An interventional study of Ketone Monoester and Placebo in Ketosis and Exogenous Ketosis, sponsored by University of Oxford. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-05-11.
Sponsored by University of Oxford · Not applicable, Interventional, and Basic science
The kinetics of circulating βHB following ingestion of the ketone monoester are dependent on several variables that determine the balance between appearance into, and disappearance from, the bloodstream. These dynamics have been well characterised in fasted humans but in the real world the ketone monoester is likely to be ingested in a fed state, pertinently within athletic spheres consumption would proceed a substantial high-carbohydrate meal. Within this, it is unclear how metabolism under exogenous ketosis might be affected in a fed versus fasted state.
This four-arm crossover study looks to characterise the relationship between feeding status, βHB pharmacokinetics, and resting metabolism.
As exogenous ketosis is known to reduce circulating glucose levels, this study will also explored if hepatic metabolism - for example, de novo lipogenesis - might consequently be altered, with implications for metabolic disease states such as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and type II diabetes.
Participants will be asked to consume either the ketone monoester drink or a placebo drink when fasted and when having previously consumed a meal.
Adults free from metabolic disease will be recruited for this randomised-counterbalanced crossover study. Participants will attend four study visits.
Participants will consume a prescribed isocaloric high-carbohydrate diet for two days prior to each visit to standardise dietary intake.
For two of these visits participants will remain 'fasted' throughout, and for the two 'fed' visits they will consume a mixed-nutrient breakfast meal. The breakfast for the 'fed' visits will provide 2g∙kg-1 bodyweight of carbohydrate.
Heavy water (D2O) will be consumed the evening preceding, and during, each fed study visit to achieve \~0.4% plasma enrichment, in order to quantify the contribution of hepatic de novo lipogenesis to VLDL-TG.
At these visits they will consume either a ketone monoester (KME) or taste/volume-matched placebo (PLA) drink. The nature of this drink will be single blinded and consumed after the breakfast meal during the 'fed' visits.
Therefore the four visits will be as follows: fed-KME, fed-PLA, fasted-KME, fasted-PLA.
Blood and breath samples will be collected at fasting and across a 6 hour period after consuming the KME or PLA drink. Subjective measures of gastrointestinal distress and appetite will also be assessed.
This study aims to establish how feeding state might affect the appearance of βHB into the bloodstream, circulating metabolism, and hepatic metabolism.
Exclusion Criteria:
Ketone monoester drink (573 mg∙kg-1 body weight) provided 1 hour after a 2 g∙kg-1 bodyweight of carbohydrate mixed nutrient breakfast meal
Dietary Supplement: Ketone Monoester
Placebo drink provided 1 hour after a 2 g∙kg-1 bodyweight of carbohydrate mixed nutrient breakfast meal
Dietary Supplement: Placebo
Ketone monoester drink (573 mg∙kg-1 body weight) provided whilst fasted
Dietary Supplement: Ketone Monoester
Placebo drink provided whilst fasted
Dietary Supplement: Placebo
Commercial dietary supplement intended raise blood ketone body levels
Also known as: deltaG, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
Placebo drink (2mM sucrose octaacetate) taste and volume matched to the ketone monoester drinks
Also known as: Sucrose Octaacetate
Plasma β-hydroxybutyrate (βHB) kinetics
Changes in concentration of plasma βHB (mM) over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Plasma glucose kinetics
Changes in concentration of plasma glucose (mM) over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Postprandial de novo lipogenesis (DNL)
DNL in the fed visits - quantified as the incorporation of deuterium from heavy water into newly synthesised palmitate within very low-density lipoprotein-triglyceride (VLDL-TG)
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Plasma biochemistry
Changes in concentration of plasma lactate, insulin, nonesterified fatty acid (NEFA), triglyceride (TG), glycerol, and urea (all mM) over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Very low-density lipoprotein-triglyceride (VLDL-TG) fatty acid composition
Changes in fatty acid composition (mol%) of VLDL-TG over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Breath acetone
Changes in concentration of breath acetone (arbitrary units) over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Urine volume
Volume (ml) of urine over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Urine composition
βHB concentration (mM) of urine over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Indirect calorimetry
Changes in Respiratory Quotient (RQ; unitless) over the post-drink time period
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Subjective measures of appetite
Changes in perceptions of appetite over the post-drink period Appetite sensations will be assessed using a validated 10-point visual analogue scale (score: 0 - minimal, 10 - maximal) which will be presented to participants on printed paper This posed four questions - "How hungry do you feel?", "How full do you feel?", "How satisfied do you feel?", and "How much do you think you can eat now?"
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Subjective measures of gastrointestinal distress
Changes in perceptions of gastrointestinal (GI) distress over the post-drink period GI distress will be assessed using a literature-standard 0-8 Likert scale questionnaire quantified at upper abdominal (reflux, bloating, nausea, vomiting), lower abdominal (cramps, flatulence, abdominal pain, diarrhoea), and systemic (dizziness, headache, muscle cramp, urge to urinate) levels (severity score: 0 - minimal, 8 - maximal)
Time frame: 7 hours (fasted arrival through to 6 hours after consumption of the KME or PLA drink)
Plan to share: No
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University of Oxford