An Early Phase 1 interventional study of Carvedilol 25mg and Placebo oral capsule in Sleep Deprivation, Sleep Wake Disorders and Sleep, sponsored by Gitte Moos Knudsen. Completed at 1 site in Denmark. Open to participants aged 18 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-11-23.
Sponsored by Gitte Moos Knudsen · Early Phase 1, Interventional, and Basic science
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.
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.
309 studies on the registry are indexed under Sleep Deprivation; 62 are open to participants now.
This study's enrollment of 22 is below the median of 44 across 253 interventional studies indexed under Sleep Deprivation.
Browse Sleep Deprivation studies →Gitte Moos Knudsen is the lead sponsor of 8 studies on the registry; 2 are open to participants now.
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Exclusion Criteria:
Carvedilol (25 mg) followed by Placebo oral capsule is administered in a crossover manner.
Drug: Carvedilol 25mg · Drug: Placebo oral capsule
Placebo oral capsule followed by Carvedilol (25 mg) is administered in a crossover manner.
Drug: Carvedilol 25mg · Drug: Placebo oral capsule
Cross-over, randomized, placebo-controlled study.
Also known as: Coreg
Cross-over, randomized, placebo-controlled study.
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
Measure and compare functional Magnetic Resonance Imaging (fMRI)-detected glymphatic flow in baseline sleep and in sleep-deprived sleep
Time frame: Baseline to follow-up 5±3 days
Measure and compare fMRI-detected glymphatic flow in placebo and carvedilol condition
Time frame: Placebo compared to treatment 5±3 days apart.
Correlate fMRI-detected glymphatic flow with simultaneous detected EEG sleep slow wave activity
Time frame: Nocturnal sleep compared to sleep during Magnetic Resonance scans within same 1 day.
Measure EEG slow wave activity during Magnetic Resonance imaging and compare Carvedilol with placebo to see how sleep is affected by the treatment
Time frame: Placebo compared to treatment 5±3 days apart.
Measure if fMRI-detected glymphatic flow correlates with subjective sleepiness ratings
Time frame: Measurements collected within the same 1 day
Measure fMRI-detected glymphatic flow and whether it correlates with cognitive performance before and after MR imaging
Time frame: Measurements collected within the same 1 day
Measure fMRI-detected glymphatic flow and whether correlates with changes in cognitive performance from before to after MR imaging
Time frame: Measurements collected within the same 1 day
Measure whether Carvedilol improves sleepiness after the MR scan compared to placebo
Time frame: Measurements collected within the same 1 day
Measure whether Carvedilol improves cognitive performance (measurement: psychomotor vigilance test) after the MR scan compared to placebo
Time frame: Measurements collected within the same 1 day
Measure whether fMRI-detected glymphatic flow is spatially correlated with simultaneous EEG NREM slow wave activity
Time frame: Measurements collected within the same 1 day
Measure whether fMRI-detected glymphatic flow correlates with simultaneous NREM EEG activity
Time frame: Measurements collected within the same 1 day
Measure whether fMRI-detected glymphatic flow is positively correlated with sleep driven structural changes in T2 and diffusion weighted (DWI) images
Time frame: Measurements collected within the same 1 day
Measure whether Carvedilol modulates nocturnal recovery sleep (measurement: EEG slow wave activity) after sleep deprivation
Time frame: Baseline to follow-up 5±3 days
Measure whether the psychomotor vigilance test is modulated by carvedilol
Time frame: Placebo compared to treatment 5±3 days apart.
Measure whether the visual attention (measurement: Theory of Visual Attention task) is modulated by carvedilol
Time frame: Placebo compared to treatment 5±3 days apart.
Measure whether the visual attention (measurement: Theory of Visual Attention task) is modulated by sleep-deprivation
Time frame: Baseline to follow-up 5±3 days
Measure whether emotional memory performance (measurement: emotional word pair task) is modulated by carvedilol
Time frame: Placebo compared to treatment 5±3 days apart.
Measure whether emotional memory performance (measurement: emotional word pair task) is modulated by sleep-deprivation
Time frame: Baseline to follow-up 5±3 days
Plan to share: 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.
Supporting information: Study protocol
Time frame: Data will be made available upon data-analyses completion, about year: 2020.
Access criteria: Data can be accessed via website or by contacting the NRU lab. Mainly research teams in Europe are granted access.
Data sharing details ↗ · cimbi.dk
This study is completed, as verified in Nov 2022. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Carvedilol
Gitte Moos Knudsen