AzTrials
AzTrials

Sleep DeprivationEarly Phase 1NCT03576664

Effects of Sleep Deprivation and Adrenergic Inhibition on Glymphatic Flow in Humans

A Early Phase 1 study testing Carvedilol 25mg in people with Sleep Deprivation and Sleep Wake Disorders, run by Gitte Moos Knudsen at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The project is aimed at identifying how the adrenergic antagonist 'carvedilol' modulates the effects of sleep deprivation in healthy volunteers. The study is a double-blind, randomized, placebo-controlled, cross-over study. Read more about this study

Who is it for?
Ages 18 to 35 yearsHealthy volunteers can take part
Conditions the study is for
Sleep Deprivation, Sleep Wake Disorders, Sleep
What is being tested?
Carvedilol 25mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
22 participants
Where
1 siteDenmark
Study dates
28 Aug 2018to 1 Oct 2019
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 35 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Healthy volunteer (male or female) between 18 and 35 years.
  • Good sleeper with sleep efficiency above 80%.

Who cannot join

  • Current or former primary psychiatric disorder in volunteer of first degree relatives (DSM IV Axis I or WHO ICD-10 diagnostic classification).
  • Current or previous neurological disease, severe somatic disease, or the consumption of drugs likely to influence the test results.
  • Claustrophobia or fear of being in an MR-scanner.
  • Alcohol or drug abuse.
  • Regular smoking or nicotine addiction
  • Extreme morning or evening type, or extreme short or long sleeper.
Show all 22Show fewer
  • Disordered sleep, regular shift-work or extreme tiredness (e.g. Epworth Sleepiness Scale (ESS) > 10).
  • Crossing of multiple time zones within the last 6 months.
  • Extreme use of stimulants such as caffeine.
  • Not adhering to the prescribed sleep-wake schedule before study initiation.
  • Left handedness.
  • Obesity (BMI > 27.5).
  • Non-fluent in Danish or pronounced visual or auditory impairments.
  • Current or past learning disability.
  • Large head size (>59 cm in circumference).
  • Pregnancy
  • Contraindications for MRI (pacemaker, metal implants, etc.).
  • Allergy to the ingredients in the administered drug.
  • Abnormal ECG (e.g. prolonged QT syndrome, etc.)
  • Dizzy when changing from supine to upright position (e.g. postural orthostatic tachycardia syndrome).
  • Mild hypotension (blood pressure below 100/70 mmHg)
  • Hypertension (blood pressure above 140/90 mmHg).

Trial locations and contacts

1 site in 1 country.

Denmark1 site
  • Neurobiology Research Unit, Rigshospitalet

    Copenhagen, 2100

Other trials in Denmark

About this study

The project is aimed at identifying how the adrenergic antagonist 'carvedilol' modulates the effects of sleep deprivation in healthy volunteers. The study is a double-blind, randomized, placebo-controlled, cross-over study. Investigators will include 20 healthy volunteers who will undergo three functional magnetic resonance (fMRI) imaging sessions, one at baseline, and two after sleep deprivation (one night without sleep). The two sleep-deprivation scans are performed in a randomized order where subjects receive placebo or carvedilol, in a within-subject, cross-over study design.

The following domains will be described: 1) fMRI imaging of cerebrospinal fluid (CSF) pulsations (glymphatic flow) in the human brain, performed by a combination of fMRI protocols that includes structural (T1, T2, diffusion weighted) and functional (multiband/fast imaging, spectroscopy) imaging. 2) fMRI imaging during wakefulness and sleep are determined by simultaneous electroencephalographic (EEG) recordings. 3) The effects of sleep deprivation on the fMRI derived glymphatic flow signal. 4) The effects of the adrenergic antagonist carvedilol on fMRI measurements and sleep intensity. 5) Quantification of cognitive performance before and after a nap in the MRI. Cognitive testing includes: assessments of visual attention, reaction time, paired-associative memory, working memory, emotional recognition and subjective ratings of sleepiness and mood.

