A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of TAK-925 Study in Sleep-Deprived Healthy Adults

Sponsor

Takeda (Industry)

Overall Status

Completed

CT.gov ID

NCT03522506

Collaborator

(none)

Enrollment

Location

Arms

Actual Duration (Months)

3.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: TAK-925 Drug: TAK-925 Placebo Drug: Modafinil Drug: Modafinil Placebo	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Other

Official 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

Actual Study Start Date :

May 9, 2018

Actual Primary Completion Date :

Nov 7, 2018

Actual Study Completion Date :

Nov 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-925 Low Dose + Placebo + TAK-925 High Dose + Modafinil 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.	Drug: TAK-925 TAK-925 intravenous infusion. Drug: TAK-925 Placebo TAK-925 placebo-matching given as saline intravenous infusion. Drug: Modafinil Modafinil tablets. Drug: Modafinil Placebo Modafinil placebo-matching tablet.
Experimental: TAK-925 High Dose + TAK-925 Low Dose + Modafinil + Placebo 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.	Drug: TAK-925 TAK-925 intravenous infusion. Drug: TAK-925 Placebo TAK-925 placebo-matching given as saline intravenous infusion. Drug: Modafinil Modafinil tablets. Drug: Modafinil Placebo Modafinil placebo-matching tablet.
Experimental: Modafinil + TAK-925 High Dose + Placebo + TAK-925 Low Dose 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.	Drug: TAK-925 TAK-925 intravenous infusion. Drug: TAK-925 Placebo TAK-925 placebo-matching given as saline intravenous infusion. Drug: Modafinil Modafinil tablets. Drug: Modafinil Placebo Modafinil placebo-matching tablet.
Experimental: Placebo + Modafinil + TAK-925 Low Dose + TAK-925 High Dose 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.	Drug: TAK-925 TAK-925 intravenous infusion. Drug: TAK-925 Placebo TAK-925 placebo-matching given as saline intravenous infusion. Drug: Modafinil Modafinil tablets. Drug: Modafinil Placebo Modafinil placebo-matching tablet.

Outcome Measures

Primary Outcome Measures

Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 2 Hours Post-infusion Start [Day 1: 2 hours post-infusion start]
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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Latency to Sleep Onset on MWT at 4 Hours Post-infusion Start [Day 1: 4 hours post-infusion start]
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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Latency to Sleep Onset on MWT at 6 Hours Post-infusion Start [Day 1: 6 hours post-infusion start]
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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Latency to Sleep Onset on MWT at 8 Hours Post-infusion Start [Day 1: 8 hours post-infusion start]
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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Latency to Sleep Onset on MWT at 1 Hour Post-end of Infusion [Day 1: 1 hour post-end of infusion]
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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.

Secondary Outcome Measures

AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-925 and Its Metabolites M-I and M-II [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
CL: Total Clearance After Intravenous Administration for TAK-925 [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
Vz: Volume of Distribution During the Terminal Disposition Phase After Intravenous Administration for TAK-925 [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925 [Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose]
Sleepiness on KSS [Day 1: 14, 10, 6, 2 hours pre-infusion; 2.75, 4.75, 6.75. 8.75 hours post-infusion start; 1.75 hours post-infusion end]
The KSS scale measures the subjective level of sleepiness at a particular time during the day. On this scale participants indicate which level best reflects the psycho-physical state experienced in the last 10 minutes. The KSS is a 9-item Likert-type rating scale for assessing subjective sleepiness, where 1=very alert, 3=alert, 5=neither alert nor sleepy, 7=sleepy (but not fighting sleep), 9=very sleepy (fighting sleep). Lower score indicates more alertness.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Be a nonsmoker who has not used tobacco- or nicotine-containing products (example, nicotine patch) for at least 6 months before study drug administration of the initial dose of study drug.
Have regular sleep-wake habits (example, routinely spending 6.5 to 8 hours sleeping nightly, not oversleeping by more than 3 hours on weekends, that is, 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.
Be willing to have actigraphy monitoring during the week before randomization and in each interval.

