Healthy
Conditions
Keywords
sleep, performance, night shift, Ramelteon, Healthy Individuals
Brief summary
Night shift-workers are often advised to take a prophylactic nap prior to starting the shift in order to improve alertness and performance. However, individuals often report difficulty initiating and maintaining sleep at that time of the day secondary to the alerting influence of the near-24 hour circadian rhythm (biological clock). A sleep-promoting medication may improve the quality of an evening nap and subsequent alertness and performance during a night shift. We will use Ramelteon, a melatonin agonist that is FDA approved for insomnia, in order to test the following hypotheses: 1. ramelteon, compared with placebo, will significantly increase sleep efficiency during a 2-hour nap; 2. sleep inertia, as assessed by neurobehavioral tests and subjective and objective sleepiness assessments will not be significantly increased after ramelteon treatment compared with placebo treatment; and 3. neurobehavioral performance, subjective and objective sleepiness, and subjective mood during a simulated 8-hour night shift will be significantly improved when ramelteon is given prior to a prophylactic nap compared to a prophylactic nap with placebo.
Interventions
DRUGRamelteon
Ramelteon 8 mg tablet by mouth x 1 dose
DRUGplacebo
placebo identical in appearance to active experimental drug x 1 dose
Sponsors
Takeda
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Aged between 18-35 years; * Non-smoking for at least 6 months; * Healthy (no medical, psychiatric or sleep disorders); * No clinically significant deviations from normal in medical history, vital signs, physical examination, blood chemistry and hematology, and ECG; * Women of childbearing potential must agree to use an acceptable method of birth control, and must have a negative serum pregnancy test; * Body mass index of \> 18 or \< 30 kg/m∧2; * No drugs or medication likely to affect sleep or alertness, as determined by the investigators; * Habitual caffeine consumption \< 300 mg per day on average; * Habitual alcohol consumption \< 10 alcoholic units per week on average.
Exclusion criteria
* History of alcohol or substance abuse; * Positive result on drugs of abuse screening; * Current or past history of sleep disorders, including but not limited to obstructive sleep apnea, or any significant sleep complaint; * Psychiatric disorder, including a history of depression or dysthymia (characterized by depressed mood on the majority of days for at least two years); * Recent acute or chronic medical disorder, including but not limited to hepatic impairment and severe chronic obstructive pulmonary disease; * History of intolerance or hypersensitivity to melatonin or melatonin agonists; * Pregnancy or lactation; * Shift work; * Transmeridian travel (2 or more time zones) in past 2 months; * Any other scientific or medical reason, as determined by the PI, such as non-compliance with protocol or intolerance to inpatient study conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sleep Efficiency | 2 hours | total sleep time/time in bed \* 100% (higher values indicate better outcome) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Post Nap Assessment - Karolinska Sleepiness Scale | 71 minutes | numerical scale of increasing sleepiness from 1-9 (higher values indicate worse outcome) |
| Post Nap Assessment - Digit Symbol Substitution Test (Correct Answers) | 71 minutes | A cognitive throughput task consisting of matching symbols to numerical keys; higher numbers indicate a better score |
| Post-nap Assessment - Visual Analog Scale | 71 minutes | numerical scale of increasing alertness from 0-100 (higher values are better outcome) |
| Psychomotor Vigilance Task - Median Reaction Time | 8 hours | Visual-motor reaction time in which participants hit a button on a response box as fast as possible in response to a visual target (lower values indicate better outcome) |
| Psychomotor Vigilance Task - Number of Lapses | 8 hours | Number of trials per test battery with a reaction time \>0.5 seconds (higher values indicate worse outcome) |
| Post Nap Assessment - Karolinska Drowsiness Test | 71 minutes | EEG spectral analysis of 5.5-9.0 Hz frequency activity (theta low-frequency alpha), with higher activity indicating increased drowsiness and worse outcome |
Participant flow
Recruitment details
Healthy volunteers were recruited
Pre-assignment details
