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| Name | Class |
|---|---|
| Wellcome Trust | OTHER |
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Sleep-wake regulation affects every person's life, yet the molecular mechanisms underlying these processes remain poorly understood. In particular, the microstructure of sleep has not been sufficiently studied to explain how sleep produces a feeling of restoration the following morning. Stress also plays a significant role in sleep regulation. This study aims to investigate the role of norepinephrine in these processes.
Following a screening night and a baseline sleep recording, participants undergo three experimental nights in the sleep laboratory. On each of these nights, sleep is intentionally disrupted using auditory stimuli to induce fragmentation. To investigate potential counteracting effects on sleep quality, participants receive either a low dose (64 µg), a high dose (96 µg) of dexmedetomidine (DMTN)-a compound known to reduce norepinephrine levels-or a placebo. All participants experience each condition in a randomized, double-blind, crossover design, with the sequence of administration varying between individuals. Neither the participants nor the study team are aware of the assigned condition on any given night.
In a second part of the study, three additional nights are conducted to assess the pharmacokinetics and pharmacodynamics of dexmedetomidine. During these nights, participants again receive either the low dose (64 µg), high dose (96 µg), or placebo (in randomized order). Blood samples are collected at multiple time points to characterize the compound's pharmacokinetic profile, and additional physiological outcomes are measured to evaluate pharmacodynamic effects.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low Dose | Experimental | Experimental: 64 µg Dexmedetomidine |
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| High Dose | Experimental | Experimental: 96 µg Dexmedetomidine |
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| Placebo | Placebo Comparator | Placebo |
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| Low Dose + Auditory Stimulation | Experimental | Experimental: 64 µg Dexmedetomidine + Auditory Stimulation |
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| High Dose + Auditory Stimulation | Experimental | Experimental: 96 µg Dexmedetomidine + Auditory Stimulation |
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| Placebo + Auditory Stimulation | Placebo Comparator | Placebo + Auditory Stimulation |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| DMTN | Drug | Dexmedetomidine is a highly selective alpha-2 adrenergic receptor agonist that reduces the release of norepinephrine by inhibiting activity in the locus coeruleus, a key brain region involved in arousal and stress responses. In this study, dexmedetomidine will be administered as an oro-dispersible tablet applied buccally, allowing for rapid absorption through the oral mucosa. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Total Sleep Time (TST) | The total amount of time spent in all sleep stages (N1, N2, N3, and REM) combined, measured in minutes. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Change in Wake After Sleep Onset (WASO) | The total time spent awake in minutes after sleep has been initiated and before the final awakening. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Change in Sleep Efficiency | The percentage of time spent asleep relative to the total time spent in bed (Total Sleep Time / Time in Bed * 100). | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Change in Sleep Onset Latency (SOL) | The time in minutes from "lights out" to the first epoch of any sleep stage. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Percentage of Time in N1, N2, N3 and REM-Sleep | The proportion of Total Sleep Time spent in Stage N1, N2, N3 and REM-Sleep. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Change in Arousal Index | The number of EEG arousals per hour of sleep. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Maximum Plasma Concentration (Cmax) of Dexmedetomidine |
| Measure | Description | Time Frame |
|---|---|---|
| Dim Light Melatonin Onset (DLMO) | The clock time at which the concentration of salivary melatonin first exceeds a calculated threshold, determined by serial sampling in dim light conditions. DLMO is a key marker of circadian phase. | Evening after Experimental Night 1, Evening after Experimental Night 2, Evening after Experimental Night 3 |
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Inclusion Criteria:
Exclusion Criteria:
Use of condom and/or hormonal contraceptive (e.g., oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non-hormonal intrauterine device used for at least 4 weeks prior to sexual intercourse for the female partner;
Simultaneous use of condom and hormonal contraceptive (e.g., oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non-hormonal intrauterine device used for at least 4 weeks prior to sexual intercourse for the female partner;
- Females of non-childbearing potential who are neither: Post-menopausal (status defined as an absence of menses for at least 12 months prior to the first study drug administration); or Surgically sterilized (complete hysterectomy or bilateral oophorectomy at least 3 months prior to the first study drug administration)
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rafael Wespi, PhD | Contact | +41 44 635 59 61 | rafael.wespi@pharma.uzh.ch |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Zurich, Institute of Pharmacology and Toxicology | Recruiting | Zurich | 8057 | Switzerland |
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| Label | URL |
|---|---|
| Paper of our previous research project, providing the background for the current study | View source |
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Any disclosure of information to individuals not directly involved in the study must be approved by the owner of the data.