Exclusion Criteria:

Has a positive alcohol or drug screen.
Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to: beer [354 milliliter per (mL/)12 ounces], wine (118 mL/4 ounces), or distilled spirits (29.5 mL/1 ounce)] per day).
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.
Currently experiencing or having a history of any known/suspected sleep disorder, any disorder associated with excessive daytime somnolence (EDS), or any diagnosis interfering with assessment of sleepiness.
Abnormal findings on the initial polysomnography (PSG) conducted on Day -1 (check-in), as specified in the study manual.
Traveled across 2 or more time zones 2 weeks or less before screening.
Caffeine consumption of more than 400 milligram per day (mg/day) for 2 weeks before screening (1 serving of coffee is approximately equivalent to 120 mg of caffeine).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PRA Health Sciences	Salt Lake City	Utah	United States	84124

Sponsors and Collaborators

Takeda

Investigators

Study Director: Medical Director, Takeda

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Takeda

ClinicalTrials.gov Identifier:

NCT03522506

Other Study ID Numbers:

TAK-925-1002
U1111-1211-2133

First Posted:

May 11, 2018

Last Update Posted:

Mar 26, 2021

Last Verified:

Mar 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Takeda

Drug Therapy

Additional relevant MeSH terms:

Modafinil

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in the United States from 09 May 2018 to 07 November 2018.
Pre-assignment Detail	Healthy sleep deprived participants were enrolled in 1 of the 4 treatment sequences of this 4-period crossover study to receive: TAK 925 44 milligram (mg) (Low dose), TAK-925 112 mg (High dose), modafinil 300 mg, and placebo.

Arm/Group Title	TAK-925 44 mg + Placebo + TAK-925 112 mg + Modafinil 300 mg	TAK-925 112 mg + TAK-925 44 mg + Modafinil 300 mg + Placebo	Modafinil 300 mg + TAK-925 112 mg + Placebo + TAK-925 44 mg	Placebo + Modafinil 300 mg + TAK-925 44 mg + TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 4.	TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Treatment Period 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 4.	Placebo, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 4.
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	5
COMPLETED	5	5	5	5
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	5
COMPLETED	5	5	5	4
NOT COMPLETED	0	0	0	1
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	4
COMPLETED	5	5	5	4
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	4
COMPLETED	5	5	5	3
NOT COMPLETED	0	0	0	1
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	3
COMPLETED	5	5	5	3
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	3
COMPLETED	5	5	5	3
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1 (2 Days)
STARTED	5	5	5	3
COMPLETED	5	5	5	3
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	TAK-925 44 mg + Placebo + TAK-925 112 mg + Modafinil 300 mg	TAK-925 112 mg + TAK-925 44 mg + Modafinil 300 mg + Placebo	Modafinil 300 mg + TAK-925 112 mg + Placebo + TAK-925 44 mg	Placebo + Modafinil 300 mg + TAK-925 44 mg + TAK-925 112 mg	Total
Arm/Group Description	TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 4.	TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Treatment Period 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by placebo once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 4.	Placebo, once on Day 1 of Treatment Period 1, followed by a minimum of 7-days washout period, further followed by modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 2, followed by a minimum of 7-days washout period, further followed by TAK-925 44 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 3, followed by a minimum of 7-days washout period, further followed by TAK-925 112 mg, injection, intravenously, administered as 9-hour infusion, once on Day 1 of Treatment Period 4.	Total of all reporting groups
Overall Participants	5	5	5	5	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.8 (4.55)	26.4 (3.78)	27.4 (3.44)	26.0 (1.22)	26.9 (3.28)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%
Male	5 100%	5 100%	5 100%	5 100%	20 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%	0 0%	3 60%	3 60%	7 35%
Not Hispanic or Latino	4 80%	5 100%	2 40%	2 40%	13 65%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 20%	0 0%	1 5%
White	5 100%	5 100%	4 80%	5 100%	19 95%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	5 100%	5 100%	5 100%	5 100%	20 100%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	82.6 (11.10)	78.8 (6.52)	84.2 (10.73)	83.0 (11.59)	82.2 (9.58)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	182.1 (5.32)	176.1 (5.83)	175.6 (8.60)	175.2 (4.70)	177.3 (6.46)
Body mass index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	24.9 (2.95)	25.4 (1.31)	27.2 (1.67)	27.0 (2.89)	26.1 (2.36)