Participants received 1 dose of ramelteon or placebo during the first inpatient visit and then returned approximately four weeks later for the other condition, counterbalanced for order
Participants by arm
| Arm | Count |
|---|---|
| Ramelteon in First Crossover Period Ramelteon 8 mg will be given prior to a 2-hour nap | 6 |
| Placebo in First Crossover Period Placebo will be given prior to a 2-hour nap | 5 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo in First Crossover Period | Ramelteon in First Crossover Period | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 6 Participants | 11 Participants |
| Age Continuous | 26.8 years STANDARD_DEVIATION 3.2 | 22.7 years STANDARD_DEVIATION 4.1 | 24.5 years STANDARD_DEVIATION 4.1 |
| Region of Enrollment United States | 5 participants | 6 participants | 11 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 11 | 0 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 |
Outcome results
Primary
Sleep Efficiency
total sleep time/time in bed \* 100% (higher values indicate better outcome)
Time frame: 2 hours
Population: All participants that completed both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Sleep Efficiency | 89.1 percent | Standard Deviation 9.8 |
| Placebo | Sleep Efficiency | 83.3 percent | Standard Deviation 14.3 |
Other Pre-specified
Post Nap Assessment - Digit Symbol Substitution Test (Correct Answers)
A cognitive throughput task consisting of matching symbols to numerical keys; higher numbers indicate a better score
Time frame: 71 minutes
Population: All participants that completed both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Post Nap Assessment - Digit Symbol Substitution Test (Correct Answers) | 50.4 correct answers | Standard Deviation 9.3 |
| Placebo | Post Nap Assessment - Digit Symbol Substitution Test (Correct Answers) | 53.3 correct answers | Standard Deviation 9.3 |
Other Pre-specified
Post Nap Assessment - Karolinska Drowsiness Test
EEG spectral analysis of 5.5-9.0 Hz frequency activity (theta low-frequency alpha), with higher activity indicating increased drowsiness and worse outcome
Time frame: 71 minutes
Population: All participants completing both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Post Nap Assessment - Karolinska Drowsiness Test | 4.9 microvolts^2/Hz | Standard Deviation 4.5 |
| Placebo | Post Nap Assessment - Karolinska Drowsiness Test | 4.0 microvolts^2/Hz | Standard Deviation 5.6 |
Other Pre-specified
Post Nap Assessment - Karolinska Sleepiness Scale
numerical scale of increasing sleepiness from 1-9 (higher values indicate worse outcome)
Time frame: 71 minutes
Population: All participants that completed both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Post Nap Assessment - Karolinska Sleepiness Scale | 5.4 units on a scale | Standard Deviation 1.6 |
| Placebo | Post Nap Assessment - Karolinska Sleepiness Scale | 4.8 units on a scale | Standard Deviation 1.8 |
Other Pre-specified
Post-nap Assessment - Visual Analog Scale
numerical scale of increasing alertness from 0-100 (higher values are better outcome)
Time frame: 71 minutes
Population: All participants that completed both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Post-nap Assessment - Visual Analog Scale | 61.1 units on a scale | Standard Deviation 18.6 |
| Placebo | Post-nap Assessment - Visual Analog Scale | 67.1 units on a scale | Standard Deviation 22.8 |
Other Pre-specified
Psychomotor Vigilance Task - Median Reaction Time
Visual-motor reaction time in which participants hit a button on a response box as fast as possible in response to a visual target (lower values indicate better outcome)
Time frame: 8 hours
Population: All participants completing both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Psychomotor Vigilance Task - Median Reaction Time | 0.662 seconds | Standard Deviation 0.16 |
| Placebo | Psychomotor Vigilance Task - Median Reaction Time | 0.362 seconds | Standard Deviation 0.25 |
Other Pre-specified
Psychomotor Vigilance Task - Number of Lapses
Number of trials per test battery with a reaction time \>0.5 seconds (higher values indicate worse outcome)
Time frame: 8 hours
Population: All participants completing both crossover periods
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Psychomotor Vigilance Task - Number of Lapses | 15.5 lapses | Standard Deviation 16.3 |
| Placebo | Psychomotor Vigilance Task - Number of Lapses | 13.2 lapses | Standard Deviation 16 |