Read the detailed description

Aims and background:

Sleep is a universal biological process. Lack of, or insufficient sleep, has been associated with a range of diseases including obesity, cardiovascular disease, reduced cognition, impaired learning, and increased risk of motor vehicle accidents. Sleep is also associated with neuromolecular alterations in the brain, including reduced firing of arousal maintaining epinephrine and norepinephrine neurons.

A novel molecular function of sleep known as the glymphatic system has recently been described in rodents. This system is specifically activated during non-rapid eye movement (NREM) sleep, and glymphatic flow appear strongly enhanced during sleep when compared to wakefulness. Moreover, it has been shown that adrenergic antagonists enhance glymphatic clearance and flow in rodents. This study aims at applying newly developed functional magnetic resonance imaging (fMRI) protocols to investigate the extent of the glymphatic system non-invasively in humans.

In order for us to quantify the change in glymphatic clearance between sleep and wakefulness, it is necessary to measure the glymphatic process in both vigilance states, requiring that volunteers nap in the MRI scanner. Moreover, to clarify causal relationships, this study will challenge the glymphatic system via adrenergic inhibition. To do so, the investigators will administer the adrenergic antagonist Carvedilol, which can cross the blood-brain barrier. The drug will be perorally administered before a nap in the MRI, in a double blind, placebo controlled manner. To assess sleep quality and function, cognitive testing will be performed before and after the nap in the MRI scanner. Moreover, to distinguish sleep and wakefulness, electroencephalographic (EEG) recordings will be performed during magnetic resonance (MR)-imaging. Because sleep is a strong homeostatic regulated process, sleep quality, duration and timing will be controlled by EEG monitoring, immediately prior to and during the study to ensure that data is intra- and inter-individually comparable.

Hypotheses:

Investigators hypothesis that the fMRI data collected awake and during a nap will be altered by the adrenergic treatment. Specifically, investigator propose the following hypotheses: 1. Sleep promotes cerebrospinal fluid pulsations (glymphatic flow) in the human brain, as measured with fMRI. 2. Challenging the sleep-homeostat by sleep deprivation promotes the fMRI glymphatic flow signal further. 3. The rate of glymphatic flow is expected to be proportional to simultaneously measured non-rapid eye movement EEG slow wave activity. 4: The adrenergic antagonist carvedilol will enhance glymphatic clearance and sleep intensity. 5. The fMRI determined glymphatic flow is associated with improved cognitive performance following sleep. 6. Enhanced glymphatic flow is correlated with enhanced cognitive performance, including: assessments of visual attention, reaction time, paired-associative memory, working memory, emotional recognition and subjective ratings of sleepiness and mood.

Being tested
Carvedilol 25mg, Placebo oral capsule
Keywords
carvedilol, adrenergic antagonists, glymphatic system, volunteers, Molecular Mechanisms of Pharmacological
Medical subject headings
Sleep Deprivation, Sleep Wake Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Carvedilol 25mgDrug

    Also called Coreg

    Cross-over, randomized, placebo-controlled study.

  • Placebo oral capsuleDrug

    Cross-over, randomized, placebo-controlled study.

Study groups in NCT03576664
Study groupRoleWhat they receive
Carvedilol firstExperimentalCarvedilol (25 mg) followed by Placebo oral capsule is administered in a crossover manner.
Receives: Drug: Carvedilol 25mg; Drug: Placebo oral capsule
Placebo firstExperimentalPlacebo oral capsule followed by Carvedilol (25 mg) is administered in a crossover manner.
Receives: Drug: Carvedilol 25mg; Drug: Placebo oral capsule

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Measure the change in functional Magnetic Resonance Imaging (fMRI)-detected glymphatic flow in wakefulness and sleep at baseline

    Measured: Baseline compared to baseline - within same 1 day

  2. Measure and compare functional Magnetic Resonance Imaging (fMRI)-detected glymphatic flow in baseline sleep and in sleep-deprived sleep

    Measured: Baseline to follow-up 5±3 days

  3. Measure and compare fMRI-detected glymphatic flow in placebo and carvedilol condition

    Measured: Placebo compared to treatment 5±3 days apart.