Outcome Measures

1. Primary Outcome

Title	Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 2 Hours Post-infusion Start
Description	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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Time Frame	Day 1: 2 hours post-infusion start

Outcome Measure Data

Analysis Population Description
Pharmacodynamics (PD) analysis set: all participants who received at least 1 dose of study drug and have at least 1 evaluable postdose PD endpoint derived from MWT, polysomnography (PSG), Karolinska Sleepiness Scale (KSS), or Cambridge Cognition Computerized Battery of Tests (CCBT). PD analysis set where data at specified time points was available.

Arm/Group Title	Placebo	TAK-925 44 mg	TAK-925 112 mg	Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	20	18	18	19
Least Squares Mean (Standard Error) [minute]	15.68 (2.305)	35.74 (2.445)	40.02 (2.445)	35.57 (2.368)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The least squares mean (LSM) sleep latency for each treatment and the associated standard error and 95% confidence interval (CI) was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	20.06
	Confidence Interval	(2-Sided) 95% 13.35 to 26.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	24.35
	Confidence Interval	(2-Sided) 95% 17.64 to 31.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effects model
	Comments

Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	19.89
	Confidence Interval	(2-Sided) 95% 13.30 to 26.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-925 and Its Metabolites M-I and M-II
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
TAK-925	940.4 (127.26)	2303.7 (174.23)
M-I	572.0 (196.75)	1368.3 (489.96)
M-II	12.3 (7.91)	30.7 (19.39)

3. Secondary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration. The PK analysis set where data at specified time points was available.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
TAK-925	963.7 (134.70)	2368.7 (185.04)
M-I	586.8 (204.08)	1405.6 (510.25)
M-II	15.2 (7.38)	32.0 (20.26)

4. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
TAK-925	105.8 (11.74)	266.0 (40.10)
M-I	61.9 (21.41)	144.7 (55.64)
M-II	1.3 (0.88)	3.2 (2.32)

5. Secondary Outcome

Title	Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
TAK-925	103.4 (14.21)	253.4 (34.35)
M-I	64.0 (21.25)	151.1 (55.94)
M-II	1.5 (0.88)	3.7 (2.34)

6. Secondary Outcome

Title	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
TAK-925	9.000	9.000
M-I	9.030	9.000
M-II	9.170	9.000

7. Secondary Outcome

Title	T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration. The PK analysis set where data at specified time points was available.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
TAK-925	3.134 (0.7064)	3.252 (0.8597)
M-I	2.424 (0.2989)	2.490 (0.3638)
M-II	2.235 (0.6945)	2.516 (0.9660)

8. Secondary Outcome

Title	CL: Total Clearance After Intravenous Administration for TAK-925
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
Mean (Standard Deviation) [liter per hour (L/h)]	46.4 (5.98)	47.6 (3.56)

9. Secondary Outcome

Title	Vz: Volume of Distribution During the Terminal Disposition Phase After Intravenous Administration for TAK-925
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
Mean (Standard Deviation) [liter]	207.4 (41.51)	223.1 (61.20)

10. Secondary Outcome

Title	Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925
Description
Time Frame	Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose

Outcome Measure Data

Analysis Population Description
The PK analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 measurable plasma concentration.

Arm/Group Title	TAK-925 44 mg	TAK-925 112 mg
Arm/Group Description	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	18	18
Mean (Standard Deviation) [liter]	106.7 (18.90)	112.5 (25.33)

11. Secondary Outcome

Title	Sleepiness on KSS
Description	The KSS scale measures the subjective level of sleepiness at a particular time during the day. On this scale participants indicate which level best reflects the psycho-physical state experienced in the last 10 minutes. The KSS is a 9-item Likert-type rating scale for assessing subjective sleepiness, where 1=very alert, 3=alert, 5=neither alert nor sleepy, 7=sleepy (but not fighting sleep), 9=very sleepy (fighting sleep). Lower score indicates more alertness.
Time Frame	Day 1: 14, 10, 6, 2 hours pre-infusion; 2.75, 4.75, 6.75. 8.75 hours post-infusion start; 1.75 hours post-infusion end

Outcome Measure Data

Analysis Population Description
The PD analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 evaluable postdose PD endpoint derived from the MWT, PSG, KSS, or CCBT. The PD analysis set where data at specified time points was available.

