Polysomnography
Conditions
Brief summary
The purpose of this randomized, double-blind, placebo-controlled, 5-period crossover study is to assess the effect of single oral doses of MK-1064 on latency to persistent sleep (LPS) as measured by polysomnography (PSG) in healthy young male participants, and to evaluate the safety and tolerability of single oral doses of MK-1064 and MK-6096 in healthy young male participants. The primary efficacy hypothesis is that at least one dose of MK-1064 is superior to placebo in decreasing LPS in healthy male participants as assessed by PSG.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Body Mass Index (BMI) ≤31 kg/m\^2 * In good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests * Nonsmoker and has not used nicotine or nicotine-containing products for at least 6 months * No history of any sleep disorder * Has not used prescription or over the counter sedation or alerting medication in 4 weeks prior to screening * Participant has a usual bedtime between 8:00 PM and 12:00 AM * Participant has total sleep duration of ≥6.5 and ≤9 hours during the 4 weeks prior to screening * Male participants with female partner(s) of child-bearing potential must agree to use a medically acceptable method of contraception during the study and for 90 days after the last dose of study drug
Exclusion criteria
* Mentally or legally incapacitated, significant emotional problems at screening or expected during the conduct of the study or history of a clinically significant psychiatric disorder within the last 10 years * History of any persistent sleep abnormality (including difficulty falling asleep, difficulty staying asleep) lasting for 3 months or more, or history of obstructive sleep apnea, restless leg syndrome, or narcolepsy * History of clinically significant sleep disorders within the last 5 years * History of circadian rhythm sleep disorder, clinically important parasomnia, or primary insomnia * History of repeated falls or fractures secondary to falling within the past 2 years * Participant works a night shift and is not able to avoid night shift work a minimum of 1 week prior to screening and for the duration of the study * Participant has traveled across 3 or more time zones (transmeridian travel) in the last 2 weeks prior to study * Is a regular user of sedative-hypnotic agents * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases * History of stroke, peripheral neuropathy, chronic seizures or other clinically significant neurological disorder or cognitive impairment * History of cancer * History of cataplexy * Participant is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies, beginning approximately 2 weeks prior to administration of the initial dose of study drug and throughout the study * Participant consumes \>3 servings of alcohol a day * Participant consumes \>6 caffeine servings a day * Participant has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to screening, or participated in another investigational study within 3 months prior to first dose of study drug * History of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Is currently a regular user of any illicit drugs or has a history of drug (including alcohol) abuse within 2 years of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Study Due to an AE | Up to 14 days after the last dose of study drug (Up to approximately 42 days) | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study drug, is also an AE. |
| Latency to Persistent Sleep (LPS) Following Single Doses of MK-1064 and Placebo | 1 to 9 hours post dose, within each treatment period | LPS is measured during overnight sleep laboratory (polysomnography \[PSG\]) assessment and is defined as the duration of time from the beginning of PSG assessment to the first interval of 10 consecutive minutes of sleep. |
| LPS Following Single Doses of MK-6096 and Placebo | 1 to 9 hours post dose, within each treatment period | LPS is measured during overnight sleep laboratory (PSG) assessment and is defined as the duration of time from the beginning of PSG assessment to the first interval of 10 consecutive minutes of sleep. |
| Number of Participants With Adverse Events (AEs) | Up to 14 days after the last dose of study drug (Up to approximately 42 days) | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study drug, is also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Wake Time After Sleep Onset (WASO) Following Single Doses of MK-1064 and Placebo | 1 to 9 hours post dose, within each treatment period | WASO is measured during overnight sleep laboratory (PSG) assessment and is defined as the duration of wakefulness from the onset of persistent sleep (i.e., 10 consecutive minutes of sleep) to the end of PSG assessment the following morning. |
| WASO Following Single Doses of MK-6096 and Placebo | 1 to 9 hours post dose, within each treatment period | WASO is measured during overnight sleep laboratory (PSG) assessment and is defined as the duration of wakefulness from the onset of persistent sleep (i.e., 10 consecutive minutes of sleep) to the end of PSG assessment the following morning. |
| Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Pre-dose and 10 hours post dose, within each treatment period | CRT assessment used in this study is a two-choice, computer-controlled test in which the participant responds to stimulus words presented on the screen of a laptop computer. During the test either the word NO or the word YES is presented on the screen and the participant is instructed to press the corresponding button as quickly as possible. There are 50 trials for which each stimulus word is chosen randomly with equal probability and there is a varying inter-stimulus interval. The mean reaction time of accurate responses is determined. The assessment is performed pre-dose and at 10 hours post dose. The outcome measure is change from baseline to post dose in reaction time. |
