fruit Juice
Subjects will refrain from consuming grapefruit juice, grapefruits, and products containing 
grapefruit beginning approximately 7 days before administration of the first dose of study drug, 
throughout the study (including the washout interval between treatment periods), and until the 
follow-up visit.
Subjects also will refrain from consuming all juices 12 hours before and after administration of 
each dose of study drug on PK sampling days (Days 1 and 2 of each treatment period). 
Consumption of all fruits other than grapefruit is allowed on all days of the study.
7.3.3
Alcohol
Alcohol consumption is not allowed during the entire study.
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7.3.4
Caffeine
Subjects will refrain from consuming caffeinated beverages 24 hours before the screening visit and 
follow-up visit and from 24 hours before and until the last PK blood sample has been collected in 
each treatment period. At all other times, caffeinated beverages or xanthine-containing products 
will be limited to amounts of no more than 400 mg/day.
7.3.5
Smoking
Smoking or use of nicotine or tobacco products is not allowed during the entire study.
7.4
Diet, Fluids, and Activity
7.4.1
Diet and Fluids
On Day 1, study drug will be administered beginning at approximately 9:45 PM for tablet 
(modafinil or placebo) and approximately 10:45 PM for IV infusion (TAK-925 or placebo) for 
each treatment period. The modafinil or matching placebo will be given with 240 mL of water for 
PO administration. Subjects will be NPO for 2 hours after the PO modafinil/placebo 
administration.
Since study drug administration does not begin until evening, subjects will have a standard 
breakfast, lunch, and dinner on Day 1. Snacks may be given up until approximately 8:30 PM on the 
day of dosing (Day 1). No other food will be consumed until breakfast on Day 2. Subjects will fast 
from all food and drink except water between meals and snacks. The caloric content and 
composition of meals will be the same for all subjects in each treatment period. On Day 2, 
breakfast will be provided after the fourth MWT, KSS, and cognitive testing have been completed. 
After the postdose procedures have been completed, subsequent meals and snacks will be 
unrestricted in caloric content, composition, and timing.
Subjects will refrain from consuming mustard greens (ie, kale, broccoli, watercress, collard 
greens, kohlrabi, Brussel sprouts, and mustard) and charbroiled meat 7 days before administration 
of the first dose of study drug, throughout the study (including the washout interval between 
treatment periods), and until the follow-up visit.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc) from the screening visit until administration of the initial dose of study drug, 
throughout the study (including washout intervals between treatment periods), and until the 
follow-up visit.
Starting at approximately 8:30 PM, the subject’s activities will be restricted so that they are not 
overstimulated or upset. Cell phone use will be restricted from approximately 8:30 PM until after 
recovery sleep the next day. Activities permitted from approximately 8:30 PM on until the start of 
recovery sleep are board games, puzzles, adult coloring books, drawing, reading, listening to 
music (not on cell phones), watching television or non-violent movies, and walking and talking 
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with other participants/staff. Subjects may bring in small craft projects they are interested in or are 
working on.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities:
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.2.13.1), if the following circumstances occur at any 
time during the study drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8x upper limit 
of normal (ULN), or
–
ALT or AST >5x ULN and persists for more than 2 weeks, or
–
ALT or AST >3x ULN in conjunction with elevated bilirubin >2x ULN or international 
normalized ratio (INR) >1.5 ULN, or
–
ALT or AST >3x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

Suicidality:
–
Study drug should be discontinued immediately for subjects at imminent risk of suicide 
per the C-SSRS (score of 5) or per the investigator’s clinical judgment.

BP increase:
–
Sustained SBP >180 mmHg, sustained DBP >110 mmHg, or sustained increase in SBP 
>40 mmHg from baseline (measured just before the start of infusion).
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
4. Voluntary withdrawal. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF. Note: All attempts should be made to 
determine the underlying reason for the withdrawal and, where possible, the primary 
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underlying reason should be recorded (ie, withdrawal due to an AE should not be recorded in 
the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Other. Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit.
If a BP reading meets 1 of the criteria outlined in Section 7.5, the BP will be repeated at 5 minutes 
to confirm the value. If the subject has no cardiac or neurological symptoms, BP will continue to 
be observed at 15-minute intervals. If there are cardiac or neurological symptoms, the drug should 
be discontinued immediately, and the subject treated to lower BP according to the best judgment of 
the investigator and in accordance with good medical practice, and further emergency medical 
evaluation sought. Elevation to >200 mmHg SBP or >120 mmHg DBP will result in immediate 
discontinuation of drug. Sustained BP elevation at values >180 mmHg and ≤200 mmHg SBP, 
>110 mmHg and ≤120 mmHg DBP, or a sustained increase of 40 mmHg SBP will result in the 
infusion being discontinued, with duration of increased BP tolerated being 1 hour or based on 
investigator judgment and in accordance with good medical practice. If the BP does not fall after 
drug discontinuation within 30 to 60 minutes, the subject should be treated according to the best 
judgment of the investigator and in accordance with good medical practice. If the drug is 
discontinued in any one subject due to a BP increase, the subject will not be rechallenged with 
TAK-925 infusion.
7.7
Subject Replacement
If a subject discontinues from the study, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The study site should contact the sponsor for the 
replacement of subject’s treatment assignment and allocation number.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Details regarding the composition and extemporaneous preparation of the active drug and placebo 
are found in the Pharmacy Manual. Clinical study drug will be packaged to support enrollment and 
replacement subjects as required. When a replacement subject is required, the sponsor needs to be 
contacted before dosing.
8.1.1
Clinical Study Drug Labeling
Clinical study drug will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Clinical study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of study drug must be recorded by an 
authorized unblinded person at the trial site.
8.1.3
Clinical Study Drug Blinding
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. 
Study drug will be provided to an unblinded pharmacist or other qualified study site personnel who 
will blind the study supplies. Treatment identity (name and strength or potency) will be included 
on the study drug container label; randomization code/disclosure envelopes or lists will be 
provided.
8.1.4
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
The clinical study drug blind will be maintained through a randomization schedule held by the site 
unblinded pharmacist. The clinical study drug blind shall not be broken by the investigator unless 
information concerning the clinical study drug is necessary for the medical treatment of the 
subject. If possible, the medical monitor should be contacted before the study drug blind is broken. 
Unblinding will be performed per the standard operating procedures of the site contract research 
organization.
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8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical study drug received 
from the sponsor or designee, the amount dispensed to and returned by the subjects, and the 
amount remaining at the end of the study. For all study sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for clinical study drug 
accountability, return, and destruction.
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9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the Schedule of Study Procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, per the 
discretion of the investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters 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 1 screening number. Screening numbers must not be reused for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event.
All eligible subjects will be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another 
subject. A single subject cannot be assigned more than 1 randomization number.
9.1.1.2
Study Drug Assignment
On Day 1 of Treatment Period 1, subjects will be assigned a randomization number in ascending 
numerical order at the clinical site. The randomization number encodes the sequence in which each 
subject will receive TAK-925 LD mg, TAK-925 HD mg, modafinil, 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.
9.1.2
Inclusion and Exclusion 
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
9.1.3
Medical History, Demographics, and Prior and Concomitant Medications
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the site’s standard of care and appropriate clinical judgment, and also 
subject demographics.
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Qualified site personnel will review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vaccines, supplements, nutraceuticals, and 
PO herbal preparations.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
Qualified site personnel will conduct full physical examinations.
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.
9.2.3
BMI
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
BMI will be rounded to the nearest whole number according to the standard convention of 0.1 to 
0.4, round down, and 0.5 to 0.9, round up.
9.2.4
Vital Signs
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (ie, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a bed with the head of the bed at 30 degrees for at least 5 minutes before 
vital signs are measured. Vital signs will include HR, respiratory rate, SBP, and DBP. The same 
method (eg, same size cuff, manual or automated) must be used for all measurements for each 
individual subject and should be the same for all subjects. 
Subjects should continue to rest in a bed with the head of the bed at 30 degrees from the time of 
dosing until 4 hours postdose except to stand for the measurement of standing vital signs (if 
needed) or other trial-related procedure.
9.2.5
Continuous Monitoring with Digital Technology
BP data will be collected using a wrist- or finger-based device for measurement of radial arterial 
pressure or digital arterial pressure. BP and HR will be continuously monitored during the 
confinement period. BP data will be collected during the NPSG on the first night of the study and 
continuously during study drug infusion such that time points of BP collection during these 
periods are approximately matched.
9.2.6
12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement.
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Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement.
QTcF intervals will be calculated in this study.
For each treatment period, a predose ECG will be obtained within approximately 1 hour before 
study drug dosing. This measurement will be used as the baseline assessment. The principal 
investigator should arrange to have a study cardiologist available as needed to review ECG 
tracings with abnormalities.
During each treatment period, if a subject demonstrates an increase in QTcF interval 
≥40 milliseconds compared with a predose baseline measurement, the ECG will be repeated 
within 5 minutes. The average value of the QTcF interval from the 2 ECGs will represent the value 
at that time point. If the average QTcF interval increase from baseline for any postdose time point 
is ≥40 milliseconds, the subject will continue to be monitored by repeat 12-lead ECGs every 60 
minutes for at least 4 hours or until the QTcF interval is within 40 milliseconds of the baseline 
value. If prolongation of the QTcF interval ≥40 milliseconds persists, a consultation with a study 
cardiologist may be appropriate and the sponsor should be notified.
If the QTcF interval is ≥500 milliseconds, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be monitored by telemetry (until the QTcF interval 
is <500 milliseconds) or should be considered for transfer to a location where closer monitoring is 
available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted by 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: HR, PR interval, QRS interval, QT interval, 
QTcF interval, and the interpretation of the ECG profile by the principal investigator.
9.2.7
Study Drug Administration
On Day 1 of each treatment period, trial drug (TAK-925 LD mg, TAK-925 HD mg, modafinil 
[300 mg], or placebo) will be administered as described in Section 7.4.1.
9.2.8
C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures (see Section 3.0). Two versions of the C-SSRS will be used in this study: the 
Screening/Baseline C-SSRS Lifetime and the Since-Last-Visit C-SSRS. Any suicidal ideation or 
suicidal behavior during trial periods detected by C-SSRS will be recorded as AEs. The 
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investigator will ensure that any suicidal ideation or behavior is medically addressed, including 
assessment and treatment by qualified medical personnel.
9.2.9
Drug-Liking VAS
Following recovery sleep in each treatment period, subjects will undergo a self-administered 
100-point (0 = strongly dislike to 100 =strongly like) drug-liking VAS to assess abuse potential.
9.2.10 Actigraphy
Subjects will be monitored with actigraphy from Day -6 through Day -1 of each treatment period 
to confirm that subjects have a normal sleep-wake cycle (defined as at least 6 hours of sleep per 
night, and other criteria as specified in the inclusion/exclusion criteria). The actigraphy will be 
deployed on Day -6 and used continuously until subjects arrive at the study site. Actigraphy data 
will not be collected while subjects are confined.
9.2.11 Sleep Deprivation
Subjects will be required to stay awake in between MWT tests. During the MW study, subjects 
will be instructed to sit quietly and remain awake for as long as possible during each of the 
40-minute MWT sessions. Each MWT test will be terminated after 40 minutes of wakefulness or 
after the onset of an EEG-detected sleep signal lasting up to 30-second epoch of any sleep stage.
9.2.12 AE Monitoring
AE monitoring begins after signing of the informed consent form. Changes in subject health status 
from the baseline assessment until study drug administration should be captured in the subject’s 
medical history. A complete description of AE collections and procedures is provided in 
Section 10.0.
9.2.13 Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken on the days stipulated in the Schedule of Study Procedures (Section 3.0).
9.2.13.1 Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (RBCs)
Leukocytes (WBCs) with absolute differential
Hematocrit
Platelets
Hemoglobin
Abbreviations: RBCs, red blood cells; WBCs, white blood cells.
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Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Chloride
Alkaline phosphatase
Creatinine
ALT
GGT
AST
Glucose
Bilirubin (total), if above ULN total bilirubin will be 
fractionated
Potassium
Blood urea nitrogen
Protein (total)
Calcium
Sodium
Carbon dioxide
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase; ULN, 
upper limit of normal.
If subjects experience ALT or AST >3× ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyl transferase, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was noted.
If ALT or AST remains elevated >3× ULN on these 2 consecutive occasions, the investigator must 
contact the medical monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study drug, and discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE.
Please refer to Section 7.5 for subject discontinuation criteria regarding abnormal LFTs and 
Section 10.2.8.4 for guidance on reporting abnormal LFTs.
Urinalysis
Urinalysis will consist of the following tests:
Blood
Nitrite
Glucose
Protein
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cells/high-power field, white blood cells/high-power field, and casts.
9.2.13.2 Diagnostic Screening
Serum
The serum diagnostic screening assessment will include the following tests:
HIV 
Hepatitis screen (HBsAg, HCV)
Abbreviations: HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
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Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Urine Drug Screen
The urine drug screening assessment will include the following tests:
Amphetamines
MDMA
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Abbreviation: MDMA, 3,4-methylenedioxy-methamphetamine.
9.3
PK, Biomarker, PD, and Pharmacogenomic Samples
9.3.1
PK, Biomarker, PD, and Pharmacogenomic Evaluations
Samples for PK, biomarker, PD, and pharmacogenomic (PGx) analysis will be collected as 
specified in the Schedule of Study Procedures (Section 3.0). Please refer to the Laboratory Manual 
for information on the collection, processing, and shipment of samples to the central laboratory.
The decision as to which plasma samples collected will be assayed for evaluation of PK will be 
determined by the sponsor. If indicated, these samples may also be assayed and/or pooled to 
measure metabolites in an exploratory manner.
It is anticipated that the total blood volume drawn in this study will be approximately 285 mL.
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Blood sample for PGx
Blood
DNA
Blood sample for PGx analysis
Optional
Plasma sample for PK
Blood
Plasma
Plasma sample for PK
Mandatory
Abbreviations: PGx, pharmacogenomic; PK, pharmacokinetics.
9.3.2
PK Measurements 
The PK parameters of TAK-925 and its metabolites M-I and M-II will be determined from plasma 
concentrations from all evaluable subjects using noncompartmental analysis methods. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations involving 
sampling times.
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The following PK parameters will be calculated from plasma concentrations of TAK-925 and its 
metabolites M-I and M-II, as data permit:

