Optimized Caffeine for Sleep Deprivation

(2B-2 Trial)

Recruiting at 1 trial location

Overseen By William D Killgore, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Arizona

Must not be taking: Sleep aids, Psychiatric meds, Illicit drugs, others

Disqualifiers: Sleep disorders, Neurologic disorders, Cardiovascular disease, others

Compensation: Varies

Number of Visits: 2

180 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you use products or drugs that cannot be safely discontinued during the in-laboratory phases, you may be excluded from participating. This will be determined on a case-by-case basis by the examining study physician.

What data supports the idea that Optimized Caffeine for Sleep Deprivation is an effective drug?

The available research shows that Optimized Caffeine for Sleep Deprivation, such as a novel pulsatile-release caffeine formula, can effectively improve alertness and reduce grogginess after waking up. In one study, this formula improved reaction times, mood, and reduced sleep inertia symptoms in sleep-restricted volunteers. Another study demonstrated that a caffeine optimization tool could enhance performance by up to 64% while using the same amount of caffeine, or maintain performance with up to 65% less caffeine. These findings suggest that optimized caffeine dosing can be an effective way to manage sleep deprivation. ^{1 2 3 4 5}

What safety data is available for caffeine treatments?

The safety data for caffeine treatments includes studies on the pharmacokinetics of caffeine administered in chewing gum, which examined multiple doses in healthy volunteers. Additionally, research has evaluated the absorption and bioavailability of caffeine in gum versus capsules. Caffeine citrate has been studied for stability in intravenous solutions. An optimization algorithm for caffeine dosing to enhance alertness during sleep loss has been developed, showing improved performance with reduced caffeine consumption. Pharmacokinetics in food-limited rats have also been studied, highlighting differences in caffeine metabolism under various conditions. ^{2 4 6 7 8}

Is the drug Caffeine Gum, Personalized Caffeine Dosing Regimen, Standard Caffeine Dosing Regimen a promising treatment for sleep deprivation?

Yes, this drug is promising for sleep deprivation. It can improve alertness and performance during sleep loss by optimizing caffeine intake. The personalized dosing regimen can enhance performance by up to 64% or reduce caffeine consumption by up to 65% while maintaining effectiveness. Additionally, a novel caffeine formula can help reduce grogginess upon waking, making it easier to transition from sleep to being awake. ^{1 2 3 4 9}

What is the purpose of this trial?

This clinical trial will be a comparison between personalized recommended caffeine dosing regimen versus the standard recommended caffeine dosing regimen for sustaining performance during sleep deprivation and minimizing side effects and subsequent sleep disruption. The questions this study aims to answer are: Whether the personalized caffeine recommendations improve vigilance, sleepiness, and cognition after total sleep deprivation, compared to standard recommendations; Whether the personalized caffeine recommendation better addresses the physical and emotional side effects of total sleep deprivation, compared to standard recommendations; And whether personalized caffeine recommendations aids in better recovery sleep after total sleep deprivation, compared to standard recommendations. Participants will be asked to: 1. Complete a 13-day at-home portion, wearing an actigraph watch to measure activity and sleep, and complete motor vigilance tests up to six times a day. 2. Complete a 4-day in-lab portion, where participants will have to complete one night of baseline sleep, undergo 62-hours of total sleep deprivation, and then complete one night of recovery sleep. 3. During the in-lab portion of the study, participants will be asked to complete more motor vigilance tests. Researchers will be comparing the personalized caffeine recommendation group against the standard caffeine recommendation to see if it is better at addressing each of the main questions.

Eligibility Criteria

This trial is for individuals aged 18-39 who understand the study protocol, as shown by scoring at least 80% on a quiz. It's designed for those experiencing sleep deprivation and will test if personalized caffeine dosing can improve alertness, mood, cognition during wakefulness, and enhance recovery sleep.

Inclusion Criteria

Must demonstrate adequate comprehension of the protocol by achieving a score of at least 80% correct on a short multiple-choice quiz

Exclusion Criteria

Self-reported morning wake-up times later than approximately 0900 on average during weekdays (Monday through Friday)

Score of 41 or above on the Spielberger Trait Anxiety Inventory (STAI-T)

I have kidney disease or abnormalities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

At-home Testing

Participants complete a 13-day at-home portion, wearing an actigraph watch to measure activity and sleep, and complete motor vigilance tests up to six times a day.

