Healthy Volunteers
Conditions
Keywords
Drug Therapy
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.
Interventions
DRUGTAK-925
TAK-925 intravenous infusion.
DRUGTAK-925 Placebo
TAK-925 placebo-matching given as saline intravenous infusion.
DRUGModafinil
Modafinil tablets.
Modafinil placebo-matching tablet.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. 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. 2. 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. 3. Be willing to have actigraphy monitoring during the week before randomization and in each interval.
Exclusion criteria
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 \[354 milliliter per (mL/)12 ounces\], 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 (EDS), or any diagnosis interfering with assessment of sleepiness. 5. Abnormal findings on the initial polysomnography (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. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 | — |
| 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. |
| 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 | — |
| 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 | — |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| TAK-925 44 mg + Placebo + TAK-925 112 mg + Modafinil 300 mg 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. | 5 |
| TAK-925 112 mg + TAK-925 44 mg + Modafinil 300 mg + Placebo 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. | 5 |
| Modafinil 300 mg + TAK-925 112 mg + Placebo + TAK-925 44 mg 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. | 5 |
| Placebo + Modafinil 300 mg + TAK-925 44 mg + TAK-925 112 mg 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. | 5 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Washout Period 1 (7 Days) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
| Washout Period 2 (7 Days) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Modafinil 300 mg + TAK-925 112 mg + Placebo + TAK-925 44 mg | TAK-925 44 mg + Placebo + TAK-925 112 mg + Modafinil 300 mg | Total | TAK-925 112 mg + TAK-925 44 mg + Modafinil 300 mg + Placebo | Placebo + Modafinil 300 mg + TAK-925 44 mg + TAK-925 112 mg |
|---|---|---|---|---|---|
| Age, Continuous | 27.4 years STANDARD_DEVIATION 3.44 | 27.8 years STANDARD_DEVIATION 4.55 | 26.9 years STANDARD_DEVIATION 3.28 | 26.4 years STANDARD_DEVIATION 3.78 | 26.0 years STANDARD_DEVIATION 1.22 |
| Body mass index (BMI) | 27.2 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.67 | 24.9 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.95 | 26.1 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.36 | 25.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.31 | 27.0 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 7 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 13 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 175.6 centimeter (cm) STANDARD_DEVIATION 8.6 | 182.1 centimeter (cm) STANDARD_DEVIATION 5.32 | 177.3 centimeter (cm) STANDARD_DEVIATION 6.46 | 176.1 centimeter (cm) STANDARD_DEVIATION 5.83 | 175.2 centimeter (cm) STANDARD_DEVIATION 4.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 5 Participants | 19 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 5 Participants | 5 Participants | 20 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 20 Participants | 5 Participants | 5 Participants |
| Weight | 84.2 kilogram (kg) STANDARD_DEVIATION 10.73 | 82.6 kilogram (kg) STANDARD_DEVIATION 11.1 | 82.2 kilogram (kg) STANDARD_DEVIATION 9.58 | 78.8 kilogram (kg) STANDARD_DEVIATION 6.52 | 83.0 kilogram (kg) STANDARD_DEVIATION 11.59 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 18 | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 4 / 20 | 5 / 18 | 11 / 18 | 11 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 18 | 0 / 18 | 0 / 19 |
Outcome results
Primary
Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 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.
Time frame: Day 1: 2 hours post-infusion start
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 2 Hours Post-infusion Start | 15.68 minute | Standard Error 2.305 |
| TAK-925 44 mg | Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 2 Hours Post-infusion Start | 35.74 minute | Standard Error 2.445 |
| TAK-925 112 mg | Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 2 Hours Post-infusion Start | 40.02 minute | Standard Error 2.445 |
| Modafinil 300 mg | Latency to Sleep Onset on Maintenance of Wakefulness Test (MWT) at 2 Hours Post-infusion Start | 35.57 minute | Standard Error 2.368 |
p-value: <0.00195% CI: [13.35, 26.77]Linear mixed effect model
p-value: <0.00195% CI: [17.64, 31.06]Linear mixed effect model
p-value: <0.00195% CI: [13.3, 26.49]Linear mixed effects model
Primary
Latency to Sleep Onset on MWT at 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.
