Exogenous Ketones for Obstructive Sleep Apnea

(KETO-SLEEP 1 Trial)

Overseen By Athena Mavronis

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Johns Hopkins University

Must not be taking: Opiates, Acetazolamide, SGLT2 inhibitors

Disqualifiers: Concomitant sleep disorder, Respiratory impairment, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Obstructive Sleep Apnea (OSA) is a common medical disorder that is associated with reduced quality of life and higher risk of cardiovascular disease. Treatments for OSA and limited and not well tolerated. Our lab has shown that a low carbohydrate, high fat ketogenic diet (KD) can reduce OSA severity. Since it can be challenging to adhere to a ketogenic diet, the investigators propose that ingesting exogenous ketones can be an alternative method to improve OSA. Specifically the investigators will examine the effect of taking a commercially available product (Ketone-IQ) at bedtime on overnight ketones and sleep quality. The investigators will also examine the effect of Ketone-IQ on sleep apnea severity, compared to placebo. This project will examine the pharmacokinetics, tolerability, and sleep impacts of ingesting exogenous ketones before sleep in patients with sleep apnea, while under treatment for OSA. \[Aim 2: Examine the preliminary efficacy of ingesting exogenous ketones before sleep on OSA\]

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you use nightly medications that affect breathing or SGLT2 inhibitors.

Is the use of exogenous ketones safe for humans?

Research indicates that exogenous ketones, such as ketone monoesters and diesters, are generally safe for human consumption. Studies have shown they are well-tolerated, although some people may experience mild gastrointestinal effects, especially at higher doses. ^{1 2 3 4 5}

How does the treatment Ketone-IQ differ from other treatments for obstructive sleep apnea?

Ketone-IQ is unique because it uses exogenous ketones, which are compounds that can provide an alternative energy source for the brain, potentially improving sleep-related issues. Unlike traditional treatments for obstructive sleep apnea, which often involve devices or surgeries, Ketone-IQ focuses on altering metabolism to support better sleep. ^{5 6 7 8 9}

Research Team

Jonathan Jun, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for people with Obstructive Sleep Apnea (OSA), a condition that disrupts sleep and can lead to health problems. Participants should be currently receiving treatment for OSA but are looking for additional ways to improve their sleep quality.

Inclusion Criteria

I am between 18 and 65 years old with a BMI between 18 and 35.

I have been diagnosed with moderate to severe sleep apnea.

I use my CPAP machine regularly, at least 4 hours on most nights.

Exclusion Criteria

I do not have any sleep disorders.

Currently on a low carbohydrate (<130 g carbohydrate/day) or ketogenic diet, intermittent fasting, or consuming exogenous ketones

Pregnancy or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants ingest exogenous ketones (Ketone IQ) or placebo before sleep to assess pharmacokinetics, tolerability, and sleep impacts

2 weeks

Multiple nights of in-home monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketone-IQ

Trial Overview The study tests if taking Ketone-IQ, an exogenous ketone supplement, at bedtime can improve overnight ketones and sleep quality in OSA patients. It compares the effects of this supplement to a placebo on how severe the sleep apnea is.

Participant Groups

Group I: Ketone Intervention Experimental Treatment 1 Intervention

Participants with sleep apnea using CPAP will undergo open-label procedures. They will ingest (1) nothing, (2) Ketone IQ 20 g or (3) Ketone IQ 40 g before bedtime and undergo objective and subjective sleep assessments.

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

KETONE-IQ

Collaborator

Trials

2

Recruited

60+

HVMN Inc

Industry Sponsor

Trials

3

Recruited

80+

Findings from Research

In a study involving 10 well-trained cyclists, ketone ester (KE) intake significantly improved sleep efficiency and quality after strenuous exercise, counteracting disruptions like reduced REM sleep and increased wakefulness.

