Optimized Caffeine for Sleep Deprivation

(2B-2 Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: University of Arizona

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

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

Trial Summary

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.

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}

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

I am between 18 and 39 years old.

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.

Trial 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)

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Arizona Psychiatry Department Tucson, AZ

University of Arizona Tucson, AZ

Who Is Running the Clinical Trial?

University of Arizona Lead Sponsor

Biotechnology High Performance Computing Software Applications Institute Collaborator

U.S. Army Medical Research Acquisition Activity Collaborator

References

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

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening. [2023] 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, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

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

Multiple dose pharmacokinetics of caffeine administered in chewing gum to normal healthy volunteers. [2013] The purpose of this study was to examine the pharmacokinetics of three doses of caffeine administered as Stay Alert chewing gum in a multiple dose regimen.

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

Slow-release caffeine: a new response to the effects of a limited sleep deprivation. [2015] The aim of this study is to assess the interest of the intake of a new galenic form of caffeine called "slow-release" caffeine (SR caffeine) during a decrease of vigilance due to a limited sleep deprivation.

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

Caffeine dosing strategies to optimize alertness during sleep loss. [2019] Sleep loss, which affects about one-third of the US population, can severely impair physical and neurobehavioural performance. Although caffeine, the most widely used stimulant in the world, can mitigate these effects, currently there are no tools to guide the timing and amount of caffeine consumption to optimize its benefits. In this work, we provide an optimization algorithm, suited for mobile computing platforms, to determine when and how much caffeine to consume, so as to safely maximize neurobehavioural performance at the desired time of the day, under any sleep-loss condition. The algorithm is based on our previously validated Unified Model of Performance, which predicts the effect of caffeine consumption on a psychomotor vigilance task. We assessed the algorithm by comparing the caffeine-dosing strategies (timing and amount) it identified with the dosing strategies used in four experimental studies, involving total and partial sleep loss. Through computer simulations, we showed that the algorithm yielded caffeine-dosing strategies that enhanced performance of the predicted psychomotor vigilance task by up to 64% while using the same total amount of caffeine as in the original studies. In addition, the algorithm identified strategies that resulted in equivalent performance to that in the experimental studies while reducing caffeine consumption by up to 65%. Our work provides the first quantitative caffeine optimization tool for designing effective strategies to maximize neurobehavioural performance and to avoid excessive caffeine consumption during any arbitrary sleep-loss condition.

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] Present study aimed compared pharmacokinetic profile of sustained-release CaffXtend® capsules (SR-Caffeine) with immediate-release caffeine capsules (IR-Caffeine), and the effect of SR-caffeine on memory, motivation, concentration, and attention. This open-label, randomized, single-dose, two-treatment, two-sequence, two-period, two-way crossover oral bioavailability study block randomized (1:1) healthy subjects (N = 15) to receive SR-Caffeine (200 mg) and IR-Caffeine (200 mg). Blood samples were collected at 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36 and 48 h in each period. Primary study outcome included comparing relative bioavailability of SR-Caffeine 200 mg and IR-Caffeine 200 mg under fasting conditions, and changes in caffeine research visual analogue scale (Caff-VAS) scores ('relaxed', 'alert', 'jittery', 'tired', 'tense', 'headache', 'overall mood' and 'mentally fatigued') were also evaluated. Fifteen subjects completed the study. Mean tmax was 4.08 ± 2.13h for SR-Caffeine compared to 0.83 ± 0.39h for IR-Caffeine, (p < 0.0001). Similarly, mean t½ was 7.07 ± 3.48h for SR-Caffeine compared to 5.78 ± 2.11h for IR-Caffeine (p = 0.04189). However, total exposure was similar for SR-Caffeine and IR-Caffeine (90% CI: 89.89-120.50% to 94.49-123.82% for geometric least square mean of ln-transformed AUC0-t and AUC0-∞). In the Caff-VAS evaluation, the SR-Caffeine group showed significantly better scores for 'jitteriness', 'tiredness', 'alertness' and 'overall mood' for 8-12 h than the IR-Caffeine group. No adverse events were reported. Results demonstrated sustained release of caffeine over 24 h from SR-Caffeine as compared to IR-Caffeine, which showed significant improvements in the scores for 'relaxed', 'alertness' and 'overall mood' and significantly lower scores for the parameters-'jittery' and 'tired' for extended period.Clinical trial registration: CTRI/2021/06/034185.

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] The purpose of this study was to evaluate the rate of absorption and relative bioavailability of caffeine from a Stay Alert chewing gum and capsule formulation.

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

Stability of caffeine citrate injection in intravenous admixtures and parenteral nutrition solutions. [2019] The stability of caffeine citrate injection in various intravenous admixtures and parenteral nutrition solutions at room temperature over a 24-h period. The compound was found to be stable under all the conditions studied.

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

Oral and IP caffeine pharmacokinetics under a chronic food-limitation condition. [2019] For food-limited rats, serum caffeine was proportional to IP caffeine doses (10-40 mg/kg) for Cmax and area under the curve [AUC(0-24 h)], whereas the three dimethylxanthine (DMX) metabolites of caffeine were disproportional over the dose range. Steady-state concentrations of caffeine and the three metabolites were evident at the 11th day of chronic, daily caffeine IP 20 mg/kg doses. Both caffeine and the three metabolites were dose proportional for Cmax and AUC(0-24 h) by schedule-induced oral caffeine self-administration within the dose range taken (9-38 mg/kg). These results contrast with the nonlinear kinetics of caffeine reported for rats under ad lib conditions. Elimination rate constants (Kel) remained the same for the two routes, but apparent volume of distribution (AVd) and clearance (Cl) were different. The order of the Kel values was caffeine > paraxanthine > theophylline > theobromine. The effects of linear vs. nonlinear caffeine pharmacokinetics may have distinct implications for the resulting pharmacodynamics.

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

Evodiamine Reduces Caffeine-Induced Sleep Disturbances and Excitation in Mice. [2020] Worldwide, caffeine is among the most commonly used stimulatory substances. Unfortunately, significant caffeine consumption is associated with several adverse effects, ranging from sleep disturbances (including insomnia) to cardiovascular problems. This study investigates whether treatment with the Evodia rutaecarpa aqueous extract (ERAE) from berries and its major molecular component, evodiamine, can reduce the adverse caffeine-induced sleep-related and excitation effects. We combined measurements from the pentobarbital-induced sleep test, the open field test, and the locomotor activity test in mice that had been dosed with caffeine. We found that ERAE and evodiamine administration reduced the degree of caffeine-induced sleep disruption during the sleep test. Additionally, we found that evodiamine significantly inhibits caffeine-induced excitation during the open field test, as well as decreasing hyperlocomotion in the locomotor activity test. Additional in vitro experiments showed that caffeine administration decreased the expression of γ-aminobutyric acid (GABA)A receptor subunits in the mouse hypothalamus. However, evodiamine treatment significantly reversed this expression reduction. Taken together, our results demonstrate that ERAE and its major compound, evodiamine, provide an excellent candidate for the treatment or prevention of caffeine-induced sleep disturbances and excitatory states, and that the mechanism of these beneficial effects acts, at least in part, through the GABAA-ergic system.