| Change From Baseline in CRT Following Single Doses of MK-6096 and Placebo | Pre-dose and 10 hours post dose, within each treatment period | CRT assessment used in this study is a two-choice, computer-controlled test in which the participant responds to stimulus words presented on the screen of a laptop computer. During the test either the word NO or the word YES is presented on the screen and the participant is instructed to press the corresponding button as quickly as possible. There are 50 trials for which each stimulus word is chosen randomly with equal probability and there is a varying inter-stimulus interval. The mean reaction time of accurate responses is determined. The assessment is performed pre-dose and at 10 hours post dose. The outcome measure is change from baseline to post dose in reaction time. |
Participant flow
Pre-assignment details
Participants were randomized to 1 of 4 treatment sequences of single doses of MK-1064 or placebo, administered over 4 study periods in a crossover design; then in Period 5 participants received, according to separate randomization, either a single dose of 20 mg MK-6096 or placebo, in an 18:2 ratio for overall study population.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 5 - MK-6096 or Placebo | Protocol Violation | 0 | 0 | 0 | 0 | 2 | 0 |
| Washout After Period 4 | Withdrawal by Subject | 0 | 1 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 29.2 years STANDARD_DEVIATION 4.6 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 20 | 2 / 20 | 5 / 20 | 3 / 14 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 14 | 0 / 20 |
Outcome results
Primary
Latency to Persistent Sleep (LPS) Following Single Doses of MK-1064 and Placebo
LPS is measured during overnight sleep laboratory (polysomnography \[PSG\]) assessment and is defined as the duration of time from the beginning of PSG assessment to the first interval of 10 consecutive minutes of sleep.
Time frame: 1 to 9 hours post dose, within each treatment period
Population: Per-Protocol. Note: Data included are those obtained from subjects during administration of MK-1064 doses in Period 1-4 and during administration of placebo in Period 1-4
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1064 50 mg | Latency to Persistent Sleep (LPS) Following Single Doses of MK-1064 and Placebo | 4.27 minutes |
| MK-1064 120 mg | Latency to Persistent Sleep (LPS) Following Single Doses of MK-1064 and Placebo | 3.68 minutes |
| MK-1064 250 mg | Latency to Persistent Sleep (LPS) Following Single Doses of MK-1064 and Placebo | 2.67 minutes |
| Placebo | Latency to Persistent Sleep (LPS) Following Single Doses of MK-1064 and Placebo | 17.93 minutes |
Comparison: Analysis used a step-down approach. Mean log treatment difference of the highest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% confidence interval (CI) were computed and back-transformed to obtain the 90% CI interval for LPS treatment ratio. If the CI lies completely below 1, testing continued to next lower MK-1064 dose. The hypothesis that MK-1064 is superior to placebo in decreasing LPS was supported if the CI lies below 1 for at least one dose.90% CI: [0.12, 0.47]
Comparison: Analysis used a step-down approach. Mean log treatment difference of the highest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for LPS treatment ratio. If the CI lies completely below 1, testing continued to next lower MK-1064 dose. The hypothesis that MK-1064 is superior to placebo in decreasing LPS was supported if the CI lies below 1 for at least one dose.90% CI: [0.1, 0.41]
Comparison: Analysis used a step-down approach. Mean log treatment difference of the highest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for LPS treatment ratio. If the CI lies completely below 1, testing continued to next lower MK-1064 dose. The hypothesis that MK-1064 is superior to placebo in decreasing LPS was supported if the CI lies below 1 for at least one dose.90% CI: [0.08, 0.3]
Primary
LPS Following Single Doses of MK-6096 and Placebo
LPS is measured during overnight sleep laboratory (PSG) assessment and is defined as the duration of time from the beginning of PSG assessment to the first interval of 10 consecutive minutes of sleep.
Time frame: 1 to 9 hours post dose, within each treatment period
Population: Per-Protocol. Note: Data included are those obtained from subjects during MK-6096 dose in Period 5 and during administration of placebo in any period. 1 subject took placebo within Periods 1-4 and also in Period 5. Data for both administrations of placebo are included (i.e., for placebo, analysis includes 21 observations from 20 subjects)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1064 50 mg | LPS Following Single Doses of MK-6096 and Placebo | 0.87 minutes |
| MK-1064 120 mg | LPS Following Single Doses of MK-6096 and Placebo | 17.79 minutes |
Comparison: Mean log treatment difference of MK-6096 versus placebo (MK-6096 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for LPS treatment ratio.90% CI: [0.02, 0.11]
Primary
Number of Participants Who Discontinued Study Due to an AE
An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study drug, is also an AE.