13 days

In-lab Sleep Deprivation

Participants complete a 4-day in-lab portion, including one night of baseline sleep, 62 hours of total sleep deprivation, and one night of recovery sleep. Caffeine or placebo gum is administered during sleep deprivation.

4 days

Continuous in-lab stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including further psychomotor vigilance testing.

1 day

1 visit (in-person)

Treatment Details

Interventions

• Caffeine Gum
• Personalized Caffeine Dosing Regimen
• Placebo Gum
• Standard Caffeine Dosing Regimen

Trial Overview Participants will compare two caffeine dosing regimens: one tailored to their personal needs (using caffeine gum) versus a standard dose (placebo gum). They'll track sleep with an actigraph watch at home and undergo tests in-lab after staying awake for over two days.

Participant Groups

Group I: Standard Caffeine Dose Both Nights Active Control 2 Interventions

Participants will be administer the standard caffeine recommendation (200mg/2 hr. up to 800mg/24 hr.) using caffeinated and non-caffeinated gum during both nights of Phase 2.

Group II: Optimized Caffeine Dose Both Nights Active Control 2 Interventions

Participants will be administer the optimized caffeine recommendation (0-300mg/2 hr. up to 800mg/24 hr.) potentially using caffeinated and non-caffeinated gum, depending on optimized dosage, during both nights of Phase 2.

Group III: Placebo Dose 1st Night/Standard Caffeine Dose 2nd Night Active Control 2 Interventions

Participants will be administer non-caffeinated, placebo gum during the first night of Phase 2. Then, participants will be administer the standard caffeine recommendation (200mg/2 hr. up to 800mg/24 hr.) using caffeinated and non-caffeinated gum during the second night of Phase 2.

Group IV: Placebo Dose 1st Night/Optimized Caffeine Dose 2nd Night Active Control 2 Interventions

Participants will be administer non-caffeinated, placebo gum during the first night of Phase 2. Then, participants will be administer the optimized caffeine recommendation (0-300mg/2 hr. up to 800mg/24 hr.) potentially using caffeinated and non-caffeinated gum, depending on optimized dosage, during the second night of Phase 2.

Group V: Placebo Dose Both Nights Placebo Group 1 Intervention

Participants will be administer non-caffeinated, placebo gum during both nights of Phase 2.

Caffeine Gum is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Caffeine for:

• Fatigue
• Sleep deprivation
• Alertness

Approved in European Union as Caffeine for:

• Fatigue
• Sleep deprivation
• Alertness

Approved in Canada as Caffeine for:

• Fatigue
• Sleep deprivation
• Alertness

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

Biotechnology High Performance Computing Software Applications Institute

Collaborator

Trials

3

Recruited

210+

U.S. Army Medical Research Acquisition Activity

Collaborator

Trials

26

Recruited

10,500+

Findings from Research

A new pulsatile-release caffeine formulation was tested in 22 sleep-restricted volunteers and showed significant improvements in reducing sleep inertia symptoms upon awakening, including faster reaction times and better mood.

This innovative caffeine delivery method, taken before planned awakening, effectively enhances the transition from sleep to wakefulness, suggesting it could be beneficial for individuals experiencing severe grogginess after waking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening. Dornbierer, DA., Yerlikaya, F., Wespi, R., et al.[2023]

A study involving 48 healthy participants showed that Stay Alert chewing gum effectively delivers caffeine in a dose-dependent manner, with higher doses resulting in higher plasma caffeine levels.

The pharmacokinetics of caffeine from the gum demonstrated linearity across multiple doses, indicating that it can be a reliable method for maintaining alertness in sleep-deprived individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple dose pharmacokinetics of caffeine administered in chewing gum to normal healthy volunteers. Syed, SA., Kamimori, GH., Kelly, W., et al.[2013]

A study involving 24 healthy volunteers showed that 300 mg of slow-release caffeine significantly improved vigilance and performance during periods of sleep deprivation, lasting up to 13 hours after intake.