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| ID | Term |
|---|---|
| D020447 | Parasomnias |
| ID | Term |
|---|---|
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D000161 | Acoustic Stimulation |
| ID | Term |
|---|---|
| D013812 | Therapeutics |
| D026421 | Sensory Art Therapies |
| D000529 | Complementary Therapies |
| D010812 | Physical Stimulation |
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Each participant will first spend a screening night to adapt to the sleep laboratory environment, followed by a baseline night without any interventions. Subsequently, they will complete three experimental nights, during which sleep will be disrupted using auditory stimulation. On each of these nights, participants will receive either a high dose, a low dose of dexmedetomidine, or a placebo. The order in which these three conditions are administered will be randomized across participants. In a second part of the study, participants will spend three nights again receiving the high dose, low dose, or placebo in randomized order. During these nights, blood samples will be collected for pharmacokinetic analyses, and additional physiological measures will be recorded to assess pharmacodynamic effects.
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| Auditory Stimulation | Other | Auditory tones will be presented throughout the night at individually calibrated intensities, adjusted to each participant's hearing threshold, in order to induce controlled sleep fragmentation without full awakenings. |
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| Placbo | Drug | Oro-dispersible placebo tablet identical in appearance and packaging to the active Dexmedetomidine tablet. |
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The maximum observed concentration of dexmedetomidine in plasma following administration, determined from serial blood sampling. |
| Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3 |
| Time to Maximum Plasma Concentration (Tmax) of Dexmedetomidine | The time at which the maximum plasma concentration (Cmax) of dexmedetomidine is observed following administration. | Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3 |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Point (AUC0-t) of Dexmedetomidine | The cumulative drug exposure over time, calculated as the area under the dexmedetomidine plasma concentration versus time curve from the time of dosing to the last quantifiable plasma concentration. | Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3 |
| Change in Plasma Noradrenaline Concentration | Assessment of the change in endogenous noradrenaline levels in plasma, measured from samples collected at predetermined timepoints following intervention. | Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3 |
| Change in Autonomic Arousal Measured by Pupillometry |
To quantify autonomic arousal, pupillometry will be performed at different schedules. During sleep-focused visits, assessments are at pre-dose, 15 minutes post-dose, and 15 minutes after lights on. During pharmacokinetic-focused visits, additional assessments are made at 2 and 4 hours post-dose. Autonomic arousal will be reported as a single index derived from pupil diameter and its fluctuations. |
| Pre-dose, 15 minutes post-dose, 2 hours post-dose (only PK-Part), 4 hours post-dose (only PK-Part), 15 minutes after lights on. |
| Change in Heart Rate Variable | Heart rate variables, will be continuously monitored to assess autonomic nervous system regulation. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Resting-state EEG spectral analysis | Wake-state EEG will be recorded before and after sleep to assess changes in power spectral density, especially in alpha and theta bands. | Pre-sleep (evening) and post-sleep (morning) at the baseline night and each of the 3 overnight experimental visits (together with the "Change in Autonomic Arousal Measured by Pupillometry" acquisition). |
| Nocturnal thermoregulation | Body temperature will be continuously monitored to evaluate effects of Dexmedetomidine on thermoregulation. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Pre-sleep arousal levels (PSAS) | The Pre-Sleep Arousal Scale (PSAS, score range 16 - 80, with higher scores indicating higher levels of arousal) will be administered to assess cognitive and somatic arousal prior to bedtime. | Morning of Baseline Night, Morning of Experimental Night 1, Morning of Experimental Night 2, Morning of Experimental Night 3 |