Arm/Group Title	Placebo	TAK-925 44 mg	TAK-925 112 mg	Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Intervention Periods 1 to 4.	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Intervention Periods 1 to 4.
Measure Participants	20	18	18	19
14 hours pre-infusion	3.05 (0.320)	2.85 (0.339)	3.29 (0.339)	2.79 (0.328)
10 hours pre-infusion	2.50 (0.283)	2.79 (0.300)	2.51 (0.300)	2.32 (0.291)
6 hours pre-infusion	2.80 (0.294)	2.79 (0.312)	2.51 (0.312)	2.58 (0.302)
2 hours pre-infusion	3.90 (0.403)	4.01 (0.426)	3.46 (0.426)	3.32 (0.414)
2.75 hours post -infusion start	6.85 (0.405)	4.85 (0.429)	3.24 (0.429)	3.69 (0.416)
4.75 hours post-infusion start	8.15 (0.376)	6.46 (0.397)	3.85 (0.397)	4.32 (0.386)
6.75 hours post-infusion start	8.50 (0.317)	7.79 (0.336)	5.18 (0.336)	5.79 (0.326)
8.75 hours post-infusion start	8.33 (0.325)	8.07 (0.340)	6.07 (0.340)	6.69 (0.330)
1.75 hours post-infusion end	8.15 (0.294)	8.46 (0.312)	8.01 (0.312)	7.16 (0.302)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	14 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.664
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95% -1.13 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	14 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.605
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95% -0.69 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	14 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.574
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95% -1.17 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	10 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.483
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95% -0.53 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	10 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.972
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95% -0.81 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	10 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.654
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95% -0.99 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	6 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.984
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95% -0.86 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	6 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.508
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95% -1.14 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	6 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.605
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95% -1.06 to 0.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	2 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.847
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95% -1.06 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	2 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.455
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95% -1.61 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	2 hours pre-infusion: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.317
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95% -1.74 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	2.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-2.00
	Confidence Interval	(2-Sided) 95% -3.18 to -0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	2.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-3.61
	Confidence Interval	(2-Sided) 95% -4.79 to -2.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	2.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-3.16
	Confidence Interval	(2-Sided) 95% -4.32 to -2.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	4.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-1.69
	Confidence Interval	(2-Sided) 95% -2.78 to -0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	4.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-4.30
	Confidence Interval	(2-Sided) 95% -5.39 to -3.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	4.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-3.83
	Confidence Interval	(2-Sided) 95% -4.91 to -2.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	6.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.130
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95% -1.63 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	6.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-3.32
	Confidence Interval	(2-Sided) 95% -4.24 to -2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	6.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-2.71
	Confidence Interval	(2-Sided) 95% -3.62 to -1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	8.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.577
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95% -1.20 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	8.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-2.26
	Confidence Interval	(2-Sided) 95% -3.20 to -1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	8.75 hours post-infusion start: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95% -2.57 to -0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	1.75 hours post-infusion end: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.475
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95% -0.55 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	1.75 hours post-infusion end: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.753
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95% -0.99 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	1.75 hours post-infusion end: A linear mixed effect models was performed for all observed KSS parameters at scheduled time points. The LSM sleepless scale for each treatment and the associated standard error and 95% CI was 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.

Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.99
	Confidence Interval	(2-Sided) 95% -1.83 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Latency to Sleep Onset on MWT at 4 Hours Post-infusion Start
Description	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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Time Frame	Day 1: 4 hours post-infusion start

Outcome Measure Data

Analysis Population Description
The PD analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 evaluable postdose PD endpoint derived from the MWT, PSG, KSS, or CCBT. The PD analysis set where data at specified time points was available.