Cmax

AUClast

Ceoi

AUC∞

Tmax

CL (TAK-925 only)

t1/2z

Vss

Vz (TAK-925 only)
Additional PK parameters may be calculated as appropriate. A detailed PK analysis plan will be 
prepared before PK parameter computation.
The PK profile of modafinil has already been reported and will not be evaluated in this study.
9.3.2.1
Plasma for PK Measurements
Blood samples (one 3-mL sample per scheduled time) for PK analysis of TAK-925 will be 
collected into chilled blood collection tubes (vacutainer) containing the anticoagulant dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) according to the schedules in Section 3.0.
The actual time of sample collection will be recorded on the source document and eCRF. Sampling 
time points may be adjusted based on the preliminary emerging concentration data collected from 
prior subject(s), but the total number of samples collected per subject should not exceed the 
planned number.
Instructions for collecting, processing, and shipping of PK samples are provided in the Laboratory 
Manual.
9.3.2.2
PK Sample Analysis
Plasma concentrations of TAK-925 and its metabolites MI and MII will be measured by a 
validated high-performance liquid chromatography with tandem mass spectrometry assay. Part of 
the archival plasma samples may be used for potential analysis of unknown metabolite 
characterization, if appropriate. 
9.3.3
Biomarker Measurements
EEG will be used as the primary translational biomarker to assess the efficacy of TAK-925. There 
is the potential to add other biomarkers which are reported to be increased by sleep disturbances, 
including serum superoxide dismutase, plasma Aβ42, low-density lipoprotein receptor-related 
protein, and soluble receptors for advanced glycation end products [30,31]. However, as the study 
is being conducted in healthy normal subjects who are undergoing only 1 night of sleep 
deprivation in each period, the likelihood of finding significant changes, as well as changes related 
to study drug, is low. Therefore, fluid biomarkers will not be collected in this study. 
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9.3.4
PD Measurements
The PD assessments described below will be performed according to the Schedule of Study 
Procedures in Section 3.0. Additional details regarding these PD assessments are provided in the 
Study Manual.
9.3.4.1
PSG
Subjects will undergo an 8-hour (11:00 PM-7:00 AM) NPSG to exclude any sleep disorders. The 
PSG will be evaluated shortly after completion utilizing the American Academy of Sleep Criteria 
Scoring to ensure that subjects do not have an abnormal PSG before randomization into the study 
(scoring criteria specified in study manual). The Day -1 PSG will be performed once; subsequent 
treatment periods will not require the NPSG before dosing and testing.
When the final MWT test and cognitive testing has been completed, subjects will be allowed to 
sleep (recovery sleep) for at approximately 6 hours. PSG recording will be done during this time.
9.3.4.2
MWT
The MWT is a validated objective measure that evaluates a person’s ability to remain awake under 
soporific conditions for a defined period of time. As there is no biological measure of wakefulness, 
this is measured indirectly by the inability or delayed tendency to fall asleep. This tendency to fall 
asleep is measured via EEG-derived sleep latency in MWT.
9.3.4.3
KSS
The KSS is a 9-item Likert-type rating scale for assessing subjective sleepiness. 1 = very alert, 
3 = alert, 5 = neither alert nor sleepy, 7 = sleepy (but not fighting sleep), 9 = very sleepy (fighting 
sleep). This scale measures the subjective level of sleepiness at a particular time during the day. On 
this scale subjects indicate which level best reflects the psycho-physical sate experienced in the 
last 10 minutes.
9.3.4.4
CCBT
The CCBT is a computer-based cognitive assessment system consisting of a battery of several 
neuropsychological tests relevant to the effects of sleep deprivation. The cognition areas covered 
by the battery include reaction time, processing speed, attention and sustained vigilance, and 
episodic memory. The test battery will take approximately 20 minutes.
9.3.4.5
POMS
The POMS is a well-validated self-report measure of mood states. The original English version 
consists of 65 items, consisting of adjectives which are rates with regard to the participant’s 
current mood on a 6-point Likert scale ranging from 0 (not at all) to 5 (extremely). Answers 
provide standardized scores for 6 identified subscales: anger-hostility, confusion-bewilderment, 
depression-dejection, fatigue-inertia, tension-anxiety, and vigor-activity. Higher scores indicate 
more negative mood states, except for vigor-activity for which lower scores denote a more 
negative mood state.
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9.3.5
PGx Measurements 
9.3.5.1
Blood Sample for DNA PGx Measurements
Sampling of whole blood for PGx analysis is optional in this study and will only be performed for 
subjects who provide consent to participate in this assessment.
PGx is the study of variations of DNA characteristics as related to drug response. There is 
increasing evidence that an individual’s genetic background may impact the PK (absorption, 
distribution, metabolism, and excretion), PD (pharmacologic effects), and/or clinical effects 
(efficacy and/or safety) of a drug.
PGx research in this study may be conducted to understand how individual genetic variation in 
subjects impacts their response to study drug treatment. This information may also be used, for 
example, to develop a better understanding of the safety and efficacy of TAK-925 and other study 
drugs, to increase understanding of the disease/condition being studied and other related 
conditions, to gain a better understanding of the drug pharmacology, and to generate information 
needed for research, development, and regulatory approval of tests to predict response to 
TAK-925.
One 5-mL whole blood sample for DNA isolation will be collected at Day -1 from each consented 
subject in the study. If necessary and feasible, a second aliquot of blood may be taken at a later 
time point if isolation of DNA from the first sample was not successful or possible.
Since, PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.3.5.2
Biological Sample Retention and Destruction
In this study, blood samples for PGx analysis will be collected as described in Section 9.3.5.1. The 
genetic material will be initially stored at a vendor or comparable laboratory, under contract to 
Takeda, with validated procedures in place, and then preserved and retained at a long-term storage 
vendor, or a comparable laboratory, with validated procedures in place, for up to but not longer 
than 15 years from the end of the study when the 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 
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numbers; the samples are stripped of all personal identifying information but a key linking the 
samples to clinical analysis data exists. This link means that the subject may be identified but only 
indirectly. The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a PGx sample for DNA analysis can withdraw their consent 
at any time and request disposal of a stored sample. Any remaining sample that can be identified as 
coming from the subject will be destroyed. The investigator and sponsor may continue to use and 
distribute any information and test results gathered before the request to withdraw.
9.3.6
Confinement
Subjects will report to the clinical site on Day -1 in each treatment period and will leave after 
completion of all study-related procedures on Day 2.
At the discretion of the investigator, subjects may be requested to remain in the clinical site longer.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
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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). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before the signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, to capture this important safety information consistently in the database. 
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AEs associated with an overdose will be documented on AE case report forms (CRFs) 
according to Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
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10.2.7 Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and Abnormal LFTs) will commence at the time the subject 
signs the informed consent. Routine collection of AEs will continue until approximately 30 days 
after the last dose of investigational product. For subjects who discontinue before the 
administration of study medication, AEs will be followed until the subject discontinues study 
participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE before the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin before the first exposure to 
investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
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changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Appendix 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
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fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.13.1 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9). 
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, investigators and IRBs or IECs, as 
applicable, in accordance with national regulations in the countries where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, suspected unexpected serious adverse reactions will be submitted within 7 days for fatal 
and life-threatening events and 15 days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
products administration or in the overall conduct of the study. The investigational site also will 
forward a copy of all expedited reports to his or her IRB or IEC in accordance with national 
regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
A blinded data review will be conducted before database lock. This review will assess the accuracy 
and completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety set will consist of all subjects who were enrolled and received at least 1 dose of study 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
11.1.1.2 PK Set
The PK analysis set will consist of all subjects who received at least 1 dose of study drug and have 
at least 1 measurable plasma concentration.
11.1.1.3 PD Set
The PD analysis set will consist of all subjects who received at least 1 dose of study drug and have 
at least 1 evaluable PD endpoint.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized and listed by treatment 
sequence and overall. Descriptive statistics will be used to summarize data for continuous 
variables such as age and weight (number of subjects [N], mean, median, SD, minimum, and 
maximum) and for categorical variables such as sex, ethnicity, and race (number and percentage of 
subjects within each category). Medical history and medication history will be listed by subject.
11.1.3 PK Analysis
Plasma concentrations of TAK-925 and its metabolites M-I and M-II and PK parameter estimates 
will be listed for each subject and summarized using descriptive statistics by each time point for 
each dose.
Additionally, the relationships between TAK-925 plasma concentrations and selected measures of 
efficacy (eg, MWT, CCBT, and KSS) and safety (eg, BP) will be explored as deemed appropriate.
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11.1.4 PD Analysis 
11.1.4.1 Primary and Secondary Analyses
Sleep latency on the MWT will be summarized (N, mean, median, SD, minimum, and maximum) 
by treatment and time.
The effect of TAK-925 will be evaluated with a mixed effects model appropriate for a 4-period 
crossover study. The response variable in the model will be the observed value of sleep latency. 
The model will contain fixed effects for sequence, period, treatment (TAK-925 LD, TAK-925 HD, 
modafinil, and placebo), time (as a categorical variable), and the treatment-by-time interaction, 
and a random effect for subject.
The estimated mean sleep latency for each treatment and the associated standard error and 95% CI
will be extracted from the model at each time, along with all treatment differences and associated 
standard errors, 95% CIs, and p-values. The same quantities, averaged over all timepoints at which 
an MWT is performed, will also be extracted from the model using an appropriate contrast. The 
study objectives will be addressed using the results of the average treatment difference across all 
time points.
A similar analysis will be performed for the KSS.
11.1.4.2 Exploratory Analyses
11.1.5 Safety Analysis
Unless stated otherwise, baseline for safety parameters is defined as the last measurement 
collected before study drug administration, and summary statistics will be N, mean, median, SD, 
minimum, and maximum.
11.1.5.1 AEs
All AEs will be coded by system organ class and preferred term using MedDRA (Medical 
Dictionary for Regulatory Activities). TEAEs will be summarized by treatment.
11.1.5.2 Clinical Laboratory Evaluations