| Sedation depth (OAAS scale) | Observer-rated sedation will be assessed using the Observer's Assessment of Alertness/Sedation Scale (score 1 - 5). | Completed at each of the 3 overnight experimental visits similar to the blood sampling timepoints in the sleep opportunity window. |
| Mood states (POMS-16 and A-SIQ) | Mood and sleep inertia will be evaluated using the 16-item Profile of Mood States (POMS-16, 16 items from 0-4; assesses mood across five subscales, with higher scores indicating greater intensity except for vigor) and the Acute Sleep Inertia Questionnaire (A-SIQ, 22 items from -3 - +3, with higher scores indicate more sleep inertia and 1 item with visual analoge scale) upon awakening. | Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3 |
| State-Trait Anxiety Inventory (STAI) | Trait and state anxiety will be assessed via the STAI-Y1 (STAI-Y1, 20 items from 1-4; higher scores reflect greater momentary anxiety) questionnaire to explore mood modulation effects of the experimental sleep fragmentation and Dexmedetomidine. | Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3 |
| Psychomotor vigilance (PVT) | Vigilance performance will be assessed using the Psychomotor Vigilance Task (PVT) upon awakening. | Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3 |
| Number of Participants with Orthostatic Intolerance as Defined by Schellong Test Criteria | The number of participants who are unable to complete the full duration of the Schellong test or exhibit clear signs of intolerance. This is defined as the occurrence of any of the following: participant-reported dizziness or pre-syncope requiring termination of the test; investigator-observed excessive swaying or stumbling requiring intervention; or early termination of the test at the participant's request. | Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3 |
| Number of Participants Exhibiting Clinically Significant Gait Instability During a Standardized Gait Task | Postural stability and adaptation during walking will be assessed via a standardized gait task. Clinically significant instability is defined as the occurrence of any of the following during the task: any stumble, trip, or loss of balance; requiring physical assistance or support from an external surface (e.g., a wall); or an inability to complete the prescribed walking task as instructed. | In the morning after 8 hours sleep opportunity window of the baseline night and each of the 3 overnight experimental visits. For the PK part additional timepoints (2 & 4 hours post dosing) will be measured during sleep opportunity window of 8 hours. |
| Change in Power of EEG Infra-Slow Oscillations (<0.1 Hz) During NREM Sleep | The power spectral density of EEG activity (measured in μV²/Hz) in the infra-slow frequency band (<0.1 Hz), calculated from overnight polysomnography (PSG) recordings during NREM sleep. The change from the placebo condition to the DMTN condition will be calculated to assess the drug's effect on rhythmic noradrenergic signalling. | Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3 |
| Change in Blood Oxygen Saturation (SpO2) | Peripheral blood oxygen saturation (SpO2), measured as a percentage, will be continuously monitored via pulse oximetry during the pharmacokinetic (PK) study visits. | Continuously during each 3 of the the pharmacokinetic overnight experimental visits. |
| Change in Systolic Blood Pressure | Systolic blood pressure (SBP), measured in mmHg, will be assessed at discrete time points in the evening and morning to evaluate autonomic changes. | Evening and Morning of Baseline Night, Evening and Morning of Experimental Night 1, Evening and Morning of Experimental Night 2, Evening and Morning of Experimental Night 3 |
| Change in Diastolic Blood Pressure | Diastolic blood pressure (DBP), measured in mmHg, will be assessed at discrete time points in the evening and morning to evaluate autonomic changes. | Evening and Morning of Baseline Night, Evening and Morning of Experimental Night 1, Evening and Morning of Experimental Night 2, Evening and Morning of Experimental Night 3 |
| D008919 |
| Investigative Techniques |