Arm/Group Title	Placebo	TAK-925 44 mg	TAK-925 112 mg	Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	20	18	18	19
Least Squares Mean (Standard Error) [minute]	9.10 (2.186)	32.04 (2.320)	40.05 (2.320)	35.60 (2.246)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	22.94
	Confidence Interval	(2-Sided) 95% 16.58 to 29.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effects model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	30.95
	Confidence Interval	(2-Sided) 95% 24.59 to 37.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	26.50
	Confidence Interval	(2-Sided) 95% 20.24 to 32.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Primary Outcome

Title	Latency to Sleep Onset on MWT at 6 Hours Post-infusion Start
Description	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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Time Frame	Day 1: 6 hours post-infusion start

Outcome Measure Data

Analysis Population Description
The PD analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 evaluable postdose PD endpoint derived from the MWT, PSG, KSS, or CCBT. The PD analysis set where data at specified time points was available.

Arm/Group Title	Placebo	TAK-925 44 mg	TAK-925 112 mg	Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	20	18	18	19
Least Squares Mean (Standard Error) [minute]	6.15 (2.589)	20.71 (2.742)	38.36 (2.742)	31.89 (2.659)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	14.56
	Confidence Interval	(2-Sided) 95% 7.04 to 22.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	32.21
	Confidence Interval	(2-Sided) 95% 24.68 to 39.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	25.74
	Confidence Interval	(2-Sided) 95% 18.33 to 33.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Primary Outcome

Title	Latency to Sleep Onset on MWT at 8 Hours Post-infusion Start
Description	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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Time Frame	Day 1: 8 hours post-infusion start

Outcome Measure Data

Analysis Population Description
The PD analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 evaluable postdose PD endpoint derived from the MWT, PSG, KSS, or CCBT. The PD analysis set where data at specified time points was available.

Arm/Group Title	Placebo	TAK-925 44 mg	TAK-925 112 mg	Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	20	18	18	19
Least Squares Mean (Standard Error) [minute]	3.53 (2.146)	13.13 (2.279)	36.86 (2.279)	20.44 (2.206)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	9.60
	Confidence Interval	(2-Sided) 95% 3.35 to 15.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	33.33
	Confidence Interval	(2-Sided) 95% 27.08 to 39.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The effect of TAK-925 was evaluated with a linear mixed effects model appropriate for a 4-period crossover study. The LSM sleep latency for each treatment and the associated standard error and 95% CI was estimated from the model at each time, along with differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effect model
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	16.91
	Confidence Interval	(2-Sided) 95% 10.77 to 23.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Primary Outcome

Title	Latency to Sleep Onset on MWT at 1 Hour Post-end of Infusion
Description	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. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were 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. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake.
Time Frame	Day 1: 1 hour post-end of infusion

Outcome Measure Data

Analysis Population Description
The PD analysis set consisted of all participants who received at least 1 dose of study drug and have at least 1 evaluable postdose PD endpoint derived from the MWT, PSG, KSS, or CCBT. The PD analysis set where data at specified time points was available.

Arm/Group Title	Placebo	TAK-925 44 mg	TAK-925 112 mg	Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.	Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, 2, 3, or 4.
Measure Participants	20	18	18	19
Least Squares Mean (Standard Error) [minute]	4.65 (2.109)	2.49 (2.241)	2.36 (2.241)	21.42 (2.168)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 44 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	An analysis of variance (ANOVA) model was used to evaluate the 1 hour post the end of infusion MWT. The LSM sleep latency for each treatment and the associated standard error and 95% CI were estimated from the model, along with the differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	0.436
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-2.16
	Confidence Interval	(2-Sided) 95% -7.68 to 3.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-925 112 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	ANOVA model was used to evaluate the 1 hour post the end of infusion MWT. The LSM sleep latency for each treatment and the associated standard error and 95% CI were estimated from the model, along with the differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	0.409
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-2.29
	Confidence Interval	(2-Sided) 95% -7.81 to 3.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Modafinil 300 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	ANOVA model was used to evaluate the 1 hour post the end of infusion MWT. The LSM sleep latency for each treatment and the associated standard error and 95% CI were estimated from the model, along with the differences between active treatments and placebo, and associated standard errors, 95% CIs, and p-values.