Time frame: Up to 14 days after the last dose of study drug (Up to approximately 42 days)
Population: All Participants as Treated - all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-1064 50 mg | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
| MK-1064 120 mg | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
| MK-1064 250 mg | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
| Placebo | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
| Placebo | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
Primary
Number of Participants With Adverse Events (AEs)
An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study drug, is also an AE.
Time frame: Up to 14 days after the last dose of study drug (Up to approximately 42 days)
Population: All Participants as Treated - all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-1064 50 mg | Number of Participants With Adverse Events (AEs) | 4 participants |
| MK-1064 120 mg | Number of Participants With Adverse Events (AEs) | 4 participants |
| MK-1064 250 mg | Number of Participants With Adverse Events (AEs) | 7 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | 3 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | 3 participants |
Secondary
Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo
CRT assessment used in this study is a two-choice, computer-controlled test in which the participant responds to stimulus words presented on the screen of a laptop computer. During the test either the word NO or the word YES is presented on the screen and the participant is instructed to press the corresponding button as quickly as possible. There are 50 trials for which each stimulus word is chosen randomly with equal probability and there is a varying inter-stimulus interval. The mean reaction time of accurate responses is determined. The assessment is performed pre-dose and at 10 hours post dose. The outcome measure is change from baseline to post dose in reaction time.
Time frame: Pre-dose and 10 hours post dose, within each treatment period
Population: Per-Protocol. Note: Data included are those obtained from subjects during administration of MK-1064 doses in Period 1-4 and during administration of placebo in Period 1-4
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MK-1064 50 mg | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Baseline (Pre-dose) | 408.79 milliseconds |
| MK-1064 50 mg | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Change at 10 hours post dose | 17.25 milliseconds |
| MK-1064 120 mg | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Change at 10 hours post dose | 19.94 milliseconds |
| MK-1064 120 mg | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Baseline (Pre-dose) | 423.39 milliseconds |
| MK-1064 250 mg | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Baseline (Pre-dose) | 418.83 milliseconds |
| MK-1064 250 mg | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Change at 10 hours post dose | 21.04 milliseconds |
| Placebo | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Baseline (Pre-dose) | 414.85 milliseconds |
| Placebo | Change From Baseline in Choice Reaction Time (CRT) Following Single Doses of MK-1064 and Placebo | Change at 10 hours post dose | 14.66 milliseconds |
Comparison: Analysis used a step-up approach. Mean treatment difference in change from baseline of the lowest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed. If the CI lies completely below 25 milliseconds, testing continued to the next higher MK-1064 dose. The hypothesis that at least one dose of MK-1064 does not produce psychomotor impairment versus placebo as assessed by CRT will be supported if the CI lies below 25 milliseconds for at least one dose.90% CI: [-12.01, 17.2]
Comparison: Analysis used a step-up approach. Mean treatment difference in change from baseline of the lowest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed. If the CI lies completely below 25 milliseconds, testing continued to the next higher MK-1064 dose. The hypothesis that at least one dose of MK-1064 does not produce psychomotor impairment versus placebo as assessed by CRT will be supported if the CI lies below 25 milliseconds for at least one dose.90% CI: [-9.33, 19.88]
Comparison: Analysis used a step-up approach. Mean treatment difference in change from baseline of the lowest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed. If the CI lies completely below 25 milliseconds, testing continued to the next higher MK-1064 dose. The hypothesis that at least one dose of MK-1064 does not produce psychomotor impairment versus placebo as assessed by CRT will be supported if the CI lies below 25 milliseconds for at least one dose.90% CI: [-8.23, 20.98]
Secondary
Change From Baseline in CRT Following Single Doses of MK-6096 and Placebo
CRT assessment used in this study is a two-choice, computer-controlled test in which the participant responds to stimulus words presented on the screen of a laptop computer. During the test either the word NO or the word YES is presented on the screen and the participant is instructed to press the corresponding button as quickly as possible. There are 50 trials for which each stimulus word is chosen randomly with equal probability and there is a varying inter-stimulus interval. The mean reaction time of accurate responses is determined. The assessment is performed pre-dose and at 10 hours post dose. The outcome measure is change from baseline to post dose in reaction time.