The research indicated that while both 300 mg and 600 mg doses were effective, the 300 mg dose was optimal for maximizing benefits without side effects, and there was no difference in performance during recovery after sleep.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slow-release caffeine: a new response to the effects of a limited sleep deprivation. Lagarde, D., Batéjat, D., Sicard, B., et al.[2015]

A new optimization algorithm has been developed to guide caffeine consumption, helping individuals maximize their neurobehavioural performance during sleep loss, based on a validated model of performance.

Simulations showed that this algorithm could enhance performance by up to 64% using the same caffeine amount as in previous studies, or maintain performance while reducing caffeine intake by up to 65%, promoting safer consumption practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caffeine dosing strategies to optimize alertness during sleep loss. Vital-Lopez, FG., Ramakrishnan, S., Doty, TJ., et al.[2019]

Sustained-release CaffXtend® capsules (SR-Caffeine) provide a longer duration of caffeine release, with a mean time to peak concentration (tmax) of 4.08 hours compared to just 0.83 hours for immediate-release caffeine (IR-Caffeine), indicating a more gradual absorption.

Participants taking SR-Caffeine reported significantly better mood and alertness, along with lower feelings of jitteriness and tiredness over an 8-12 hour period, with no adverse events reported, suggesting it may be a safer and more effective option for sustained cognitive enhancement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Bioavailability and Benefits on Mental Functions of Novel Extended-Release Caffeine Capsules against Immediate-Release Caffeine Capsules: An Open-Label, Randomized, Cross-over, Single-Dose Two-Way Crossover Study. Thanawala, S., Shah, R., Abiraamasundari, R., et al.[2023]

Caffeine from Stay Alert chewing gum is absorbed significantly faster than from capsules, with peak absorption times (Tmax) ranging from 44.2 to 80.4 minutes for gum compared to 84.0 to 120.0 minutes for capsules, indicating a quicker onset of effects.

Both the gum and capsule formulations provide similar amounts of caffeine to the bloodstream, but the gum's faster absorption may be beneficial for quickly improving alertness and performance after sleep loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Kamimori, GH., Karyekar, CS., Otterstetter, R., et al.[2019]

Caffeine citrate injection remains stable in various intravenous admixtures and parenteral nutrition solutions when stored at room temperature for up to 24 hours.

This stability suggests that caffeine citrate can be safely used in clinical settings without concerns of degradation during this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of caffeine citrate injection in intravenous admixtures and parenteral nutrition solutions. Nahata, MC., Zingarelli, J., Durrell, DE.[2019]

In food-limited rats, caffeine showed a proportional relationship between dose and serum levels, indicating predictable pharmacokinetics for caffeine itself, while its metabolites displayed disproportionality, suggesting complex metabolism.

Chronic administration of caffeine led to steady-state concentrations by day 11, with differences in clearance and volume of distribution between administration routes, highlighting the importance of understanding caffeine's pharmacokinetics for its effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral and IP caffeine pharmacokinetics under a chronic food-limitation condition. Lau, CE., Ma, F., Falk, JL.[2019]

The Evodia rutaecarpa aqueous extract (ERAE) and its main component, evodiamine, effectively reduce caffeine-induced sleep disturbances and excitatory effects in mice, as shown through various behavioral tests.

Evodiamine appears to work by reversing the reduction of GABAA receptor subunits caused by caffeine, suggesting a mechanism that involves the GABAergic system, making it a promising candidate for mitigating caffeine's adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evodiamine Reduces Caffeine-Induced Sleep Disturbances and Excitation in Mice. Ko, YH., Shim, KY., Lee, SY., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Multiple dose pharmacokinetics of caffeine administered in chewing gum to normal healthy volunteers. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Slow-release caffeine: a new response to the effects of a limited sleep deprivation. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Caffeine dosing strategies to optimize alertness during sleep loss. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Comparative Bioavailability and Benefits on Mental Functions of Novel Extended-Release Caffeine Capsules against Immediate-Release Caffeine Capsules: An Open-Label, Randomized, Cross-over, Single-Dose Two-Way Crossover Study. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Stability of caffeine citrate injection in intravenous admixtures and parenteral nutrition solutions. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Oral and IP caffeine pharmacokinetics under a chronic food-limitation condition. [2019]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Evodiamine Reduces Caffeine-Induced Sleep Disturbances and Excitation in Mice. [2020]