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	16.77
	Confidence Interval	(2-Sided) 95% 11.37 to 22.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	Placebo		TAK-925 44 mg		TAK-925 112 mg		Modafinil 300 mg
Time Frame	Treatment-emergent adverse events are adverse events (AE) that started after the first dose of study drug and no more than 7 days after the last dose of study drug in Treatment Period 4 (Day 1 up to Day 36)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Arm/Group Title	Placebo		TAK-925 44 mg		TAK-925 112 mg		Modafinil 300 mg
Arm/Group Description	Placebo, once on Day 1 of Treatment Period 1, 2, 3, or 4.		TAK-925 44 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.		TAK-925 112 mg, intravenously, injection, administered as 9-hour infusion, once on Day 1 of Treatment Period 1, 2, 3, or 4.		Modafinil 300 mg, tablet, orally, once on Day 1 of Treatment Period 1, 2, 3, or 4.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Serious Adverse Events
	Placebo		TAK-925 44 mg		TAK-925 112 mg		Modafinil 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TAK-925 44 mg		TAK-925 112 mg		Modafinil 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/20 (20%)		5/18 (27.8%)		11/18 (61.1%)		11/19 (57.9%)
Eye disorders
Conjunctivitis allergic	1/20 (5%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Gastrointestinal disorders
Nausea	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		3/19 (15.8%)
Diarrhoea	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		1/19 (5.3%)
Flatulence	0/20 (0%)		0/18 (0%)		0/18 (0%)		2/19 (10.5%)
Abdominal pain	0/20 (0%)		0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Vomiting	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
General disorders
Chest discomfort	0/20 (0%)		1/18 (5.6%)		0/18 (0%)		1/19 (5.3%)
Discomfort	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Feeling jittery	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Feeling of relaxation	0/20 (0%)		0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Injury, poisoning and procedural complications
Infusion related reaction	0/20 (0%)		2/18 (11.1%)		1/18 (5.6%)		0/19 (0%)
Ligament sprain	0/20 (0%)		0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Investigations
Liver function test increased	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/20 (0%)		1/18 (5.6%)		1/18 (5.6%)		0/19 (0%)
Muscle twitching	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Myalgia	0/20 (0%)		1/18 (5.6%)		0/18 (0%)		0/19 (0%)
Tendonitis	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Nervous system disorders
Headache	0/20 (0%)		1/18 (5.6%)		1/18 (5.6%)		2/19 (10.5%)
Dizziness	0/20 (0%)		0/18 (0%)		2/18 (11.1%)		0/19 (0%)
Disturbance in attention	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Muscle contractions involuntary	0/20 (0%)		0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Paraesthesia	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Presyncope	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Tremor	1/20 (5%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Psychiatric disorders
Hypervigilance	0/20 (0%)		0/18 (0%)		2/18 (11.1%)		0/19 (0%)
Insomnia	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		1/19 (5.3%)
Anxiety	1/20 (5%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Euphoric mood	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Renal and urinary disorders
Pollakiuria	0/20 (0%)		0/18 (0%)		3/18 (16.7%)		0/19 (0%)
Dysuria	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Urine odour abnormal	0/20 (0%)		0/18 (0%)		0/18 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/20 (0%)		1/18 (5.6%)		2/18 (11.1%)		0/19 (0%)
Nasal congestion	1/20 (5%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Dyspnoea	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Nasal dryness	0/20 (0%)		0/18 (0%)		1/18 (5.6%)		0/19 (0%)
Oropharyngeal pain	1/20 (5%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Pleuritic pain	1/20 (5%)		0/18 (0%)		0/18 (0%)		0/19 (0%)
Skin and subcutaneous tissue disorders
Skin discomfort	0/20 (0%)		1/18 (5.6%)		0/18 (0%)		0/19 (0%)
Vascular disorders
Flushing	0/20 (0%)		1/18 (5.6%)		0/18 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.

Results Point of Contact

Name/Title	Medical director
Organization	Takeda
Phone	+1-877-825-3327
Email	trialdisclosures@takeda.com

Responsible Party:

Takeda

ClinicalTrials.gov Identifier:

NCT03522506

Other Study ID Numbers:

TAK-925-1002
U1111-1211-2133

First Posted:

May 11, 2018

Last Update Posted:

Mar 26, 2021

Last Verified:

Mar 1, 2021