Time frame: Day 1: 1 hour post-end of infusion
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Latency to Sleep Onset on MWT at 1 Hour Post-end of Infusion | 4.65 minute | Standard Error 2.109 |
| TAK-925 44 mg | Latency to Sleep Onset on MWT at 1 Hour Post-end of Infusion | 2.49 minute | Standard Error 2.241 |
| TAK-925 112 mg | Latency to Sleep Onset on MWT at 1 Hour Post-end of Infusion | 2.36 minute | Standard Error 2.241 |
| Modafinil 300 mg | Latency to Sleep Onset on MWT at 1 Hour Post-end of Infusion | 21.42 minute | Standard Error 2.168 |
p-value: 0.43695% CI: [-7.68, 3.36]ANOVA
p-value: 0.40995% CI: [-7.81, 3.23]ANOVA
p-value: <0.00195% CI: [11.37, 22.18]ANOVA
Primary
Latency to Sleep Onset on MWT at 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.
Time frame: Day 1: 4 hours post-infusion start
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Latency to Sleep Onset on MWT at 4 Hours Post-infusion Start | 9.10 minute | Standard Error 2.186 |
| TAK-925 44 mg | Latency to Sleep Onset on MWT at 4 Hours Post-infusion Start | 32.04 minute | Standard Error 2.32 |
| TAK-925 112 mg | Latency to Sleep Onset on MWT at 4 Hours Post-infusion Start | 40.05 minute | Standard Error 2.32 |
| Modafinil 300 mg | Latency to Sleep Onset on MWT at 4 Hours Post-infusion Start | 35.60 minute | Standard Error 2.246 |
p-value: <0.00195% CI: [16.58, 29.3]Linear mixed effect model
p-value: <0.00195% CI: [24.59, 37.31]Linear mixed effects model
p-value: <0.00195% CI: [20.24, 32.75]Linear mixed effect model
Primary
Latency to Sleep Onset on MWT at 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.
Time frame: Day 1: 6 hours post-infusion start
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Latency to Sleep Onset on MWT at 6 Hours Post-infusion Start | 6.15 minute | Standard Error 2.589 |
| TAK-925 44 mg | Latency to Sleep Onset on MWT at 6 Hours Post-infusion Start | 20.71 minute | Standard Error 2.742 |
| TAK-925 112 mg | Latency to Sleep Onset on MWT at 6 Hours Post-infusion Start | 38.36 minute | Standard Error 2.742 |
| Modafinil 300 mg | Latency to Sleep Onset on MWT at 6 Hours Post-infusion Start | 31.89 minute | Standard Error 2.659 |
p-value: <0.00195% CI: [7.04, 22.08]Linear mixed effect model
p-value: <0.00195% CI: [24.68, 39.73]Linear mixed effect model
p-value: <0.00195% CI: [18.33, 33.14]Linear mixed effect model
Primary
Latency to Sleep Onset on MWT at 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.