  4. Correlate fMRI-detected glymphatic flow with simultaneous detected EEG sleep slow wave activity

    Measured: Nocturnal sleep compared to sleep during Magnetic Resonance scans within same 1 day.

  5. Measure EEG slow wave activity during Magnetic Resonance imaging and compare Carvedilol with placebo to see how sleep is affected by the treatment

    Measured: Placebo compared to treatment 5±3 days apart.

  6. Measure if fMRI-detected glymphatic flow correlates with subjective sleepiness ratings

    Measured: Measurements collected within the same 1 day

  7. Measure fMRI-detected glymphatic flow and whether it correlates with cognitive performance before and after MR imaging

    Measured: Measurements collected within the same 1 day

  8. Measure fMRI-detected glymphatic flow and whether correlates with changes in cognitive performance from before to after MR imaging

    Measured: Measurements collected within the same 1 day

  9. Measure whether Carvedilol improves sleepiness after the MR scan compared to placebo

    Measured: Measurements collected within the same 1 day

  10. Measure whether Carvedilol improves cognitive performance (measurement: psychomotor vigilance test) after the MR scan compared to placebo

    Measured: Measurements collected within the same 1 day

Secondary outcomes (9)
  1. Measure whether fMRI-detected glymphatic flow is spatially correlated with simultaneous EEG NREM slow wave activity

    Measured: Measurements collected within the same 1 day

  2. Measure whether fMRI-detected glymphatic flow correlates with simultaneous NREM EEG activity

    Measured: Measurements collected within the same 1 day

  3. Measure whether fMRI-detected glymphatic flow is positively correlated with sleep driven structural changes in T2 and diffusion weighted (DWI) images

    Measured: Measurements collected within the same 1 day

  4. Measure whether Carvedilol modulates nocturnal recovery sleep (measurement: EEG slow wave activity) after sleep deprivation

    Measured: Baseline to follow-up 5±3 days

  5. Measure whether the psychomotor vigilance test is modulated by carvedilol

    Measured: Placebo compared to treatment 5±3 days apart.

  6. Measure whether the visual attention (measurement: Theory of Visual Attention task) is modulated by carvedilol

    Measured: Placebo compared to treatment 5±3 days apart.

  7. Measure whether the visual attention (measurement: Theory of Visual Attention task) is modulated by sleep-deprivation

    Measured: Baseline to follow-up 5±3 days

  8. Measure whether emotional memory performance (measurement: emotional word pair task) is modulated by carvedilol

    Measured: Placebo compared to treatment 5±3 days apart.

  9. Measure whether emotional memory performance (measurement: emotional word pair task) is modulated by sleep-deprivation

    Measured: Baseline to follow-up 5±3 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jul 2018
  2. Study start28 Aug 2018
  3. Primary completion1 Sep 2019
  4. Study completion1 Oct 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Model description
Randomized, cross-over, placebo-controlled study
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
22 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03576664
Sponsor's protocol ID
sleepgf
Other IDs
H-16045933
Status last verified
Nov 2022
First submitted
8 Mar 2018
Last updated
23 Nov 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage). Data will be available for neuroscience research community contingent on approval by scientific board.

Publications

  • Ulv Larsen SM, Holst SC, Olsen AS, Ozenne B, Zilstorff DB, Brendstrup-Brix K, Weikop P, Pleinert S, Kiviniemi V, Jennum PJ, Nedergaard M, Knudsen GM. Sleep deprivation and sleep intensity exert distinct effects on cerebral vasomotion and brain pulsations driven by the respiratory and cardiac cycles. PLoS Biol. 2025 Nov 20;23(11):e3003500. doi: 10.1371/journal.pbio.3003500. eCollection 2025 Nov.

    PubMed 41264592

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Carvedilol 25mg in people with Sleep Deprivation and Sleep Wake Disorders, run by Gitte Moos Knudsen at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Measure the change in functional Magnetic Resonance Imaging (fMRI)-detected glymphatic flow in wakefulness and sleep at baseline (time frame: Baseline compared to baseline - within same 1 day). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03576664, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Nov 2022.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in