Impact of Exogenous Ketones on Sleep Apnea

Phase 1

Not yet recruiting

• Conditions: Obstructive Sleep Apnea; Sleep

• Registration Number: NCT06687655
• Lead Sponsor: Johns Hopkins University

Brief Summary

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. The investigator's 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 the preliminary efficacy of ingesting exogenous ketones before sleep on sleep apnea.

Detailed Description

Sleep is a vulnerable period during which blunted respiratory drive and low airway muscle tone can cause dangerous breathing disorders. Obstructive sleep apnea (OSA) describes the intermittent collapse of the upper airway that induces O2 desaturations and arousals from sleep, placing patients at risk for cardiovascular disease, stroke, and death. In some obese patients, sleep causes carbon dioxide (CO2) accumulation progressing to daytime hypercapnia, a condition called obesity hypoventilation syndrome (OHS). Continuous positive airway pressure (CPAP) treats OSA and OHS, but is poorly tolerated, and may not fully correct sleep dysfunction.

Changes in metabolism may help to control OSA or OHS. The investigators recently published results from the Ketogenic Diet for OHS clinical trial (KETOHS, NCT04108819) showing that a 2-week ketogenic diet (high fat, low carbohydrate) for patients with OSA and OHS lowered reduced CO2, serum bicarbonate (HCO3), respiratory quotient, nocturnal hypoxemia(2). KD also significantly improved OSA. After participants resumed prior diet, CO2 returned to baseline. The mechanisms by which KD improves sleep in this population could be related to reduced CO2 production (through fat oxidation), lowering of body weight, or direct effects of ketone bodies on sleep and breathing.

It is difficult to adhere long-term to KD, and there are multiple effects of this diet that make it challenging to understand mechanistic impacts on respiration. The investigators hypothesize that increasing ketone levels in the body, without having to adhere to a ketogenic diet, may be another method to improve breathing during sleep. Indeed, some drugs affecting acid-base status (e.g. acetazolamide or sulthiame) improve OSA, presumably through increasing and stabilizing respiratory drive. In this pilot study, the investigators will examine the pharmacokinetics, tolerability, and impacts of ingesting exogenous ketones (which are commercially available products) on sleep and breathing.

The specific ketone product to be tested for its impact on sleep and breathing is 1,3 butanediol (1,3BD) in a commercially available formulation called "Ketone IQ". 1,3BD is generally recognized as safe (GRAS approved) by the FDA. 1,3BD is converted by liver metabolism into the ketone body beta-hydroxybutyrate (BHB) and has been utilized in multiple studies.

This project will be conducted in two studies, KETO-SLEEP 1 (KS1), and KETO-SLEEP 2 (KS2).

KETO-SLEEP 1: Examine the pharmacokinetics, tolerability, and sleep impacts of ingesting exogenous ketones (EK) before sleep (n=20, 10 men, 10 women). KS1 will lay the foundation for KS2 and other studies that administer exogenous ketones at bedtime, through dose-finding and assessment of tolerability. Patients with moderate-severe OSA (apnea-hypopnea index (AHI) \>15)) adherent to CPAP will ingest EK or placebo 30 minutes before sleep. The participants will measure capillary BHB levels before ingestion and at 1, 3, 5, hours post-ingestion as well as upon awakening. CPAP use will be maintained on all nights and sleep architecture will be monitored with portable EEG. Questionnaires will solicit feedback about EK palatability, GI side effects, and sleep quality. Two doses (20 g and 40 g) of Ketone-IQ will be tested each for two nights, with one night used to measure BHB levels and separate night to allow for uninterrupted sleep.

KETO-SLEEP 2: Examine the preliminary efficacy of ingesting exogenous ketones before sleep on OSA (n=20, 10 men, 10 women). KS2 will examine the respiratory effects of exogenous ketones taken before sleep. Patients with known OSA will be asked to temporarily discontinue CPAP, a technique used in the investigator's laboratory to temporarily elicit OSA(10). To account for night-to-night variability in OSA severity the investigators will use portable sleep monitoring to collect sleep and respiratory data two nights under each condition. The dose of Ketone-IQ to be administered each night will vary from 20 to 40 g, depending upon results of KS-1.

Study Timeline

• Study First Submitted: 2024-11-12
• Study First Submitted QC: 2024-11-12
• Study First Posted: 2024-11-13
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-25
• Last Update Posted: 2025-04-27
• Study Start: 2025-09-01
• Primary Completion: 2026-09-01
• Study Completion: 2026-09-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Adults aged 18-65 years old with a BMI of 18 - 35 kg/m2
2. History of moderate-severe OSA as defined by AHI >15 events/hr (American Academy of Sleep Medicine criteria),
3. Adherent to CPAP (objectively determined via device download over last 30 days) using CPAP at least 70% of days for >=4 hours.
4. CPAP pressure ≤10 cm water (H2O) (based on prescribed CPAP pressure, or median pressure on an auto-titrating CPAP device).