Time frame: Day 1: 8 hours post-infusion start
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Latency to Sleep Onset on MWT at 8 Hours Post-infusion Start | 3.53 minute | Standard Error 2.146 |
| TAK-925 44 mg | Latency to Sleep Onset on MWT at 8 Hours Post-infusion Start | 13.13 minute | Standard Error 2.279 |
| TAK-925 112 mg | Latency to Sleep Onset on MWT at 8 Hours Post-infusion Start | 36.86 minute | Standard Error 2.279 |
| Modafinil 300 mg | Latency to Sleep Onset on MWT at 8 Hours Post-infusion Start | 20.44 minute | Standard Error 2.206 |
p-value: 0.00395% CI: [3.35, 15.85]Linear mixed effect model
p-value: <0.00195% CI: [27.08, 39.58]Linear mixed effect model
p-value: <0.00195% CI: [10.77, 23.06]Linear mixed effect model
Secondary
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 963.7 h*ng/mL | Standard Deviation 134.7 |
| Placebo | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II | M-I | 586.8 h*ng/mL | Standard Deviation 204.08 |
| Placebo | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II | M-II | 15.2 h*ng/mL | Standard Deviation 7.38 |
| TAK-925 44 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 2368.7 h*ng/mL | Standard Deviation 185.04 |
| TAK-925 44 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II | M-I | 1405.6 h*ng/mL | Standard Deviation 510.25 |
| TAK-925 44 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M-I and M-II | M-II | 32.0 h*ng/mL | Standard Deviation 20.26 |
Secondary
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
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | TAK-925 | 940.4 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 127.26 |
| Placebo | 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 | M-I | 572.0 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 196.75 |
| Placebo | 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 | M-II | 12.3 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 7.91 |
| TAK-925 44 mg | 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 | TAK-925 | 2303.7 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 174.23 |
| TAK-925 44 mg | 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 | M-I | 1368.3 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 489.96 |
| TAK-925 44 mg | 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 | M-II | 30.7 hour*nanogram per milliliter (h*ng/mL) | Standard Deviation 19.39 |
Secondary
Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 103.4 ng/mL | Standard Deviation 14.21 |
| Placebo | Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II | M-I | 64.0 ng/mL | Standard Deviation 21.25 |
| Placebo | Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II | M-II | 1.5 ng/mL | Standard Deviation 0.88 |
| TAK-925 44 mg | Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 253.4 ng/mL | Standard Deviation 34.35 |
| TAK-925 44 mg | Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II | M-I | 151.1 ng/mL | Standard Deviation 55.94 |
| TAK-925 44 mg | Ceoi: Plasma Concentration Observed at the End of Infusion for TAK-925 and Its Metabolites M-I and M-II | M-II | 3.7 ng/mL | Standard Deviation 2.34 |
Secondary
CL: Total Clearance After Intravenous Administration for TAK-925
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CL: Total Clearance After Intravenous Administration for TAK-925 | 46.4 liter per hour (L/h) | Standard Deviation 5.98 |
| TAK-925 44 mg | CL: Total Clearance After Intravenous Administration for TAK-925 | 47.6 liter per hour (L/h) | Standard Deviation 3.56 |
Secondary
Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 105.8 nanogram per milliliter (ng/mL) | Standard Deviation 11.74 |
| Placebo | Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II | M-I | 61.9 nanogram per milliliter (ng/mL) | Standard Deviation 21.41 |
| Placebo | Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II | M-II | 1.3 nanogram per milliliter (ng/mL) | Standard Deviation 0.88 |
| TAK-925 44 mg | Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 266.0 nanogram per milliliter (ng/mL) | Standard Deviation 40.1 |