Clinical laboratory test data will be summarized for baseline, postdose, and changes from baseline 
by treatment and time. Only the scheduled measurements will be included in the summary.
11.1.5.3 Vital Signs
HR and BP data will be summarized for baseline (defined as Day -1 of each treatment period), 
postdose, and change from time-matched baseline by treatment and time. Only the scheduled 
measurements will be included in the summary.
CCI
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The change from time-matched baseline will be analyzed using a statistical model of the same 
form as for the primary endpoint. The estimated mean change from time-matched baseline for each 
treatment and the associated standard error and 95% CI will be extracted from the model at each 
time, along with all treatment differences and associated standard errors, 95% CIs, and p-values. 
The same quantities, averaged over all postdose timepoints, will also be extracted from the model
using an appropriate contrast.
All other vital signs will be summarized for baseline (pre-dose on Day 1 of each period), postdose, 
and change from baseline by treatment and time.
11.1.5.4 ECGs
ECG data will be summarized for baseline, postdose, and changes from baseline by treatment and 
time. Only the scheduled measurements will be included in the summary. No statistical tests will 
be performed.
11.1.5.5 C-SSRS
C-SSRS data will be listed.
11.1.5.6 Drug-liking VAS
Drug-liking VAS data will be listed.
11.1.5.7 POMS
POMS data will be summarized for baseline, postdose, and changes from baseline by treatment 
and time.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
The sample size justification is based on a similar study to assess the alertness-promoting effects of 
MK-0249, a histamine subtype-3 receptor inverse agonist, and modafinil 200 mg, in healthy 
sleep-deprived males [1]. In that study, investigators observed a mean increase in sleep latency in 
the MWT of 
 with modafinil 200 mg compared with placebo at 6 hours postdose and 
a within-subject standard deviation of approximately 
. With similar variability, 16
completers will provide approximately 
power for detecting a difference in sleep latency in the 
MWT between TAK-925 and placebo if the true increase over placebo is 
. This result is 
based on a 2-sided test with a 
.
To account for dropouts, approximately 20 subjects will be enrolled. 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.
CCI
CCI
CCI
CCI
CCI
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Sixteen completers will also provide adequate precision for the estimation of changes in BP. 
Assuming a standard deviation for the difference between periods in the change from baseline SBP 
of 
[20], a 95% CI for the true mean change in SBP between 1 dose level of TAK-925 
and placebo will extend no more than 
 from the observed difference. For example, if 
the observed difference between TAK-925 and placebo is 
, then the CI for the true 
difference will extend from 
, and this is considered to represent adequate
precision for the estimated treatment difference.
CCI
CCI
CCI
CCI
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator guarantees access for quality assurance auditors 
to all study documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International 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 state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a Federal 
Wide Assurance Number or comparable number assigned by the Department of Health and 
Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, and the date 
informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. If the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time before analysis. Notify sponsor of 
consent withdrawal.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, the Medicines and Healthcare products Regulatory Agency, the 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Study contact numbers can be found in the Study Manual, the communication plan, or other 
similar documents provided to the site.
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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
14.1.4 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC∞
area under the first moment plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration
BMI
body mass index
BP
blood pressure
Ca2+
calcium
CCBT
Cambridge Cognition Computerized Battery of Tests
Ceoi
plasma concentration observed at the end of infusion
CFR
Code of Federal Regulations
CL
total clearance after intravenous administration
Cmax
maximum observed plasma concentration
CNS
central nervous system 
CRF
case report form
CSF
cerebrospinal fluid
C-SSRS
Columbia–Suicide Severity Rating Scale
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic case report form
EDS
excessive daytime somnolence
EEG
electroencephalogram
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HD
high dose
HED
human equivalent dose
HIV
human immunodeficiency virus
HR
heart rate
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ICH
International Conference on Harmonisation
ICSD-3
International Classification of Sleep Disorders, 3rd edition
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IV
intravenous
KSS
Karolinska Sleepiness Scale
LD
low dose
LFT
liver function test
M-I, M-II
metabolites of TAK-925
MedDRA
Medical Dictionary for Regulatory Activities
MOA
mechanism of action
MWT
maintenance of wakefulness test
NPSG
nocturnal polysomnography
NT1
narcolepsy type 1
NT2
narcolepsy type 2
OX
orexin
OX1R
orexin receptor 1
OXR2
orexin receptor 2
PD
pharmacodynamic(s)
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PO
oral administration or orally
POMS
Profile of Mood States
PSG
polysomnography 
PTE
pretreatment event
QTcF
QT interval with Frederica correction method
REM
rapid eye movement
SAE
serious adverse event
SBP
systolic blood pressure
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
VAS
visual analog scale
Vss
volume of distribution at steady state after intravenous administration
Vz
volume of distribution during the terminal disposition phase after intravenous 
administration
WT
wild type
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs including the audit trails, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
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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.
Iannone R, Palcza J, Renger JJ, Calder N, Cerchio K, Gottesdiener K, et al. Acute 
alertness-promoting effects of a novel histamine subtype-3 receptor inverse agonist in 
healthy sleep-deprived male volunteers. Clin Pharmacol Ther 2010;88(6):831-9.
2.
Ohno Y, Matsumoto K, Hirose A, Nakamura M. Effects of perospirone hydrochloride, a 
novel antipsychotic agent, on EEG in rabbits and spinal reflex in cats. Clinical Report 
1997;31(2):879-92.
3.
Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. 
Annu Rev Pharmacol Toxicol 2011;51:243-66.
4.
Ruoff C, Rye D. The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical 
relevance and practicality. Curr Med Res Opin 2016:1-12.
5.
Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in 
cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA 
DQB1*0602 status. Sleep 2002;25(7):733-6.
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De la Herran-Arita AK, Garcia-Garcia F. Narcolepsy as an immune-mediated disease. Sleep 
Disord 2014;2014:792687.
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Schneider L, Mignot E. Diagnosis and Management of Narcolepsy. Semin Neurol 
2017;37(4):446-60.
8.
Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune 
basis of narcolepsy. J Autoimmun 2013;43:26-31.
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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.
10.
Lopez R, Barateau L, Evangelista E, Chenini S, Robert P, Jaussent I, et al. Temporal changes 
in the cerebrospinal fluid level of hypocretin-1 and histamine in narcolepsy. Sleep 2016.
11.
Tabuchi S, Tsunematsu T, Black SW, Tominaga M, Maruyama M, Takagi K, et al. 
Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of 
narcolepsy and orexin system function. J Neurosci 2014;34(19):6495-509.
12.
Kawai M, O'Hara R, Einen M, Lin L, Mignot E. Narcolepsy in African Americans. Sleep 
2015;38(11):1673-81.
13.
Black J, Swick T, Bogan R, Lai C, Carter LP. Impact of sodium oxybate, modafinil, and 
combination treatment on excessive daytime sleepiness in patients who have narcolepsy with 
or without cataplexy. Sleep Med 2016;24:57-62.
14.
Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with 
stimulants. ASDA standards of practice. Sleep 1994;17(4):352-71.
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15.
Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E. Circadian and 
homeostatic regulation of hypocretin in a primate model: implications for the consolidation 
of wakefulness. J Neurosci 2003;23(8):3555-60.
16.
Salomon RM, Kennedy JS, Johnson BW, Urbano Blackford J, Schmidt DE, Kwentus J, et al. 
Treatment enhances ultradian rhythms of CSF monoamine metabolites in patients with 
major depressive episodes. Neuropsychopharmacology 2005;30(11):2082-91.
17.
Huang SC, Dai YW, Lee YH, Chiou LC, Hwang LL. Orexins depolarize rostral ventrolateral 
medulla neurons and increase arterial pressure and heart rate in rats mainly via orexin 2 
receptors. J Pharmacol Exp Ther 2010;334(2):522-9.
18.
Gasior M, Freeman J, Zammit G, Donnelly P, Gao J, Ferreira-Cornwell MC, et al. 
Maintenance of wakefulness with lisdexamfetamine dimesylate, compared with placebo and 
armodafinil in healthy adult males undergoing acute sleep loss. J Clin Psychopharmacol 
2014;34(6):690-6.
19.
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.
20.
Dinges DF, Arora S, Darwish M, Niebler GE. Pharmacodynamic effects on alertness of 
single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. 
Curr Med Res Opin 2006;22(1):159-67.
21.
Broughton RJ, Fleming JA, George CF, Hill JD, Kryger MH, Moldofsky H, et al. 
Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment 
of excessive daytime sleepiness in narcolepsy. Neurology 1997;49(2):444-51.
22.
Kaida K, Takahashi M, Akerstedt T, Nakata A, Otsuka Y, Haratani T, et al. Validation of the 
Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol 
2006;117(7):1574-81.
23.
Reyner LA, Horne JA. Falling asleep whilst driving: are drivers aware of prior sleepiness? 
Int J Legal Med 1998;111(3):120-3.
24.
Veddeng A, Husby T, Engelsen IB, Kent A, Flaatten H. Impact of night shifts on 
laparoscopic skills and cognitive function among gynecologists. Acta Obstet Gynecol Scand 
2014;93(12):1255-61.
25.
Estrada A, Kelley AM, Webb CM, Athy JR, Crowley JS. Modafinil as a replacement for 
dextroamphetamine for sustaining alertness in military helicopter pilots. Aviat Space 
Environ Med 2012;83(6):556-64.
26.
Husby T, Torgersen J, Flaatten H. Cognitive effects of hospital calls in anaesthesiologists. 
Acta Anaesthesiol Scand 2014;58(2):177-84.
27.
James LM, Iannone R, Palcza J, Renger JJ, Calder N, Cerchio K, et al. Effect of a novel 
histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during 
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sleep deprivation and recovery sleep in male volunteers. Psychopharmacology (Berl) 
2011;215(4):643-53.
28.
Xu TR, Yang Y, Ward R, Gao L, Liu Y. Orexin receptors: multi-functional therapeutic 
targets for sleeping disorders, eating disorders, drug addiction, cancers and other 
physiological disorders. Cell Signal 2013;25(12):2413-23.
29.
Jara CO, Popp R, Zulley J, Hajak G, Geisler P. Determinants of depressive symptoms in 
narcoleptic patients with and without cataplexy. J Nerv Ment Dis 2011;199(5):329-34.
30.
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.
31.
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.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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Study ID TAK-925-1002
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 5 half-lives 
PLUS 90 days after the last dose of study drug. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
26. A statement that clinical trial information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives PLUS 
90 days after last dose of study drug, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with or 
without spermicidal cream or jelly). In addition, they must be advised not to donate sperm during 
this period. Females of childbearing potential who are partners of male subjects are also advised to 
use additional contraception as shown in the list containing highly effective/effective 
contraception below.
In studies with no risk of fetotoxicity/teratogenicity/genotoxicity: Male subjects are not required to 
use barrier contraception.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone 
(FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (eg, those <45 years old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.
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–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
the entire period of the study, from 1 month before the first dose until 5 half-lives 
PLUS 30 days after last dose.

