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

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

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.

Study Overview

• Status: Completed
• Conditions: Caffeine; Placebo; Sleep Inertia
• Intervention / Treatment: Dietary supplement: Caffeine; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Zürich, Switzerland, 8057
    • University of Zurich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 34 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Caffeine; 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; 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.
Placebo Comparator: Placebo; 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; Identical hydroxypropylmethylcellulose capsules without containing caffeine micropellets.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: Lokman Hekim Üniversitesi; Elixir Pharmaceuticals

Publications and helpful links

General Publications

• Dornbierer DA, Yerlikaya F, Wespi R, Boxler MI, Voegel CD, Schnider L, Arslan A, Baur DM, Baumgartner MR, Binz TM, Kraemer T, Landolt HP. A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening. Sci Rep. 2021 Oct 5;11(1):19734. doi: 10.1038/s41598-021-98376-z.

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2019
• Primary Completion (Actual): August 30, 2019
• Study Completion (Actual): August 30, 2019

Study Registration Dates

• First Submitted: February 3, 2021
• First Submitted That Met QC Criteria: July 13, 2021
• First Posted (Actual): July 23, 2021

Study Record Updates

• Last Update Posted (Actual): July 29, 2021
• Last Update Submitted That Met QC Criteria: July 22, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Sleep restriction; Proactive countermeasure
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Caffeine
• Other Study ID Numbers: Caff-Clock

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No