| TAK-925 44 mg | Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II | M-I | 144.7 nanogram per milliliter (ng/mL) | Standard Deviation 55.64 |
| TAK-925 44 mg | Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M-I and M-II | M-II | 3.2 nanogram per milliliter (ng/mL) | Standard Deviation 2.32 |
Secondary
Sleepiness on KSS
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Sleepiness on KSS | 6.75 hours post-infusion start | 8.50 unit on a scale | Standard Error 0.317 |
| Placebo | Sleepiness on KSS | 4.75 hours post-infusion start | 8.15 unit on a scale | Standard Error 0.376 |
| Placebo | Sleepiness on KSS | 1.75 hours post-infusion end | 8.15 unit on a scale | Standard Error 0.294 |
| Placebo | Sleepiness on KSS | 2 hours pre-infusion | 3.90 unit on a scale | Standard Error 0.403 |
| Placebo | Sleepiness on KSS | 6 hours pre-infusion | 2.80 unit on a scale | Standard Error 0.294 |
| Placebo | Sleepiness on KSS | 10 hours pre-infusion | 2.50 unit on a scale | Standard Error 0.283 |
| Placebo | Sleepiness on KSS | 8.75 hours post-infusion start | 8.33 unit on a scale | Standard Error 0.325 |
| Placebo | Sleepiness on KSS | 2.75 hours post -infusion start | 6.85 unit on a scale | Standard Error 0.405 |
| Placebo | Sleepiness on KSS | 14 hours pre-infusion | 3.05 unit on a scale | Standard Error 0.32 |
| TAK-925 44 mg | Sleepiness on KSS | 2.75 hours post -infusion start | 4.85 unit on a scale | Standard Error 0.429 |
| TAK-925 44 mg | Sleepiness on KSS | 6.75 hours post-infusion start | 7.79 unit on a scale | Standard Error 0.336 |
| TAK-925 44 mg | Sleepiness on KSS | 4.75 hours post-infusion start | 6.46 unit on a scale | Standard Error 0.397 |
| TAK-925 44 mg | Sleepiness on KSS | 10 hours pre-infusion | 2.79 unit on a scale | Standard Error 0.3 |
| TAK-925 44 mg | Sleepiness on KSS | 14 hours pre-infusion | 2.85 unit on a scale | Standard Error 0.339 |
| TAK-925 44 mg | Sleepiness on KSS | 6 hours pre-infusion | 2.79 unit on a scale | Standard Error 0.312 |
| TAK-925 44 mg | Sleepiness on KSS | 1.75 hours post-infusion end | 8.46 unit on a scale | Standard Error 0.312 |
| TAK-925 44 mg | Sleepiness on KSS | 8.75 hours post-infusion start | 8.07 unit on a scale | Standard Error 0.34 |
| TAK-925 44 mg | Sleepiness on KSS | 2 hours pre-infusion | 4.01 unit on a scale | Standard Error 0.426 |
| TAK-925 112 mg | Sleepiness on KSS | 2.75 hours post -infusion start | 3.24 unit on a scale | Standard Error 0.429 |
| TAK-925 112 mg | Sleepiness on KSS | 14 hours pre-infusion | 3.29 unit on a scale | Standard Error 0.339 |
| TAK-925 112 mg | Sleepiness on KSS | 10 hours pre-infusion | 2.51 unit on a scale | Standard Error 0.3 |
| TAK-925 112 mg | Sleepiness on KSS | 6 hours pre-infusion | 2.51 unit on a scale | Standard Error 0.312 |
| TAK-925 112 mg | Sleepiness on KSS | 2 hours pre-infusion | 3.46 unit on a scale | Standard Error 0.426 |
| TAK-925 112 mg | Sleepiness on KSS | 4.75 hours post-infusion start | 3.85 unit on a scale | Standard Error 0.397 |
| TAK-925 112 mg | Sleepiness on KSS | 6.75 hours post-infusion start | 5.18 unit on a scale | Standard Error 0.336 |
| TAK-925 112 mg | Sleepiness on KSS | 8.75 hours post-infusion start | 6.07 unit on a scale | Standard Error 0.34 |
| TAK-925 112 mg | Sleepiness on KSS | 1.75 hours post-infusion end | 8.01 unit on a scale | Standard Error 0.312 |
| Modafinil 300 mg | Sleepiness on KSS | 6.75 hours post-infusion start | 5.79 unit on a scale | Standard Error 0.326 |
| Modafinil 300 mg | Sleepiness on KSS | 2 hours pre-infusion | 3.32 unit on a scale | Standard Error 0.414 |
| Modafinil 300 mg | Sleepiness on KSS | 6 hours pre-infusion | 2.58 unit on a scale | Standard Error 0.302 |
| Modafinil 300 mg | Sleepiness on KSS | 1.75 hours post-infusion end | 7.16 unit on a scale | Standard Error 0.302 |
| Modafinil 300 mg | Sleepiness on KSS | 10 hours pre-infusion | 2.32 unit on a scale | Standard Error 0.291 |
| Modafinil 300 mg | Sleepiness on KSS | 14 hours pre-infusion | 2.79 unit on a scale | Standard Error 0.328 |