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method (Evaluate on compound-by-compound and 
protocol-by-protocol basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral †.

Intravaginal † (eg, ring).

transdermal †.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation1 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has been 
on contraceptive for 3 months;

Oral †.

Injectable.

Implantable.
2. If genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the investigational 
drug, comparator, background therapy or standard of care medications effective methods of 
contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.
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
Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy and 
sperm donation during the study.
5. During the study, all subjects will receive continued guidance with respect to the avoidance of 
pregnancy and sperm donation as part of the study procedures. Such guidance should include a 
reminder of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
Pregnancy
Women of childbearing potential will not be included in this study.
Any pregnancies in the female partner of a male subject during the study or for 5 half-lives PLUS 
90 days after the last dose, should also be recorded following authorization from the subject’s 
partner. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Pregnancies in female partners of subjects randomized to placebo need not be followed. 
If the female partner of a male subject agrees to the primary care physician being informed, the 
investigator should notify the primary care physician that the female partner of the subject was 
participating in a clinical study at the time she became pregnant and provide details of the study 
drug the male subject received (blinded or unblinded, as applicable).
All pregnancies in female partners of male subjects who were on active study drug (including 
comparator, if applicable) will be followed up to final outcome, using the pregnancy form. 
Pregnancies will remain blinded to the study team. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.
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Appendix E
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 01 are indicated. The 
corresponding text has been revised throughout the protocol.
Change 1: Removed Sustained Attention to Response Task (SART) assessment throughout 
protocol and updated study schematic accordingly.
The primary change occurs in Section 3.0 SCHEDULE OF STUDY PROCEDURES
Description 
of change:
Removed SART under pharmacodynamic evaluations.
Rationale for Change: Change in rating vendor who required change in rating scales.
The following sections also contain this change:

Section 1.0 STUDY SUMMARY

Section 2.0 STUDY SCHEMATIC

Section 5.1.3 Exploratory Objectives

Section 5.2.4 Exploratory Endpoints

Section 6.1 Study Design

Section 6.2.3.2 Secondary Endpoints

Section 6.2.4 Critical Procedures Based on Study Objectives: Timing of Procedures

Section 6.3 Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters

Section 9.3.4 PD Measurements

Section 11.1.1.3 PD Set

Section 11.1.4.2 Exploratory Analyses

Section 14.1.4 List of Abbreviations

Section 16.0 REFERENCES
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Change 2: Replaced Cogstate Cognitive Computerized Battery of Tests with Cambridge 
Cognition Computerized Battery of Tests (CCBT).
The primary change occurs in Section 5.1.3 Exploratory Objectives
Initial 
wording:
Amended 
or new 
wording:
Rationale for Change: Change in rating vendor who required change in rating scales.
The following sections also contain this change:

