The Role of the LC-NA System in Experimental Sleep Fragmentation

Официальное название

Phase I, Randomized, Placebo-Controlled Study on the Role of the LC-NA System in Experimental Sleep Fragmentation With Buccal Dexmedetomidine.

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат DMTN
  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.
• Другое Auditory Stimulation
  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.
• Препарат Placbo
  Oro-dispersible placebo tablet identical in appearance and packaging to the active Dexmedetomidine tablet.

Первичные конечные точки

• Change in Total Sleep Time (TST) [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Change in Wake After Sleep Onset (WASO) [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Change in Sleep Efficiency [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Change in Sleep Onset Latency (SOL) [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Percentage of Time in N1, N2, N3 and REM-Sleep [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Change in Arousal Index [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Maximum Plasma Concentration (Cmax) of Dexmedetomidine [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3]
• Change in Plasma Noradrenaline Concentration [Срок оценки: Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3]

Вторичные конечные точки (12)

• Dim Light Melatonin Onset (DLMO) [Срок оценки: Evening after Experimental Night 1, Evening after Experimental Night 2, Evening after Experimental Night 3]
• Change in Autonomic Arousal Measured by Pupillometry [Срок оценки: 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 [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Resting-state EEG spectral analysis [Срок оценки: 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 [Срок оценки: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3]
• Pre-sleep arousal levels (PSAS) [Срок оценки: Morning of Baseline Night, Morning of Experimental Night 1, Morning of Experimental Night 2, Morning of Experimental Night 3]
• Sedation depth (OAAS scale) [Срок оценки: 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) [Срок оценки: Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3]
• State-Trait Anxiety Inventory (STAI) [Срок оценки: Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3]
• Psychomotor vigilance (PVT) [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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.]

Критерии участия

Критерии включения

• Age between 18 - 35 years (inclusive)
• Body-Mass-Index (BMI): 18.5 < BMI < 25
• Non-nicotine user status
• Habitual consumption of 5 or fewer alcoholic beverages / week
• Habitual consumption of 3 or fewer caffeinated beverages / day
• Habitual average sleep duration 7-9 h / night
• Normal or corrected-to-normal vision
• Insomnia severity Index (ISI) Score: ISI < 8
• Ability to understand and speak German language
• Normal hearing ability (applies only to Sleep Study Part)
• Ability and willingness to provide informed consent as documented by dated signature

Критерии исключения

• Present use of medication that may interfere with sleep or study drugs
• Travel across 3 or more time zones within 3 months of study start
• Habitual napping
• Extreme chronotype, determined by reduced Morningness-Eveningness Questionnaire (rMEQ) score: 8 < rMEQ > 21)
• Shift working within 2 weeks prior to the screening visit
• History of or presence of a trauma- or stressor-related disorder
• Serious acute or chronic neurological, mental, or general medical conditions that, in the opinion of the investigator, may pose a risk to participation or affect study measurements
• History of or presence of a sleep wake disorder
• Use of illicit drugs (positive urinary drug screening)
• Male participants who are not vasectomised for at least 6 months prior to dosing and who are sexually active with a female partner of childbearing potential not willing to use one of the following acceptable contraceptive methods from the first dose and for 3 months after the last dose:

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;

• Male participants (including men who have had a vasectomy) with a pregnant partner not willing to use a condom from the first dose and for 3 months after the last dose.
• Male participants not willing to abstain from sperm donation for 3 months after the last dose
• Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomised at least 6 months prior to the first study drug administration) not willing to use one of the following acceptable contraceptive methods throughout the study and for at least 3 months after the last study drug administration:

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)

• Faints at the sight of blood (applies only for the pharmacokinetic-part of the study)
• Has participated in a study < 30 days or a study such as this (i.e., experimental trauma) at all.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Двойное слепое

Основная цель

Фундаментальное исследование

Центры проведения

Швейцария · 1 центр

• University of Zurich, Institute of Pharmacology and Toxicology — Zurich

Идентификаторы

NCT: NCT07167316 · 2025-01005

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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