Impact of Exogenous Ketones on Sleep Apnea (KETO-SLEEP 2)

Impact of Exogenous Ketones on Sleep Disruption in Vulnerable Populations: Phase 2 Study (KETO-SLEEP 2)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Sleep; Obstructive Sleep Apnea
• Intervention / Treatment: Dietary supplement: Ketone-IQ; Dietary supplement: Placebo

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 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 Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Mariah Potocki; Phone Number: 410-550-2233; Email: mchaney7@jhmi.edu
• Study Contact Backup: Name: Athena Mavronis; Phone Number: 410-550-4588; Email: amavron1@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center
      • Contact: Mariah Potocki; Phone Number: 410-550-2233; Email: mchaney7@jhmi.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketone-IQ first; This is a crossover study where participants will ingest either Ketone-IQ for 2 nights, or placebo for 2 nights before sleep. This arm will ingest Ketone-IQ first, then placebo.	Dietary supplement: Ketone-IQ; This is a crossover study where participants will ingest either Ketone-IQ for 2 nights, or placebo for 2 nights before sleep. This is the Ketone-IQ (1,3 Butanediol) intervention.; Dietary supplement: Placebo; This is a crossover study where participants will ingest either Ketone-IQ for 2 nights, or placebo for 2 nights before sleep. This is the Placebo intervention.
Experimental: Placebo first; This is a crossover study where participants will ingest either Ketone-IQ for 2 nights, or placebo for 2 nights before sleep. This arm will ingest Placebo first, then Ketone-IQ.	Dietary supplement: Ketone-IQ; This is a crossover study where participants will ingest either Ketone-IQ for 2 nights, or placebo for 2 nights before sleep. This is the Ketone-IQ (1,3 Butanediol) intervention.; Dietary supplement: Placebo; This is a crossover study where participants will ingest either Ketone-IQ for 2 nights, or placebo for 2 nights before sleep. This is the Placebo intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea Hypopnea Index (AHI)	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.	2 nights Ketone-IQ, 2 nights Placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal Symptoms Questionnaire	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).	2 mornings after Ketone-IQ, 2 mornings after Placebo
Sleep-Related Impairment (SRI) as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS-SRI 8a)	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	2 mornings after Ketone-IQ, 2 mornings after Placebo
Sleep Disturbance (SD) as assessed by the PROMIS SD	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)	2 mornings after Ketone-IQ, 2 mornings after Placebo
Stanford Sleepiness Scale (SSS)	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).	2 mornings after Ketone-IQ, 2 mornings after Placebo
Oxygen Saturation Level	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).	2 nights on Ketone IQ, 2 nights on placebo
Nadir Oxygen Level	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)	2 nights on Ketone IQ, 2 nights on placebo
Oxygen Desaturation Index	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).	2 nights on Ketone IQ, 2 nights on placebo

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: HVMN Inc; KETONE-IQ
• Investigators: Principal Investigator: Jonathan Jun, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Estimated): September 6, 2026
• Primary Completion (Estimated): September 6, 2028
• Study Completion (Estimated): September 6, 2028

Study Registration Dates

• First Submitted: November 12, 2024
• First Submitted That Met QC Criteria: November 12, 2024
• First Posted (Actual): November 13, 2024

Study Record Updates

• Last Update Posted (Estimated): October 10, 2025
• Last Update Submitted That Met QC Criteria: October 8, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: CPAP; sleep apnea; ketones
• Additional Relevant MeSH Terms: Nervous System Diseases; Metabolic Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Wake Disorders; Apnea; Sleep Disorders, Intrinsic; Dyssomnias; Acid-Base Imbalance; Acidosis; Nutritional and Metabolic Diseases; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Ketosis
• Other Study ID Numbers: IRB00439273-2

Plan for Individual participant data (IPD)

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

IPD Plan Description

Experimental data, including sleep data, questionnaires, and BHB measurements, will be stored as raw files on internal servers with cloud backup. Questionnaire data will be securely stored at Johns Hopkins University for three years post-study. Dr. Jun will control access to physical documents.

Documentation and Accessibility: Research protocols, instrument details, and analysis methods will be detailed in publications. Deidentified data from published studies will be available at publication, accompanied by a data dictionary, and preserved for at least five years. Standard software (Excel, R, SPSS, SAS) will be used for data access and analysis.

• IPD Sharing Time Frame: Deidentified scientific data included in published manuscripts will be made available at the time of publication and additional data will be made available to researchers upon request. Data will be made available for up to 3 years following study completion.
• IPD Sharing Access Criteria: To request access to the data, researchers will be able to contact Dr. Jonathan Jun via email. Any data attached as a supplement to publications will be available for download from the publisher's website. The intention is to allow qualified external investigators broad access to the study data for specified research purposes.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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