Section 1.0 STUDY SUMMARY

Section 2.0 STUDY SCHEMATIC

Section 3.0 SCHEDULE OF STUDY PROCEDURES

Section 5.1.3 Exploratory Objectives

Section 6.2.3.2 Secondary Endpoints

Section 9.3.4.4 CCBT

Section 14.1.4 List of Abbreviations
CCI
CCI
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Study ID TAK-925-1002
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Change 3: Updated alcohol consumption restrictions.
The primary change occurs in Section 7.3.3 Alcohol
Rationale for Change: Align protocol text with exclusion criteria.
Initial 
wording:
Subjects will refrain from consuming alcohol 7 days before the screening visit and 
follow-up visit and from 7 days before and until the last PK blood sample has been 
collected in each treatment period. At all other times, alcohol consumption is limited 
to no more than approximately 3 alcoholic beverages or equivalent (1 alcoholic 
beverage is approximately equivalent to: beer [354 mL/12 oz], wine [118 mL/4 oz], or 
distilled spirits [29.5 mL/1 oz]) per day.
Amended 
or new 
wording:
Subjects will refrain from consuming alcohol 7 days before the screening visit and 
follow-up visit and from 7 days before and until the last PK blood sample has been 
collected in each treatment period. At all other times, aAlcohol consumption is not 
allowed during the entire study limited to no more than approximately 3 alcoholic 
beverages or equivalent (1 alcoholic beverage is approximately equivalent to: beer 
[354 mL/12 oz], wine [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz]) per day.
Change 4: Updated caffeine consumption restrictions.
The primary change occurs in Section 7.3.4 Caffeine
Rationale for Change: Align protocol text with exclusion criteria.
Initial 
wording:
Subjects will refrain from consuming caffeinated beverages 24 hours before the 
screening visit and follow-up visit and from 24 hours before and until the last PK 
blood sample has been collected in each treatment period. At all other times, 
caffeinated beverages or xanthine-containing products will be limited to amounts of 
no more than 6 units per day (1 unit=120 mg of caffeine).
Amended 
or new 
wording:
Subjects will refrain from consuming caffeinated beverages 24 hours before the 
screening visit and follow-up visit and from 24 hours before and until the last PK 
blood sample has been collected in each treatment period. At all other times, 
caffeinated beverages or xanthine-containing products will be limited to amounts of 
no more than 6 units per day (1 unit=120 mg of caffeine) 400 mg/day.
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Study ID TAK-925-1002
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Protocol Incorporating Amendment No. 01
08 May 2018
Change 5: Updated smoking restrictions.
The primary change occurs in Section 7.3.5 Smoking
Rationale for Change: Align protocol text with inclusion criteria.
Initial 
wording:
Tobacco or nicotine-containing products are restricted for 1 hour before the PSG and 
40 minutes before the MWT. No excessive consumption per day is allowed (>10 
cigarettes/day) during the study.
Amended 
or new 
wording:
Tobacco Smoking or use of nicotine-containing or tobacco products are restricted for 
1 hour before the PSG and 40 minutes before the MWT. No excessive consumption 
per day is allowed (>10 cigarettes/day) is not allowed during the entire study.
Change 6: Added dose levels selected for the low dose (LD) and high dose (HD).
The primary change occurs in Section. 6.2.2 Rationale for Dose.
Initial 
wording:
This study will evaluate 2 dose levels of TAK-925, LD and HD. The dose level of HD 
will be determined once study TAK-925-1001 has completed the dose escalations in 
the healthy normal cohorts. The maximum dose of the healthy cohorts in 
TAK-925-1001 was originally 134.4 mg and an amendment is being planned to 
increase the maximum dose to 420 mg. The HD may be equivalent to the highest dose 
level (plasma concentration expected to be approximately 883 ng/mL, which is the 
estimated observed plasma concentration at steady state when 420 mg is administered) 
where safety and tolerability of 9-hour IV infusion of TAK-925 is confirmed in the 
TAK-925-1001 study. The aim of the LD is to evaluate a dose that will result in effects 
on wakefulness (as assessed by the MWT) that are greater than those seen on placebo, 
but a dose that is pharmacologically different than the HD in concentration. The LD 
will also be considered above or equal to the dose level that is expected to achieve a 
target concentration associated with effects on wakefulness, which is equivalent to the 
human equivalent dose (HED) calculated based on WT monkey pharmacology studies 
as described below. 
 
 
 
 
 
 
 
 
 
This difference will be taken into consideration when choosing 
the LD in sleep-deprived healthy subjects.
CCI
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Study ID TAK-925-1002
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Protocol Incorporating Amendment No. 01
08 May 2018
Amended 
or new 
wording:
This Based on the currently available information, this study will evaluate 2 dose 
levels of TAK-925, LD and HD. The a low dose level of HD will be determined once 
study TAK-925-1001 has completed the dose escalations in the healthy normal 
cohorts. The maximum 44 mg (LD) and high dose of the healthy cohorts in 
 
112 mg. 
 
. The HD 
of 112 mg is administered) where was selected based on the safety and tolerability 
of results in adult subjects from the ongoing FIH TAK-925-1001 study. Doses up 
to and including 134.4 mg, the maximum dose tested so far in healthy volunteers, 
were safe and well tolerated with no severe AEs or SAEs. All subjects dosed with 
112 mg TAK-925 had acceptable safety and tolerability during the 9-hour IV 
infusion of TAK-925 is confirmed in the TAK-925-1001 study. The aim of the . The 
44 mg LD is was selected to evaluate a dose that will may result in effects on 
wakefulness (as assessed by the MWT) that are greater than those seen on of placebo, 
but a dose that is
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This difference will be Thus, the potential difference in the 
pharmacological response to TAK-925 has also been taken into consideration when 
choosing the LD and HD in sleep-deprived healthy subjects.
CCI
CCI
CCI
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Study ID TAK-925-1002
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Protocol Incorporating Amendment No. 01
08 May 2018
Rationale for Change: Doses selected based on currently available safety and tolerability results 
in healthy adult subjects in the ongoing TAK-925-1001 study.
The following sections also contain this change:

Section 1.0 STUDY SUMMARY

Section 5.1.2 Secondary Objectives
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680867dfe
Amendment 1 to A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, Single Dose Study to
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-925 in Sleep-Deprived
Healthy Adults Utilizing Modafinil as an Active Comparator
Clinical Pharmacology Approval
08-May-2018 20:54 UTC
Biostatistics Approval
09-May-2018 15:18 UTC
Clinical Science Approval
09-May-2018 19:40 UTC
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, Single Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-925 in 
Sleep-Deprived Healthy Adults Utilizing Modafinil as an Active Comparator
NCT Number: NCT03522506
SAP Approve Date: 29 November 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-925-1002
A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, Single Dose Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-925 
in Sleep-Deprived Healthy Adults Utilizing Modafinil as an Active Comparator
PHASE 1
Version: Final
Date: 29 November 2018
Prepared by:
Based on:
Protocol Version: Amendment 01
Protocol Date: 08 May 2018
PPD
Property of Takeda: For
:
Proto
Prot
P
nly and subject to the applicable Terms of Use
zed, Sin
ed, S
armacod
maco
l as an A
l as an 
Final
Final
Novemb
ovemb
ommercial use on
or non-com