| Modafinil 300 mg | Sleepiness on KSS | 4.75 hours post-infusion start | 4.32 unit on a scale | Standard Error 0.386 |
| Modafinil 300 mg | Sleepiness on KSS | 2.75 hours post -infusion start | 3.69 unit on a scale | Standard Error 0.416 |
| Modafinil 300 mg | Sleepiness on KSS | 8.75 hours post-infusion start | 6.69 unit on a scale | Standard Error 0.33 |
p-value: 0.66495% CI: [-1.13, 0.73]Linear mixed effect model
p-value: 0.60595% CI: [-0.69, 1.17]Linear mixed effect model
p-value: 0.57495% CI: [-1.17, 0.66]Linear mixed effect model
p-value: 0.48395% CI: [-0.53, 1.11]Linear mixed effect model
p-value: 0.97295% CI: [-0.81, 0.84]Linear mixed effect model
p-value: 0.65495% CI: [-0.99, 0.63]Linear mixed effect model
p-value: 0.98495% CI: [-0.86, 0.85]Linear mixed effect model
p-value: 0.50895% CI: [-1.14, 0.57]Linear mixed effect model
p-value: 0.60595% CI: [-1.06, 0.62]Linear mixed effect model
p-value: 0.84795% CI: [-1.06, 1.29]Linear mixed effect model
p-value: 0.45595% CI: [-1.61, 0.73]Linear mixed effect model
p-value: 0.31795% CI: [-1.74, 0.57]Linear mixed effect model
p-value: 0.00195% CI: [-3.18, -0.83]Linear mixed effect model
p-value: <0.00195% CI: [-4.79, -2.44]Linear mixed effect model
p-value: <0.00195% CI: [-4.32, -2.01]Linear mixed effect model
p-value: 0.00395% CI: [-2.78, -0.6]Linear mixed effect model
p-value: <0.00195% CI: [-5.39, -3.21]Linear mixed effect model
p-value: <0.00195% CI: [-4.91, -2.76]Linear mixed effect model
p-value: 0.1395% CI: [-1.63, 0.21]Linear mixed effect model
p-value: <0.00195% CI: [-4.24, -2.4]Linear mixed effect model
p-value: <0.00195% CI: [-3.62, -1.8]Linear mixed effect model
p-value: 0.57795% CI: [-1.2, 0.68]Linear mixed effect model
p-value: <0.00195% CI: [-3.2, -1.32]Linear mixed effect model
p-value: <0.00195% CI: [-2.57, -0.72]Linear mixed effect model
p-value: 0.47595% CI: [-0.55, 1.16]Linear mixed effect model
p-value: 0.75395% CI: [-0.99, 0.72]Linear mixed effect model
p-value: 0.02295% CI: [-1.83, -0.15]Linear mixed effect model
Secondary
T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 3.134 hour | Standard Deviation 0.7064 |
| Placebo | T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II | M-I | 2.424 hour | Standard Deviation 0.2989 |
| Placebo | T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II | M-II | 2.235 hour | Standard Deviation 0.6945 |
| TAK-925 44 mg | T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 3.252 hour | Standard Deviation 0.8597 |
| TAK-925 44 mg | T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II | M-I | 2.490 hour | Standard Deviation 0.3638 |
| TAK-925 44 mg | T1/2z: Terminal Disposition Phase Half-life for TAK-925 and Its Metabolites M-I and M-II | M-II | 2.516 hour | Standard Deviation 0.966 |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 9.000 hour |
| Placebo | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II | M-I | 9.030 hour |
| Placebo | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II | M-II | 9.170 hour |
| TAK-925 44 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II | TAK-925 | 9.000 hour |
| TAK-925 44 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II | M-I | 9.000 hour |
| TAK-925 44 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M-I and M-II | M-II | 9.000 hour |
Secondary
Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925 | 106.7 liter | Standard Deviation 18.9 |
| TAK-925 44 mg | Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925 | 112.5 liter | Standard Deviation 25.33 |
Secondary
Vz: Volume of Distribution During the Terminal Disposition Phase After Intravenous Administration for TAK-925
Time frame: Day 1 pre-dose and at multiple time points (up to 9 hours) post-dose
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Vz: Volume of Distribution During the Terminal Disposition Phase After Intravenous Administration for TAK-925 | 207.4 liter | Standard Deviation 41.51 |
| TAK-925 44 mg | Vz: Volume of Distribution During the Terminal Disposition Phase After Intravenous Administration for TAK-925 | 223.1 liter | Standard Deviation 61.2 |