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

NCT07167316 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: 2025-01005
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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.

Conditions

The Role of the LC-NA System in Sleep Regulation

Keywords

Cross-Over; placebo controlled; randomized; sleep disturbance; auditory stimulation; healthy; Stress; LC-NA; pharmacokinetics; pharmacodynamics

Outcome Measures

Primary Outcomes (10)

• 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

  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

Secondary Outcomes (16)

• 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).

• Nocturnal thermoregulation

  Baseline Night, Experimental Night 1, Experimental Night 2, Experimental Night 3

Study Arms (6)

Low Dose

EXPERIMENTAL

Experimental: 64 µg Dexmedetomidine

Drug: DMTN

High Dose

EXPERIMENTAL

Experimental: 96 µg Dexmedetomidine

Drug: DMTN

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placbo

Low Dose + Auditory Stimulation

EXPERIMENTAL

Experimental: 64 µg Dexmedetomidine + Auditory Stimulation

Drug: DMTN; Other: Auditory Stimulation

High Dose + Auditory Stimulation

EXPERIMENTAL

Experimental: 96 µg Dexmedetomidine + Auditory Stimulation

Drug: DMTN; Other: Auditory Stimulation

Placebo + Auditory Stimulation

PLACEBO COMPARATOR

Placebo + Auditory Stimulation

Other: Auditory Stimulation; Drug: Placbo

Interventions

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.

High Dose; High Dose + Auditory Stimulation; Low Dose; Low Dose + Auditory Stimulation

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.

High Dose + Auditory Stimulation; Low Dose + Auditory Stimulation; Placebo + Auditory Stimulation

Placbo DRUG

Oro-dispersible placebo tablet identical in appearance and packaging to the active Dexmedetomidine tablet.

Placebo; Placebo + Auditory Stimulation

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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;

Sponsors & Collaborators

• Hans-Peter Landolt: lead
• Wellcome Trust: collaborator

Study Sites (1)

University of Zurich, Institute of Pharmacology and Toxicology

Zurich, 8057, Switzerland

Location

Related Links

• Paper of our previous research project, providing the background for the current study

MeSH Terms

Conditions

Parasomnias

Interventions

Acoustic Stimulation

Condition Hierarchy (Ancestors)

Sleep Wake Disorders; Nervous System Diseases; Mental Disorders

Intervention Hierarchy (Ancestors)

Therapeutics; Sensory Art Therapies; Complementary Therapies; Physical Stimulation; Investigative Techniques

Central Study Contacts

Rafael Wespi, PhD

CONTACT

+41 44 635 59 61; rafael.wespi@pharma.uzh.ch

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. sc. nat.

Model Details: 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.

Study Record Dates

• First Submitted: July 17, 2025
• First Posted: September 11, 2025
• Study Start: January 5, 2026
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: December 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)