PPD
y of Takeda: For non-commercial use only and subject to the a


TAK-925-1002
Page 3 of 28
Statistical Analysis Plan
29 November 2018
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
OBJECTIVES .................................................................................................................7
4.0
STUDY DESIGN............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.1.1
Study Definitions ...............................................................................................14
7.1.2
Definition of Study Days and Baseline...............................................................14
7.1.3
Definition of Study Visit Windows ....................................................................14
7.1.4
Conventions for Missing Adverse Event Dates...................................................15
7.1.4.1 Imputation of missing or partial dates of AE start dates................................15
7.1.4.2 Imputation of missing or partial dates of AE end dates .................................15
7.1.5
Conventions for Missing Concomitant Medication Dates...................................16
7.2
Analysis Sets ...........................................................................................................16
7.3
Disposition of Subjects ............................................................................................16
7.4
Demographic and Other Baseline Characteristics.....................................................17
7.5
Medical History and Concurrent Medical Conditions...............................................17
7.6
Medication History and Concomitant Medications...................................................17
7.7
Study Drug Exposure and Compliance.....................................................................17
7.8
Efficacy Analysis.....................................................................................................17
7.8.1
Primary Efficacy Endpoint(s).............................................................................18
7.8.2
Secondary Efficacy Endpoint(s).........................................................................18
7.8.3
Additional Efficacy Endpoint(s).........................................................................19
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................19
7.9.1
Pharmacokinetic Analysis ..................................................................................20
7.9.2
Other Pharmacodynamic Analysis......................................................................20
7.10
Safety Analysis........................................................................................................20
7.10.1 Adverse Events ..................................................................................................20
7.10.2 Clinical Laboratory Evaluations .........................................................................21
7.10.3 Vital Signs .........................................................................................................21
7.10.4 12-Lead ECGs ...................................................................................................22
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Statistical Analysis Plan
29 November 2018
7.10.5 Other Observations Related to Safety.................................................................22
7.11
Interim Analysis ......................................................................................................24
7.12
Changes in the Statistical Analysis Plan...................................................................24
8.0
REFERENCES..............................................................................................................25
LIST OF IN-TEXT TABLES
Table 4.a
Summary of Study Drug Assignment and Sequence (Double Dummy for 
Placebo)...............................................................................................................9
Table 4.b
Dosing and Sampling Scheme............................................................................10
Table 7.a
Subscales of the POMS......................................................................................23
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................26
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................27
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms.........................28
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Statistical Analysis Plan
29 November 2018
LIST OF ABBREVIATIONS
%CV
percent coefficient of variation
ADaM
Analysis Data Model
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC∞
area under the first moment plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration
BMI
body mass index
BP
blood pressure
CCBT
Cambridge Cognition Computerized Battery of Tests
Ceoi
plasma concentration observed at the end of infusion
CI
confidence interval
CL
total clearance after intravenous administration
Cmax
maximum observed plasma concentration
CPK
creatine phosphokinase
CRF
case report form
C-SSRS
Columbia–Suicide Severity Rating Scale
CV
coefficient of variation
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic case report form
EEG
electroencephalogram
GGT
-glutamyl transferase
HD
high dose
HR
heart rate
ICH
International Conference on Harmonisation
IV
intravenous
KSS
Karolinska Sleepiness Scale
LD
low dose
LFT
liver function test
LLN
lower limit of normal
LS
least square
M-I, M-II
metabolites of TAK-925
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MWT
maintenance of wakefulness test
NPSG
nocturnal polysomnography
NT1
narcolepsy type 1
NT2
narcolepsy type 2
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Statistical Analysis Plan
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OX
orexin
OX1R
orexin receptor 1
OXR2
orexin receptor 2
PD
pharmacodynamic(s)
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PO
oral administration or orally
POMS
Profile of Mood States
PSG
polysomnography 
PT
preferred term
PTE
pretreatment event
QTcF
QT interval with Frederica correction method
RBC
red blood cell 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SE
standard error
SOC
system organ class
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
VAS
visual analog scale
Vss
volume of distribution at steady state after intravenous administration
Vz
volume of distribution during the terminal disposition phase after intravenous 
administration
WBC
white blood cell
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Statistical Analysis Plan
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3.0
OBJECTIVES
Primary Objectives
1. To determine the effect of TAK-925 after a single IV dose (compared to placebo) on 
promoting wakefulness as measured by sleep latency on the MWT (performed at 
approximately 2, 4, 6, and 8 hours post-dosing starting at approximately 1:00 AM and then at 
approximate times of 3:00, 5:00, and 7:00 AM) in sleep-deprived healthy volunteers. 
Hypothesis: At least 1 of the tested doses of TAK-925 is superior to placebo for promoting 
wakefulness as measured by sleep latency on the MWT (a difference between TAK-925 and 
placebo of 9 minutes or greater is estimated).
Secondary Objectives
2. To assess the safety/tolerability and PK parameters of a single IV infusion of TAK-925 in 
sleep-deprived healthy volunteers.
Hypothesis: TAK-925 is generally well tolerated when administered as a single IV infusion, 
including effects on BP. (Overall mean difference in time-matched BP increase following 
administration of safe, tolerable, and effective dose of TAK-925 is less than or equal to 
10 mmHg over placebo.)
3. To determine the effect of a single dose of modafinil (300 mg) on promoting wakefulness as 
measured by sleep latency on the MWT in order to confirm assay sensitivity.
Hypothesis: Modafinil (300 mg) is superior to placebo on promoting wakefulness as 
measured by sleep latency on the MWT (a difference between modafinil and placebo of 
9 minutes is estimated [1].
4. To evaluate the effect of TAK-925, 44 mg (low dose [LD]) and 112 mg (high dose [HD]), on 
a measure of sleepiness, as compared to placebo.
Hypothesis: At least 1 dose of TAK-925 will be superior to placebo on the Karolinska 
Sleepiness Scale (KSS).
Additional Objectives
In sleep-deprived healthy volunteers: 
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Statistical Analysis Plan
29 November 2018
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4.0
STUDY DESIGN
This is a randomized, double-blind, double-dummy, placebo- and active-controlled, 4-period 
Williams design crossover study to evaluate the PK, PD, and safety of TAK-925 in 
sleep-deprived healthy volunteers. TAK-925 will be administered as an IV infusion over a 
9-hour period based on the safety/tolerability and PK profiles established in healthy Japanese 
subjects in ongoing Study TAK-925-1001.
Healthy adult male subjects aged 18 to 40 years, inclusive, who satisfy inclusion and exclusion 
criteria will be enrolled in the trial. Approximately 20 subjects will be enrolled to ensure that at 
least 16 subjects complete the study. 
On Day 1 of treatment period 1, eligible subjects will be equally randomized to 4 treatment 
sequence groups (Sequence 1 to 4) which define the order of the treatment administration 
(TAK-925 LD mg, TAK-925 HD mg [both delivered as a 9-hour IV infusion], modafinil 300 mg, 
and placebo).
A summary of the study drug assignment and sequence in presented in Table 4.a.
Table 4.a
Summary of Study Drug Assignment and Sequence (Double Dummy for 
Placebo)
Sequence
N
Period 1
Period 2
Period 3
Period 4
1
5
TAK-925 LD mg
Placebo
TAK-925 HD mg
Modafinil 300 mg
2
5
TAK-925 HD mg
TAK-925 LD mg
Modafinil 300 mg
Placebo
3
5
Modafinil 300 mg
TAK-925 HD mg
Placebo
TAK-925 LD mg
4
5
Placebo
Modafinil 300 mg
TAK-925 LD mg
TAK-925 HD mg
During the day before dosing on Day 1, participants will be administered the KSS and CCBT at 
scheduled timepoints. A practice MWT session, as well as one practice CCBT, will be performed 
on Day 1 Treatment Period 1 (only once during the entire study) to familiarize subjects with the 
procedures. Study drug will be administered in the clinic in the evening on Day 1 of each 
treatment period. Subjects will undergo the MWT, KSS, and CCBT at specified timepoints after 
the start of the infusion. Subjects will be required to stay awake in between the MWT tests. 
Following completion of the IV infusion on Day 2, subjects will undergo an additional MWT test. 
When the final MWT test and cognitive testing have been completed, subjects will be allowed to 
sleep (recovery sleep) for approximately 6 hours. PSG recording will be collected during this 
time. Subjects may be discharged from the unit after completion on Day 2 with continuing 
actigraphy upon discharge (to begin on Day -6 before the next treatment period). The interval of 
each subsequent treatment period will be at least 7 days to assure that the subject’s circadian 
rhythm has returned to a normal cycle. Subject’s vital signs, including BP, will be continuously 
monitored during the dosing and testing period. Blood samples for determination of TAK-925 
plasma concentrations will be collected at specified timepoints on Days 1 and 2 of each 
treatment period. Subjects will complete the C-SSRS during Screening, before study drug 
administration, and before discharge on Day 2 of each treatment period. Subjects will complete 
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Statistical Analysis Plan
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the POMS before and post study drug administration, and undergo a drug-liking VAS following 
recovery sleep in each treatment period.
An overview of the dosing and sampling scheme is provided in Table 4.b.
Table 4.b
Dosing and Sampling Scheme
Screening Period
Check-in and 
Baseline
Treatment Period
Time Interval 
Between 
Subsequent 
Treatment Period
Dose/Sample 
Collection
Sample Collection
Days -28 to -2
Day -1
NPSG/BP 
measurement a
Day 1
Sleep 
deprivation/study 
drug 
administration/study 
assessment
Day 2
Sleep 
deprivation/study 
drug continued 
infusion/study 
assessment/recovery 
sleep
Minimum of 7 days 
with actigraphy for 
5 days
X---------------------------Confinement----------------------------X
Abbreviations: BP, blood pressure; NPSG, nocturnal polysomnography.
a NPSG and time-matched BP only on Day -1 of treatment period 1. For Periods 2, 3, and 4, subjects will be 
admitted to the unit and allowed to sleep normally without NPSG or time-matched BP measurement. The time 
interval from the end of 1 period to the start of the next period will be at least 7 days.
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Statistical Analysis Plan
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5.0
ANALYSIS ENDPOINTS
Primary Endpoint
1. Latency for each MWT, defined as time to sleep onset.

Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in 
a 30-second epoch. Trials are ended after 40 minutes if no sleep occurs, or after 
unequivocal sleep, defined as 3 consecutive epochs of stage 1 sleep, or 1 epoch of any 
other stage of sleep. If no sleep has been observed according to these rules, then the 
latency is defined as 40 minutes.
Secondary Endpoints
Secondary endpoints will be assessed through the following parameters:
1. The following PK parameters calculated from plasma concentrations of TAK-925 and its 
metabolites M-I and M-II:

Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration (AUClast).

Area under the first moment plasma concentration-time curve from time 0 to infinity 
(AUC∞).

Maximum observed plasma concentration (Cmax).

Plasma concentration observed at the end of infusion (Ceoi).

Time of first occurrence of Cmax (tmax).

Terminal disposition phase half-life (t1/2z).

Total clearance after intravenous administration (CL) (TAK-925 only).

Volume of distribution during the terminal disposition phase after intravenous 
administration (Vz) (TAK-925 only).