Time frame: Pre-dose and 10 hours post dose, within each treatment period
Population: Per-Protocol. Note: Data included are those obtained from subjects during MK-6096 dose in Period 5 and during administration of placebo in any period. 1 subject took placebo within Periods 1-4 and also in Period 5. Data for both administrations of placebo are included (i.e., for placebo, analysis includes 21 observations from 20 subjects)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MK-1064 50 mg | Change From Baseline in CRT Following Single Doses of MK-6096 and Placebo | Baseline (Pre-dose) | 425.94 milliseconds |
| MK-1064 50 mg | Change From Baseline in CRT Following Single Doses of MK-6096 and Placebo | Change at 10 hours post dose | 24.04 milliseconds |
| MK-1064 120 mg | Change From Baseline in CRT Following Single Doses of MK-6096 and Placebo | Baseline (Pre-dose) | 417.81 milliseconds |
| MK-1064 120 mg | Change From Baseline in CRT Following Single Doses of MK-6096 and Placebo | Change at 10 hours post dose | 14.74 milliseconds |
Comparison: Mean treatment difference in change from baseline of MK-6096 versus placebo (MK-6096 - placebo) and 90% CI were computed.90% CI: [-7.1, 25.7]
Secondary
Wake Time After Sleep Onset (WASO) Following Single Doses of MK-1064 and Placebo
WASO is measured during overnight sleep laboratory (PSG) assessment and is defined as the duration of wakefulness from the onset of persistent sleep (i.e., 10 consecutive minutes of sleep) to the end of PSG assessment the following morning.
Time frame: 1 to 9 hours post dose, within each treatment period
Population: Per-Protocol. Note: Data included are those obtained from subjects during administration of MK-1064 doses in Period 1-4 and during administration of placebo in Period 1-4
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1064 50 mg | Wake Time After Sleep Onset (WASO) Following Single Doses of MK-1064 and Placebo | 22.41 minutes |
| MK-1064 120 mg | Wake Time After Sleep Onset (WASO) Following Single Doses of MK-1064 and Placebo | 18.01 minutes |
| MK-1064 250 mg | Wake Time After Sleep Onset (WASO) Following Single Doses of MK-1064 and Placebo | 19.90 minutes |
| Placebo | Wake Time After Sleep Onset (WASO) Following Single Doses of MK-1064 and Placebo | 26.41 minutes |
Comparison: Analysis used a step-down approach. Mean log treatment difference of the highest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for WASO treatment ratio. If the CI lies completely below 1, testing continued to next lower MK-1064 dose. The hypothesis that MK-1064 is superior to placebo in decreasing WASO was supported if the CI lies below 1 for at least one dose.90% CI: [0.67, 1.07]
Comparison: Analysis used a step-down approach. Mean log treatment difference of the highest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for WASO treatment ratio. If the CI lies completely below 1, testing continued to next lower MK-1064 dose. The hypothesis that MK-1064 is superior to placebo in decreasing WASO was supported if the CI lies below 1 for at least one dose.90% CI: [0.54, 0.86]
Comparison: Analysis used a step-down approach. Mean log treatment difference of the highest MK-1064 dose versus placebo (MK-1064 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for WASO treatment ratio. If the CI lies completely below 1, testing continued to next lower MK-1064 dose. The hypothesis that MK-1064 is superior to placebo in decreasing WASO was supported if the CI lies below 1 for at least one dose.90% CI: [0.6, 0.95]
Secondary
WASO Following Single Doses of MK-6096 and Placebo
WASO is measured during overnight sleep laboratory (PSG) assessment and is defined as the duration of wakefulness from the onset of persistent sleep (i.e., 10 consecutive minutes of sleep) to the end of PSG assessment the following morning.
Time frame: 1 to 9 hours post dose, within each treatment period
Population: Per-Protocol. Note: Data included are those obtained from subjects during MK-6096 dose in Period 5 and during administration of placebo in any period. 1 subject took placebo within Periods 1-4 and also in Period 5. Data for both administrations of placebo are included (i.e., for placebo, analysis includes 21 observations from 20 subjects)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1064 50 mg | WASO Following Single Doses of MK-6096 and Placebo | 16.65 minutes |
| MK-1064 120 mg | WASO Following Single Doses of MK-6096 and Placebo | 26.41 minutes |
Comparison: Mean log treatment difference of MK-6096 versus placebo (MK-6096 - placebo) and 90% CI were computed and back-transformed to obtain the 90% CI interval for WASO treatment ratio.90% CI: [0.5, 0.79]