Delayed-release Bedtime Caffeine and Sleep Inertia Symptoms Immediately Upon Awakening

Study Overview
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Brief Summary
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Sleep inertia (sometimes also referred to as sleep drunkenness) is a disabling state of increased sleepiness, impaired mood and reduced vigilance immediately upon awakening. Sleep inertia is highly prevalent in various neurological diseases, including neurodegenerative, affective and circadian sleep-wake rhythms disorders, as well as in frequent societal conditions such as chronic sleep restriction, jetlag and shiftwork. Reactive countermeasures against sleep inertia, i.e., strategies implemented upon wake-up, are not sufficiently effective, yet current recommendations are limited to proactive strategies, including long enough sleep at optimal times of day. These recommendations are not always easy and sometimes impossible to apply. To address this unmet medical need, the investigators developed an innovative, time-controlled, pulsatile-release formulation of 160 mg caffeine targeting an efficacious dose briefly before planned awakening.

Detailed Description
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Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, the investigators developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. The investigators comprehensively test this formulation in two placebo-controlled, double-blind, cross-over studies. First, the investigators establish the in vivo caffeine release profile in young men. Subsequently, they investigate the formulation's ability to improve sleep inertia in sleep-restricted volunteers. Following oral administration of 160 mg caffeine at habitual bedtime [22:30], the investigators keep the participants awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening [at 07:00]. Immediately upon awakening, the investigators quantify subjective state, psychomotor vigilance, cognitive performance, and the cortisol awakening response. They also record polysomnography during nocturnal sleep and a 1-hour nap opportunity at 08:00.

Official Title
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Effects of a Time-delayed, Pulsatile Caffeine Formula on Sleep Inertia, Morning Cognition, Affect and Sleepiness in Healthy Volunteers

Conditions
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Sleep Inertia, Caffeine, Placebo

Intervention / Treatment
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* Dietary Supplement: Caffeine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male sex in order to avoid the potential impact of menstrual cycle on sleep physiology or HPA axis activity, age within the range of 18 to 34 years, a body-mass-index below 25, an Epworth Sleepiness Score (ESS) below 10, habitual sleep onset latency below 20 minutes, regular sleep-wake rhythm with bedtime between 11 pm and 1 am, absence of any somatic or psychiatric disorders, no acute or chronic medication intake, non-smoking, no history of drug abuse (lifetime use > 5 occasions, except occasional cannabis use) caffeine consumption of less than 4 units per day (coffee, tea, chocolate, cola, energy drinks) Exclusion Criteria: - Failure to meet inclusion criteria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 34 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
Interventional Model Description: A randomized, double-blind, placebo controlled, cross-over design.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Caffeine<br>Administration of a time-controlled, pulsatile-release caffeine formulation (160 mg caffeine) at 22:30. Participants are kept awake until 03:00 and then given a 4-hour sleep opportunity. | Dietary Supplement: Caffeine<br>* The 160 mg caffeine pulsatile-release formulation was manufactured using a drug layering process. Caffeine and the excipients are dispersed in the coating media and then sprayed onto inert microcrystalline cellulose spheres using a fluid bed through a Wurster tube with continuous inlet air that dries the liquid in the dispersion, to obtain various layers consisting of caffeine and release-controlling polymers. The applied release-controlling polymeric system is based on methacrylate copolymers, which control the release of caffeine in pH-dependent and pH-independent manner. The release mechanism of the polymeric system is mainly driven by the swellability and permeability of the copolymers. The final micropellets are then encapsulated into hydroxypropylmethylcellulose capsules.<br>|
| Placebo Comparator: Placebo<br>Administration of a placebo formulation at 22:30. Participants are kept awake until 03:00 and then given a 4-hour sleep opportunity. | Other: Placebo<br>* Identical hydroxypropylmethylcellulose capsules without containing caffeine micropellets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Sleep Inertia Questionnaire | Modified questionnaire to assess subjective ratings of sleep inertia on physiological, emotional, cognitive and behavioral levels. | At 07:00 hours after caffeine and placebo administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polysomnographic recording of nocturnal sleep | All-night polysomnographic recordings of nocturnal sleep: electrical bio-signals include simultaneous, standardized recordings of brain waves (electroencephalogram), muscle tone on the chin (electromyogram), and slow and rapid eye movements (electrooculogram). The information will be aggregated for visual scoring of sleep stages according to standardized criteria specified by the American Academy of Sleep Medicine. | Between 03:00-07:00 hours after caffeine and placebo administration | 
| Caffeine Effects Questionnaire | Acute questionnaire to assess caffeine-related subjective effects. | Between 07:15-08:00 hours after caffeine and placebo administration | 
| Positive and Negative Affect Schedule | Questionnaire | Between 07:00-08:15 hours after caffeine and placebo administration | 
| Psychomotor vigilance task | Reaction-time task | Between 07:15-07:30 hours after caffeine and placebo administration | 
| N-back task | Working memory and brain executive function task | Between 07:30-07:40 hours after caffeine and placebo administration | 
| d2 attention task | Focused attention task | Between 07:40-07:45 hours after caffeine and placebo administration | 
| Cortisol awakening response | Physiological awakening response to address HPA-axis function | Between 07:00-08:00 hours after caffeine and placebo administration | 
| Polysomnographic recording of morning nap opportunity | Polysomnographic recordings of sleep during one-hour nap opportunity: electrical bio-signals include simultaneous, standardized recordings of brain waves (electroencephalogram), muscle tone on the chin (electromyogram), and slow and rapid eye movements (electrooculogram). The information will be aggregated for visual scoring of sleep stages according to standardized criteria specified by the American Academy of Sleep Medicine. | Between 08:00-09:00 hours after caffeine and placebo administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep restriction, Proactive countermeasure