Volume of distribution at steady state after intravenous administration (Vss).
2. Sleepiness on the KSS.
Safety Endpoints
Safety will be assessed through the following parameters:
1. TEAEs. Subjects will be monitored closely throughout the study for any AEs.
2. Physical examinations.
3. Vital signs, including time-matched BP measurement and PK-BP relationships.
4. 12-lead ECGs.
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Statistical Analysis Plan
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5. Clinical laboratory safety evaluations (hematology, blood chemistry, and urinalysis).
6. Drug-liking visual analog scale (VAS).
7. Profile of Mood States (POMS).
8. Continuous monitoring of BP and heart rate (HR), eg, Bodyconnect, at time points specified 
in the protocol, and sleep cycle from Day -5 to -1 by actigraphy with digital technology.
9. Columbia-Suicide Severity Rating Scale (C-SSRS).
Exploratory Endpoints
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Statistical Analysis Plan
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size justification is based on a similar study to assess the alertness-promoting effects 
of MK-0249, a histamine subtype-3 receptor inverse agonist, and modafinil 200 mg, in healthy 
sleep-deprived males [2]. In that study, investigators observed a mean increase in sleep latency in 
the MWT of 
 with modafinil 200 mg compared with placebo at 6 hours postdose 
and a within-subject standard deviation of approximately 
. With similar variability, 
16 completers will provide approximately 
 power for detecting a difference in sleep latency 
in the MWT between TAK-925 and placebo if the true increase over placebo is 
. This 
result is based on a 2-sided test with a 
 rate.
To account for dropouts, approximately 20 subjects will be enrolled. 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.
Sixteen completers will also provide adequate precision for the estimation of changes in BP. 
Assuming a standard deviation for the difference between periods in the change from baseline 
SBP of 
3], a 95% CI for the true mean change in SBP between 1 dose level of 
TAK-925 and placebo will extend no more than 
 from the observed difference. For 
example, if the observed difference between TAK-925 and placebo is 
, then the CI for 
the true difference will extend from 
, and this is considered to represent 
adequate precision for the estimated treatment difference.
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Statistical Analysis Plan
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
This Statistical Analysis Plan (SAP) was developed based on International Conference on 
Harmonization E3 [5] and E9 [6] Guidelines. This SAP should be read in conjunction with the 
study protocol and electronic case report forms (eCRFs). This version of the SAP was developed 
using the information provided in Protocol Amendment 01 TAK-925-1002, dated 26 April 2018
[4].
All study-related raw data, including derived data, will be presented in data listings. Continuous 
data will be summarized using: number of subjects (N), mean, standard deviation (SD), median, 
minimum, and maximum, where appropriate. Where indicated, %CV (arithmetic and/or 
geometric) and geometric mean will also be included in the summary of continuous data. 
Categorical data will be summarized using the number and percentage of subjects for each 
category where appropriate.
In the following, treatment (or study drug) refers to TAK-925 44 mg, TAK-925 112 mg, 
modafinil 300 mg, and placebo.
Statistical analysis will be performed using the SAS System®, Version 9.4 or higher, on a 
Windows platform.
7.1.1
Study Definitions
7.1.2
Definition of Study Days and Baseline
Study day prior to the first dose of study drug will be calculated as: date of assessment/event –
date of first dose of study drug; study day on or after the date of first dose of study drug will be 
calculated as: date of assessment/event – date of first dose of study drug + 1. 
Day prior to the first dose of study drug (up to Day -7) in a period will also be derived as: date of 
assessment/event – date of first dose of study drug in a period; Day on or after the date of first 
dose of study drug in a period (up to the last post dose procedure for that period) will be 
calculated as: date of assessment/event – date of first dose of study drug in that period + 1.
Unless otherwise noted, baseline for the study will be defined as the last non-missing 
measurement prior to first dose of study drug in the entire study. Baseline for a specific period 
will be defined as the last non-missing measurement prior to the first dose of study drug in the 
respective treatment period.
7.1.3
Definition of Study Visit Windows
Not applicable.
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Statistical Analysis Plan
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7.1.4
Conventions for Missing Adverse Event Dates
7.1.4.1
Imputation of missing or partial dates of AE start dates
The following methods will be used to impute missing or partial dates of AE start dates.

Month/year available and day missing:
–
If the month and year are the same as those in the first dose date and the event is not 
indicated as a pre-treatment event, the first dose date is to be used to impute the AE start 
date. 
–
If the month and year are the same as those in the first dose date and the event is 
indicated as a pre-treatment event, the date prior to the first dose date is to be used to 
impute the AE start date. If the date prior to the first dose date is in previous month/year, 
set the start month/year to the previous month/year. 
–
If the month and year are different from those in the first dose date, the first day of the 
month will be used for the start date.

Year available and month/day missing:
–
If the year is the same as the year of the first dose and the event is not indicated as a pre-
treatment event, the first dose date is to be used to impute the AE start date.
–
If the year is the same as the year of the first dose date and the event is indicated as a pre-
treatment event, the date prior to the first dose date is to be used to impute the AE start 
date. If the date prior to the first dose date is in previous month/year, set the start 
month/year to the previous month/year.
–
If the year is not the same as the year of the first dose date, set the start date as January 1.

Year/month/day all missing:
–
If the event is not indicated as a pre-treatment event, the first dose date is to be used to 
impute the AE start date.
–
If the event is indicated as a pre-treatment event, the date prior to the first dose date is to 
be used to impute the AE start date. 
7.1.4.2
Imputation of missing or partial dates of AE end dates
The following methods will be used to impute missing or partial dates of AE end dates.
If the event is indicated as ongoing at the end of the study, no imputation is needed.
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Statistical Analysis Plan
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If the event is not indicated as ongoing:
∀
Month/year available and day missing:
–
Use the last day of the month to impute the AE end date. If the imputed end date is before 
the AE start date, keep the end date same as the start date. If the subject died, use the date 
of death to impute the end date. 
∀
Year available and month/day missing:
–
If the year is the same as or before the year of the last dose, set the end date as December 
31.
–
If the year is after the year of the last dose, set the end date as January 1.
∀
Year/month/day all missing:
–
Impute the end date as December 31 of the last dose year. If the imputed end date is 
before the AE start date, keep the end date same as the start date. If the subject died, use 
the date of death to impute the end date. 
7.1.5
Conventions for Missing Concomitant Medication Dates
Missing concomitant medication dates will not be imputed.
7.2
Analysis Sets
Safety Analysis Set
The safety analysis set will consist of all subjects who are 
enrolled and received at least 1 dose of study drug. Subjects in 
this analysis set will be used for demographic, baseline 
characteristics, and safety summaries.
PK Analysis Set
The PK set will consist of all subjects who receive at least 1 dose 
of study drug and have at least 1 measurable plasma 
concentration.
7.3
Disposition of Subjects
The number and percentage of randomized subjects who complete the study and those who 
prematurely discontinue the study will be summarized for each treatment sequence and overall. 
In addition, the number and percentage of subjects will be summarized for reasons of study 
discontinuation for each sequence and overall. Subjects’ study completion data, including the 
dates of the first and last dose, and reasons for premature termination, will be listed. The number 
and percentage of subjects comprising each analysis set will be summarized for each sequence 
and overall. 
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Statistical Analysis Plan
29 November 2018
7.4
Demographic and Other Baseline Characteristics
For randomized subjects, descriptive statistics (N, mean, SD, median, minimum, and maximum) 
will be generated for continuous demographic variables and baseline characteristics variables 
(age, height, weight, BMI, etc.) by treatment sequence and overall. The number and percentage 
of subjects in each class of the categorical demographic variables and baseline characteristics 
variables (sex, ethnicity, race, etc.) will be tabulated by treatment sequence and overall.
All individual demographic and baseline characteristics will be listed by treatment sequence and 
subject number. The demographic data listing will include subject identifier, treatment sequence, 
date of informed consent, date of birth, age at date of informed consent, gender, ethnicity, race, 
height, baseline weight and baseline BMI, and other demographic and baseline information 
collected in the eCRF. 
7.5
Medical History and Concurrent Medical Conditions
Medical history includes any significant conditions that stopped at or prior to signing of 
informed consent. Concurrent medical conditions are those significant ongoing conditions that 
are present at signing of informed consent.
Medical history and concurrent medical condition verbatim reported terms will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). No summary statistics for medical 
history and concurrent medical conditions will be provided. All medical history and concurrent 
medical conditions will be listed.
7.6
Medication History and Concomitant Medications
Medication history information obtained includes any medication stopped at or within 28 days 
prior to signing of informed consent. Medications used from signing of informed consent 
through the end of study will be considered as concomitant medications.
Medication history and concomitant medications will be coded using World Health Organization 
Drug Dictionary (WHO Drug). No summary statistics for medication history and concomitant 
medications will be provided. All medication history and concomitant medications data will be 
listed.
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing. Listings and 
summary statistics for TAK-925 plasma concentrations and pharmacokinetic parameters will be 
provided. No other summary statistics for the extent of exposure to study drug or compliance 
calculations will be performed for this study.
7.8
Efficacy Analysis
All efficacy measures will be analyzed using the PD analysis set and will be presented in data 
listings.
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Statistical Analysis Plan
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7.8.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint, sleep latency on the MWT, will be summarized (N, mean, SD, 
median, minimum, and maximum) by treatment and scheduled time point.
The effect of TAK-925 will be evaluated with a linear mixed effects model appropriate for a 4-
period crossover study. The response variable in the model will be the observed post-infusion 
start value of sleep latency. The model will contain fixed effects for sequence, period, treatment, 
time (as a categorical variable), and the treatment-by-time interaction, and a random effect for 
subject. 
 
. 
The LS mean sleep latency for each treatment and the associated standard error and 95% CI will 
be estimated from the model at each time, along with differences between active treatments and 
placebo, and associated standard errors, 95% CIs, and p-values. The same quantities, averaged 
over the 4 timepoints during the infusion (2, 4, 6, and 8 hours post-infusion start), will be 
extracted from the model using an appropriate contrast. 
 
 
In addition, an ANOVA model will be used to evaluate the 1 hour post the end of infusion MWT.
The response variable in the model will be the observed 1 hour post the end of the infusion start 
value of sleep latency. The model will contain fixed effects for sequence, subject within 
sequence, period, treatment. The error term for the sequence effect will be subjects within 
Sequence. The LS mean sleep latency for each treatment and the associated standard error and 
95% CI will be estimated from the model, along with the differences between active treatments 
and placebo, and associated standard errors, 95% CIs, and p-values.
A mean profile plot of sleep latency over time will be produced. The scheduled time point (2, 4, 
6, 8 hours post the start of the infusion and 1 hour post the end of the infusion) will be the x-axis; 
the LS mean (± SE) sleep latency (estimated from above two models) will be on the y-axis. All 
treatments will be displayed on the same plot and differentiated by different symbols.
7.8.2
Secondary Efficacy Endpoint(s)
Similar analysis described for the MWT will be performed for sleepiness as assessed by the KSS.
A linear mixed effect models will be performed for all observed KSS parameters at scheduled 
time points. The response in the model will be the observed KSS value. The model will contain 
fixed effects for sequence, period, treatment, time (9 scheduled timepoints including the 1 hour 
post the end of infusion, as a categorical variable), and the treatment-by-time interaction, and a 
random effect for subject.
 
