Phase I, Randomized, Placebo-Controlled Study on the Role of the LC-NA System in Experimental Sleep Fragmentation With Buccal Dexmedetomidine.
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Enrollment
- 42
- Locations
- 2
- Primary Endpoint
- Change in Total Sleep Time (TST)
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 35 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •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
Exclusion Criteria
- •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.
Arms & Interventions
Low Dose
Experimental: 64 µg Dexmedetomidine
Intervention: DMTN (Drug)
Low Dose + Auditory Stimulation
Experimental: 64 µg Dexmedetomidine + Auditory Stimulation
Intervention: DMTN (Drug)
High Dose
Experimental: 96 µg Dexmedetomidine
Intervention: DMTN (Drug)
Placebo
Placebo
Intervention: Placbo (Drug)
Low Dose + Auditory Stimulation
Experimental: 64 µg Dexmedetomidine + Auditory Stimulation
Intervention: Auditory Stimulation (Other)
Placebo + Auditory Stimulation
Placebo + Auditory Stimulation
Intervention: Auditory Stimulation (Other)
Placebo + Auditory Stimulation
Placebo + Auditory Stimulation
Intervention: Placbo (Drug)
High Dose + Auditory Stimulation
Experimental: 96 µg Dexmedetomidine + Auditory Stimulation
Intervention: DMTN (Drug)
High Dose + Auditory Stimulation
Experimental: 96 µg Dexmedetomidine + Auditory Stimulation
Intervention: Auditory Stimulation (Other)
Outcomes
Primary Outcomes
Change in Total Sleep Time (TST)
Time Frame: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3
The total amount of time spent in all sleep stages (N1, N2, N3, and REM) combined, measured in minutes.
Change in Wake After Sleep Onset (WASO)
Time Frame: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3
The total time spent awake in minutes after sleep has been initiated and before the final awakening.
Change in Sleep Efficiency
Time Frame: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3
The percentage of time spent asleep relative to the total time spent in bed (Total Sleep Time / Time in Bed \* 100).
Change in Sleep Onset Latency (SOL)
Time Frame: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3
The time in minutes from "lights out" to the first epoch of any sleep stage.
Percentage of Time in N1, N2, N3 and REM-Sleep
Time Frame: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3
The proportion of Total Sleep Time spent in Stage N1, N2, N3 and REM-Sleep.
Change in Arousal Index
Time Frame: Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3
The number of EEG arousals per hour of sleep.
Maximum Plasma Concentration (Cmax) of Dexmedetomidine
Time Frame: Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3
The maximum observed concentration of dexmedetomidine in plasma following administration, determined from serial blood sampling.
Time to Maximum Plasma Concentration (Tmax) of Dexmedetomidine
Time Frame: Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3
The time at which the maximum plasma concentration (Cmax) of dexmedetomidine is observed following administration.
Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Point (AUC0-t) of Dexmedetomidine
Time Frame: Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3
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.
Change in Plasma Noradrenaline Concentration
Time Frame: Up to 24 hours post-dose on Experimental Night 1, Experimental Night 2, and Experimental Night 3
Assessment of the change in endogenous noradrenaline levels in plasma, measured from samples collected at predetermined timepoints following intervention.
Secondary Outcomes
- Nocturnal thermoregulation(Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3)
- Dim Light Melatonin Onset (DLMO)(Evening after Experimental Night 1, Evening after Experimental Night 2, Evening after Experimental Night 3)
- Change in Autonomic Arousal Measured by Pupillometry(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(Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3)
- Resting-state EEG spectral analysis(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).)
- Pre-sleep arousal levels (PSAS)(Morning of Baseline Night, Morning of Experimental Night 1, Morning of Experimental Night 2, Morning of Experimental Night 3)
- Sedation depth (OAAS scale)(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)(Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3)
- State-Trait Anxiety Inventory (STAI)(Morning following Baseline Night, Morning following Experimental Night 1, Morning following Experimental Night 2, Morning following Experimental Night 3)
- Psychomotor vigilance (PVT)(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(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(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(Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3)
- Change in Blood Oxygen Saturation (SpO2)(Continuously during each 3 of the the pharmacokinetic overnight experimental visits.)
- Change in Systolic Blood Pressure(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(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)
Investigators
Hans-Peter Landolt
Prof. Dr. sc. nat.
University of Zurich