Exclusion Criteria

1. No concomitant sleep disorder (such as insomnia, restless leg syndrome, narcolepsy, idiopathic hypersomnia)
2. No current daytime respiratory impairment such as uncontrolled asthma, or uncontrolled chronic obstructive pulmonary disease (COPD), pneumonia, interstitial lung disease.
3. No use of supplemental oxygen.
4. Currently on a low carbohydrate (<130 g carbohydrate/day) or ketogenic diet, intermittent fasting, or consuming exogenous ketones
5. Pregnancy or breastfeeding
6. Alcohol consumption of > 10 standard drinks per week
7. Use of nightly medications that affect breathing (e.g. opiates, acetazolamide)
8. Use of Sodium-glucose cotransporter-2 (SGLT2) inhibitors. For example, Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), Ertugliflozin (Steglatro)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Primary Outcome Measures

Name	Time	Method
Apnea Hypopnea Index (AHI)	2 nights Ketone-IQ, 2 nights Placebo	Sleep studies will be performed using NOX T3 devices at home. The device will be worn for 2 consecutive nights during each intervention (Ketone IQ, Placebo); 4 nights total (2 nights Ketone-IQ, 2 nights Placebo). Apnea hypopnea index (AHI); mean number of apnoeas and hypopnoeas per hour of sleep will be calculated from NOX T3 data.

Secondary Outcome Measures

Name	Time	Method
Gastrointestinal Symptoms Questionnaire	2 mornings after Ketone-IQ, 2 mornings after Placebo	A questionnaire about gastro-intestinal symptoms will be administered each morning; 4 times total (2 mornings after Ketone-IQ, 2 mornings after Placebo). The instrument has 4 questions about upper GI symptoms, 4 questions about lower GI symptoms, and 4 questions about systemic symptoms. All questions are scored from 0 (no symptoms) to 8 (unbearable) for a score range of 0-96 (higher score = worse outcome).
Sleep-Related Impairment (SRI) as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS-SRI 8a)	2 mornings after Ketone-IQ, 2 mornings after Placebo	Sleep related impairment will be assessed by PROMIS-SRI 8a. Two mornings after Ketone-IQ, 2 mornings after Placebo; 4 nights total. A T-score is calculated from a raw score using conversion tables on the PROMIS website. The T-score (range 0-100) indicates the level of sleep-related impairment, with higher scores representing greater impairment
Sleep Disturbance (SD) as assessed by the PROMIS SD	2 mornings after Ketone-IQ, 2 mornings after Placebo	The PROMIS SD uses a 5-point Likert scale composed of eight items rated from 1 (not at all, very poor, or never) to 5 (very much, always, or very good) with four items reversed scored. Total raw scores range from 8 to 40 with higher scores indicating greater disturbance. Sleep disturbance will be measured a total of 4 times (2 mornings after Ketone-IQ, 2 mornings after Placebo)
Stanford Sleepiness Scale (SSS)	2 mornings after Ketone-IQ, 2 mornings after Placebo	The SSS consists of only one item. The scale requires respondents to select one of seven statements best representing their level of perceived sleepiness. Respondents use a scale from 1 to 7 to indicate their current level of sleepiness from 1 (feeling active and vital) - 7 (almost in reverie). Measured a total of 4 times (2 mornings after Ketone-IQ, 2 mornings after Placebo).
Oxygen Saturation Level	2 nights on Ketone IQ, 2 nights on placebo	NOX T3 data will be used to calculate metrics of oxygen saturation including mean oxygen level; measured a total of 4 times (2 nights on Ketone IQ, 2 nights on placebo).
Nadir Oxygen Level	2 nights on Ketone IQ, 2 nights on placebo	NOX T3 data will be used to calculate nadir oxygen level. Measured a total of 4 times (2 nights on Ketone IQ, 2 nights on placebo)
Oxygen Desaturation Index	2 nights on Ketone IQ, 2 nights on placebo	NOX T3 data will be used to calculate oxygen desaturation index. Measured a total of 4 times (2 nights on Ketone IQ, 2 nights on placebo).

Trial Locations

Locations (1)

Johns Hopkins Bayview Medical Center; 🇺🇸 Baltimore, Maryland, United States