The LS mean sleepless scale for each treatment and the associated standard error and 95% CI
will be estimated from the model at each time point, along with the differences between active 
treatments and placebo, and associated standard errors, 95% CIs, and p-values. 
 
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Statistical Analysis Plan
29 November 2018
. The difference 
between the average of the 4 time points after and before the start of the infusion (delta: after –
before) will be calculated for each regimen, along with the associated standard errors and 95% 
CI. In addition, the differences between the active regimens and placebo in the “deltas” (double 
delta), associated standard error and 95% CI, will be derived.
A mean profile plot of KSS over time will be produced. The scheduled time point will be the x-
axis; the LS mean (± SE) sleep latency will be on the y-axis. All treatments will be displayed on 
the same plot and differentiated by different symbols.
7.8.3
Additional Efficacy Endpoint(s)
7.9
Pharmacokinetic/Pharmacodynamic Analysis
The relationship between TAK-925 exposure and efficacy will be explored graphically. A 
scatterplot of TAK-925 plasma concentration (x-axis) versus the observed post-infusion start 
measurement of sleep latency on the MWT (y-axis) will be produced. TAK-925 plasma 
concentrations for placebo data will be included in the plot with a concentration of 0. A 
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Statistical Analysis Plan
29 November 2018
horizontal reference line will be drawn at the mean post-infusion start sleep latency. Only 
measurements from time points common to both assessments (MWT and PK) will be used. Data 
from the low dose and high dose of TAK-925 will be displayed together in the plot with different 
symbols. 
Similar scatterplots will be produced for changes in HR, SBP, and DBP. TAK-925 plasma 
concentration will be plotted on the x-axis; the change from time-matched baseline in HR and 
BP (separately for SBP and DBP) will be plotted on the y-axis. 
In addition, mean profile plots of TAK-925 plasma concentration and the change from time-
matched baseline in HR, SBP, and DBP will be produced. The scheduled time point will be the 
x-axis, mean (± SD) TAK-925 plasma concentration will be on the left y-axis, and LS mean (± 
SE) change from time-matched baseline in HR (separately for SBP and DBP) will be on the right 
y-axis. Both dose levels of TAK-925 will be presented on the same plot with different symbols. 
7.9.1
Pharmacokinetic Analysis
Plasma concentrations of TAK-925 and its metabolites M-I and M-II and the PK parameter 
estimates described in Section 5.0 will be listed for each subject and summarized using 
descriptive statistics (N, mean, SD, %CV, median, minimum, and maximum) by each time point 
for each treatment. Geometric means, in addition, will be computed for Cmax, AUClast, and AUC∞.
Mean (± SD) concentration-time profiles will be produced for TAK-925 and the metabolites M-I 
and M-II.
7.9.2
Other Pharmacodynamic Analysis
7.10
Safety Analysis
7.10.1 Adverse Events
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA. 
The TEAE summary tables will include numbers and percentages of subjects experiencing at 
least one TEAE by SOC and PT and will be tabulated by treatment. The TEAEs will also be 
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Statistical Analysis Plan
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summarized for all subjects in the overview assessment. The following is a list of TEAE 
summary tables to be generated: 
–
Overview of TEAEs
–
TEAEs by SOC and PT
–
Subject Mappings for TEAEs
–
TEAEs by PT
–
Drug-Related TEAEs by SOC and PT
–
Relationship of TEAEs to Study Drug by SOC and PT (related vs not related)
–
Intensity of TEAEs by SOC and PT
–
Intensity of Drug-Related TEAEs by SOC and PT. 
Additional AE summary tables may be added as appropriate. 
Data listings will be provided for all AEs including pre-treatment events (PTE), TEAEs, and AEs 
leading to death, AEs leading to study drug or study visit discontinuation, SAEs, and signs and 
symptoms of AEs related to increased liver function tests.
7.10.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include clinical chemistry, hematology, and urinalysis. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) of clinical laboratory 
variables will be summarized for baseline, post-dose, and change from baseline to post-dose by 
treatment and time. Only the scheduled measurements will be included in the summary. No 
statistical tests will be performed. 
Individual results for clinical laboratory tests will be evaluated against the Takeda predefined 
laboratory markedly abnormal values (MAV) criteria (Appendix A) using the result and criteria 
in SI units. All subjects with at least 1 post-dose laboratory result that meets the MAV criteria 
will be presented in a data listing. 
The number and percentage of subjects with at least 1 post-dose markedly abnormal laboratory 
test result will also be summarized by treatment. Subjects who meet the MAV criteria will be 
mapped to their respective qualifying laboratory result. All post-dose clinical lab MAV results, 
including scheduled and unscheduled measurements, will be included in the MAV summaries. 
All clinical laboratory data will be presented in both SI and conventional units in data listings. 
7.10.3 Vital Signs
Vital sign measurements include blood pressure (SBP and DBP), HR, respiratory rate, and body 
temperature. 
Heart rate, SBP, and DBP will be summarized (N, mean, SD, median, minimum and maximum) 
for baseline (defined, here, as all time-matched measurements on Day -1 and Day 1 prior to 
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Statistical Analysis Plan
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dosing of each treatment period), post-dose, and change from time-matched baseline to post-dose 
by treatment and time. Only the scheduled measurements will be included in the summary. 
In addition, the change from time-matched baseline will be analyzed using a statistical model of 
the same form as for sleep latency on the MWT. The LS mean change from time-matched 
baseline for each treatment and the associated standard error and 95% CI will be extracted from 
the model at each time, along with differences to placebo and associated standard errors, 95% 
CIs, and p-values. The same quantities, averaged over all post-dose timepoints, will be extracted 
from the model using an appropriate contrast. Only the scheduled measurements will be included 
in the analysis.
All other vital signs will be summarized for baseline (last non-missing value prior to dose), post-
dose, and change from baseline by treatment and time. Only the scheduled measurements will be 
included in the summary. No statistical tests will be performed.
All individual vital signs that meet Takeda’s predefined criteria for MAVs (Appendix B) will be 
listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal vital 
sign measurement will be summarized by treatment. Subjects who meet the MAV criteria will be 
mapped to their respective qualifying vital sign result. All post-dose MAV vital signs, including 
both scheduled and unscheduled measurements, will be included in the MAV summaries.
All vital signs data will be presented in both SI and conventional units in data listings. 
7.10.4 12-Lead ECGs
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will manually interpret the ECG using 1 of the following categories: within 
normal limits, abnormal but not clinically significant, or abnormal and clinically significant. 
The following parameters will be calculated automatically by the ECG machine: heart rate, PR 
interval, QT interval, QRS interval, and QT interval with Fridericia correction method (QTcF). 
Descriptive statistics of the continuous ECG parameters will be summarized for baseline, post-
dose, and change from baseline at each post-dose time point by treatment and time. Only the 
ECGs collected at the scheduled visits or time points will be included in the summary. No 
statistical tests will be performed for the observed ECG parameters.
All individual ECGs that meet Takeda’s predefined criteria for MAVs (Appendix C) will be 
listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal ECG 
measurement will be summarized by treatment. Subjects who meet the MAV criteria will be 
mapped to their respective qualifying ECG result. All post-dose MAV ECG parameters, 
including both scheduled and unscheduled measurements, will be included in the MAV 
summaries. 
Individual subject ECGs will be presented in a data listing. 
7.10.5 Other Observations Related to Safety
The C-SSRS, physical examinations, and cases of overdoses will be listed. 
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Statistical Analysis Plan
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CCI
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Statistical Analysis Plan
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7.11
Interim Analysis
Not applicable. 
7.12
Changes in the Statistical Analysis Plan 
Not applicable.
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Statistical Analysis Plan
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8.0
REFERENCES
1. Gasior M, Freeman J, Zammit G, Donnelly P, Gao J, Ferreira-Cornwell MC, et al. 
Maintenance of wakefulness with lisdexamfetamine dimesylate, compared with placebo and 
armodafinil in healthy adult males undergoing acute sleep loss. J Clin Psychopharmacol 
2014;34(6):690-6.
2. Iannone R, Palcza J, Renger JJ, Calder N, Cerchio K, Gottesdiener K, et al. Acute alertness-
promoting effects of a novel histamine subtype-3 receptor inverse agonist in healthy sleep-
deprived male volunteers. Clin Pharmacol Ther 2010;88(6):831-9.
3. Dinges DF, Arora S, Darwish M, Niebler GE. Pharmacodynamic effects on alertness of 
single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. 
Curr Med Res Opin 2006;22(1):159-67.
4. Protocol Amendment 01: A Phase 1b, 4-Period Crossover, Placebo-Controlled, Randomized, 
Single Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-925 in Sleep-Deprived Healthy Adults Utilizing Modafinil as an 
Active Comparator, 26 April 2018.
5. Guideline on Structure and Content of Clinical Study Reports, International Conference on 
Harmonisation, Section ICH E3, 1996.
6. Guideline on Statistical Principles for Clinical Trials, International Conference on 
Harmonisation, Section ICH E9, 1998.
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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
CPK
Both
--
>5x ULN
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CPK=creatine phosphokinase, GGT=-glutamyl 
transferase, LLN=lower limit of normal, ULN=upper limit of normal.
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Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
< 35.6
>37.7
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Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms
Parameter
Lower Criteria 
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and ≥450 
milliseconds
QRS
≤80 milliseconds
≥180 milliseconds
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