The positive effects of KE on sleep were linked to increased dopamine excretion, suggesting that KE may enhance sleep regulation mechanisms following high-intensity workouts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep after Strenuous Exercise. Robberechts, R., Albouy, G., Hespel, P., et al.[2023]

In a study involving 14 healthy young adults, both ketone monoester (KME) and ketone monoester/salt (KMES) formulations significantly increased circulating R-beta-hydroxybutyrate (R-βHB) levels in a dose-dependent manner, with KME10 reaching a peak concentration of 2.4 mM after 15 minutes.

Both formulations were well-tolerated, but KMES was slightly more acceptable due to a better taste, while KME was associated with a more frequent decrease in appetite, indicating that user experience may vary between different ketone products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. Bolyard, ML., Graziano, CM., Fontaine, KR., et al.[2023]

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

In a 28-day study involving 59 healthy adults, the novel exogenous ketone diester bis-hexanoyl-(R)-1,3-butanediol (BH-BD) was found to be well-tolerated and safe, with no significant differences in tolerability scores compared to a placebo.

BH-BD effectively increased blood ketone levels one hour after consumption, indicating its potential for promoting nutritional ketosis without adverse effects on vital signs or laboratory measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Chen, O., Blonquist, TM., Mah, E., et al.[2021]

Sleep disorders are often overlooked and can include a variety of conditions such as insomnia and sleep apnea, highlighting the need for better recognition and treatment.

The ketogenic diet (KD), which is high in fats and low in carbohydrates, has shown promise in treating sleep disorders, particularly obstructive sleep apnea, by potentially influencing sleep homeostasis through the effects of ketone bodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there a relationship between the ketogenic diet and sleep disorders? Barrea, L., Pugliese, G., Frias-Toral, E., et al.[2022]

A ketogenic diet (KD) and exogenous ketone supplements significantly increased blood ketone levels in rodent models, which correlated with a delayed onset of isoflurane-induced anesthesia, indicating that ketosis may influence anesthetic induction.

The study, involving chronic and sub-chronic feeding of KD and ketone supplements to different rodent models, suggests that elevated ketone levels could alter the effectiveness of anesthetics, potentially requiring adjustments in surgical anesthetic dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional ketosis delays the onset of isoflurane induced anesthesia. Ari, C., Kovács, Z., Murdun, C., et al.[2019]

A hypocaloric ketogenic diet (KD) significantly increased levels of beta-hydroxybutyrate (BHB) in participants, and this effect was enhanced by the addition of exogenous ketone salts (KS), leading to a 26% increase in ketonemia compared to a placebo.

The combination of the KD and KS not only augmented ketonemia but also resulted in a 6% reduction in fasting glucose levels, suggesting that the hypoglycemic effects of a ketogenic diet may be further improved with exogenous ketones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts. Buga, A., Kackley, ML., Crabtree, CD., et al.[2023]

Oral administration of exogenous ketone supplements over 28 days effectively induced sustained nutritional ketosis in male rats, achieving ketone levels greater than 0.5 mM without the need for carbohydrate restriction.

The study showed that these supplements led to a rapid increase in β-hydroxybutyrate (βHB) levels and a decrease in blood glucose, while having minimal impact on lipid levels, indicating their potential safety and efficacy for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Kesl, SL., Poff, AM., Ward, NP., et al.[2020]

In a pilot study with 11 subjects, consuming a ketone ester drink helped mitigate cognitive decline during hypoxia, as indicated by improved performance on cognitive tasks compared to a placebo.

Hypoxia significantly affected cognitive performance, leading to longer blink durations and lower blink rates, but the ketone ester consumption showed potential in reducing these negative effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Metabolic Intervention for Improving Human Cognitive Performance During Hypoxia. Coleman, K., Phillips, J., Sciarini, M., et al.[2022]

References

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

Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep after Strenuous Exercise. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]

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

Is there a relationship between the ketogenic diet and sleep disorders? [2022]

6. England pubmed.ncbi.nlm.nih.gov

Nutritional ketosis delays the onset of isoflurane induced anesthesia. [2019]

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

Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. [2020]

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

A Metabolic Intervention for Improving Human Cognitive Performance During Hypoxia. [2022]