Metabolomics-based Sleepiness Markers

Study Overview
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Brief Summary
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Estimating that people sleep on average up to two hours less over the last decades, sleepiness and fatigue need to be considered as significant societal problems of the modern world. Jurisdiction is precise on how to deal with overtired offenders since they were not allowed to use machines or vehicles in the first place, similar to drunk individuals or consumers of illicit drugs. In contrast to alcohol or illicit drug use, however, there are no quick roadside or workplace tests as objective (analytical) biomarkers for sleepiness. Investigators hypothesize that increasing sleep drive or impaired wakefulness can be assessed by qualitative or quantitative fluctuations of certain metabolites in biological specimens, e.g., accumulation or decrease of endogenous substances related to sleep debt. Thus, this sleep study provides the necessary biological samples of either sleep-deprived, sleep-restricted, or control subjects, which are then analysed for appropriate metabolite biomarkers utilizing an untargeted metabolomics approach. In addition to established impairment tests, a state of the art driving simulator will be employed to objectively measure driving performance under all study conditions. Participants will also rate their subjective sleepiness using validated questionnaires.

Official Title
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Study of Identification of Metabolomics-based Sleepiness Markers for Risk Prevention and Traffic Safety

Conditions
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Sleep Deprivation, Sleepiness, Insufficient Sleep Syndrome

Intervention / Treatment
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* Behavioral: Sleep deprivation
* Behavioral: Sleep restriction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: understanding and spoken command of German language good health condition Body Mass Index between 18.5-24.9 kg/m2 habitual average sleep duration between 7-9 hours / night habitual consumption of 3 or fewer caffeinated beverages / day habitual consumption of 5 or fewer alcoholic beverages / week good sleep quality: Pittsburgh Sleep Quality Index score ≤ 5 reasonable oral hygiene (≥1 tooth brushing / day) normal or corrected-to-normal vision car driving license holder since at least 2 years (obtained in a country with right hand traffic) and regular driver (≥ 1 per week) Exclusion Criteria: two or more time zone crossings in the last 3 months habitual napper history or presence of neurological disorder, psychiatric disorder, cardiovascular disorder, dental disorder or any disorder that could pose a risk in participating or that could possibly influence study measurements history or presence of a sleep disorder (screening night) use of illicit drugs (urinary drug screening) use of current medication (urinary drug screening) known to influence study measurements extreme chronotype (reduced Morningness-Eveningness-Questionnaire score ≤7 or ≥22) current smoker habitual use of energy drinks (>1 / week) severe skin allergies or hypersensitivities food allergies hospital stay in past 6 months shift worker, night worker recent past (last 3 months) or present Covid-19 infection fainting at the sight of blood or needles participation in a clinical study less than 30 days ago or is currently participating in other clinical studies simulator sickness syndrome refusal to sign informed consent

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>16/8 hours wake/sleep regime for 3 consecutive days at home and for consecutive 2 days in sleep laboratory | |
| Experimental: Sleep restriction<br>18/6 hours wake/sleep regime for 3 consecutive days at home and one day in sleep laboratory, followed by recovery night of 8 hours sleep | Behavioral: Sleep restriction<br>* Total sleep deficit of cumulative 8 hours<br>|
| Experimental: Sleep deprivation<br>16/8 hours wake/sleep regime for 3 consecutive days at home, one night of sleep deprivation (24/0 hours) in sleep laboratory, followed by recovery night of 8 hours sleep | Behavioral: Sleep deprivation<br>* Total sleep deficit of consecutive 8 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in metabolite concentrations in oral fluid quantified by liquid chromatography with mass spectrometry | Investigators will collect oral fluid samples from participants for quantification of all detectable metabolites. Investigators will analyze which metabolite concentration values undergo significant changes during sleep deficit conditions in comparison to control condition and also show effects of recovery sleep. These will serve as candidate biomarkers. | After arrival at study site (6pm, baseline), repeatedly during scheduled wakefulness (8am, 12pm, 4pm, 7pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Driving performance | Investigators will gather driving simulation results via Standardized Application for Fitness to Drive Evaluations (S.A.F.E. scale), and analyze their changes after sleep deficit in comparison to control condition. This scale has a range from 0 (best) to 10 (worst) in full steps. | morning after experimental night (10am) | 
| Psychomotor Vigilance Test | The Psychomotor Vigilance Test is a gold standard reaction time test to assess vigilance and sustained attention. | After arrival at study site (6pm, baseline), repeatedly during scheduled wakefulness (8am, 12pm, 4pm, 7pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 
| d2 Test of Attention | The d2 Test of Attention is a paper and pencil test to assess selective and sustained attention and visual scanning speed. | After arrival at study site (6pm, baseline), repeatedly during scheduled wakefulness (8am, 12pm, 4pm, 7pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 
| Visual attention test | The visual attention test is a virtual reality glasses test to assess visual skills in a complex visual environment. | After arrival at study site (8pm, baseline), repeatedly during scheduled wakefulness (10am, 2pm, 6pm, 8pm), and morning after recovery night of 8 hours of sleep (8am) | 
| Subjective situational sleepiness | Participants will complete the Karolinska Sleepiness Scale questionnaire. | After arrival at study site (6pm, baseline), repeatedly during scheduled wakefulness (8am, 12pm, 4pm, 7pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 
| Subjective sleepiness | Participants will complete the Stanford Sleepiness Scale questionnaire. | After arrival at study site (6pm, baseline), repeatedly during scheduled wakefulness (8am, 12pm, 4pm, 7pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 
| Electroencephalographic changes | Investigators will analyze changes in sleep and wake electroencephalographic patterns of participants by calculating sleep scores according to American Academy of Sleep Medicine (AASM) scoring manual. | During scheduled sleep, driving simulation test (10am), and at two time points during scheduled wakefulness (12pm, 7pm) | 
| Behavioral markers of drowsy driving | Investigators will examine participants after driving simulation test for behavioral abnormalities concerning orientation, coordination, speech, mood, appearance, reaction, and pupillary light reflex. | Once per study arm after driving simulation test (11am) | 
| Changes in metabolite concentrations in exhaled breath quantified by liquid chromatography with mass spectrometry | Investigators will collect exhaled breath samples from participants for quantification of all detectable metabolites. Investigators will analyze which metabolite concentration values undergo significant changes during sleep deficit conditions in comparison to control condition and also show effects of recovery sleep. These will serve as secondary candidate biomarkers. | After arrival at study site (8pm, baseline), repeatedly during scheduled wakefulness (10am, 2pm, 6pm, 8pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 
| Changes in metabolite concentrations in finger sweat quantified by liquid chromatography with mass spectrometry | Investigators will collect finger sweat samples from participants for quantification of all detectable metabolites. Investigators will analyze which metabolite concentration values undergo significant changes during sleep deficit conditions in comparison to control condition and also show effects of recovery sleep. These will serve as secondary candidate biomarkers. | After arrival at study site (8pm, baseline), repeatedly during scheduled wakefulness (10am, 2pm, 6pm, 8pm, 11pm), and morning after recovery night of 8 hours of sleep (8am) | 
| Correlation of metabolic changes between blood and non-invasive specimens | Investigators will compare metabolite concentrations in non-invasive matrices (oral fluid, finger sweat, exhaled breath, and dried blood spots) and compare those with blood sample. | immediately after driving simulation test (11am) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metabolomics, sleep, biomarker, impairment