A single-center exploratory trial evaluating the pharmacokinetic profile and the metabolic effects of a ketone ester food supplement in intensive care patients: The KETOCARE 2 trial

ISRCTN	ISRCTN12834375
DOI	https://doi.org/10.1186/ISRCTN12834375
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	S70969
Sponsor	Universitair Ziekenhuis Leuven
Funders	European Research Council, Flemish Government Methusalem Program

Submission date: 13/10/2025
Registration date: 12/11/2025
Last edited: 12/11/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Critically ill patients often develop muscle weakness and muscle loss during their stay in intensive care, which hinders recovery and is associated with long-term morbidity and mortality. Research in mice with sepsis showed that continuous intravenous administration of the ketone ester 3-hydroxybutyrate (3HHB) reduced the development of muscle weakness without organ damage or liver toxicity. In previous studies in critically ill patients, 3HHB was administered semi-continuously for one day and was found to be well tolerated. Based on these previous studies, a pharmacokinetic model was developed.
The aim of this study is to investigate whether prolonged ketone ester administration can safely induce ketosis for five days to critically ill patients.

Who can participate?
Adult patients admitted to the intensive care unit at UZLeuven

What does the study involve?
We will investigate the feasibility and safety of enteral 3HHB administered during five consecutive days in ICU. We are therefore planning a monocentric exploratory study in which we will evaluate the dosing regimen proposed by the pharmacokinetic model. Ten critically ill patients will receive 3-hydroxybutyrate via a gastric tube every 2 hours and a total of 7 doses per day. This will be followed by a 12-hour therapy-free interval after the last dose to prevent accumulation. Blood samples will be taken at predetermined times to monitor plasma levels of 3HB and 3HHB (metabolites).

What are the possible benefits and risks of participating?
There are no known interactions of ketone esters with drugs. Over six days a total of 172 ml blood will be collected for analysis. This small amount should not cause any problems and will be taken via a catheter that is already in place.

When is the study starting and how long is it expected to run for?
August 2025 to August 2027

Who is funding the study?
1. European Research Council (ERC)
2. Flemish Government (Belgium)

Who is the main contact?
Prof. Dr. Greet Van den Berghe, greet.vandenberghe@kuleuven.be

Contact information

Prof Greet Van den Berghe
Principal investigator

Herestraat 49
Leuven
3000
Belgium

ORCID ID	0000-0002-5320-1362
Phone	+32 (0)16 344021
Email	greet.vandenberghe@kuleuven.be

Prof Lies Langouche
Scientific

Herestraat 49
Leuven
3000
Belgium

ORCID ID	0000-0002-8564-6809
Phone	+32 (0)16 330524
Email	lies.langouche@kuleuven.be

Prof Jan Gunst
Scientific

Herestraat 49
Leuven
3000
Belgium

ORCID ID	0000-0003-2470-6393
Phone	+32 (0)16 344021
Email	jan.gunst@uzleuven.be

Mrs Helena Wintmolders
Public

Herestraat 49
Leuven
3000
Belgium

ORCID ID	0009-0007-1311-7776
Phone	+32 (0)16 340967
Email	helena.wintmolders@uzleuven.be

Dr Philippe Huynen
Scientific

Herestraat 49
Leuven
3000
Belgium

ORCID ID	0000-0002-0427-7889
Phone	+32 (0)16 344021
Email	philippe.huynen@uzleuven.be

Study information

Primary study design	Interventional
Study design	Mono-centric interventional non randomized
Secondary study design	Non randomised study
Scientific title	A single-center exploratory trial evaluating the pharmacokinetic profile and the metabolic effects of a ketone ester food supplement in intensive care patients: The KETOCARE 2 trial
Study acronym	KETOCARE 2
Study objectives	To explore the efficacy of the dosing regimen of enteral ketone esters R-3-hydroxybutyl-R-3-hydroxybutanoate (3HHB) derived from the PK-model to induce sustained ketosis. To demonstrate that prolonged, intermittent supplementation of enteral ketone esters over five consecutive days is safe.
Ethics approval(s)	Approved 18/09/2025, Ethics Committee Research UZ/KU Leuven (Herestraat 49, Leuven, 3000, Belgium; +32 16 34 86 00; ec@uzleuven.be), ref: S70969
Health condition(s) or problem(s) studied	Safety of prolonged, intermittent supplementation of enteral ketone esters in critically ill adult patients
Intervention	Ten critically ill patients will all receive 3-hydroxybutyrate via a gastric tube every 2 hours, for a total of 7 doses per day. This will be followed by a 12-hour therapy-free interval after the last dose to prevent accumulation. Blood samples will be taken at predetermined times to monitor plasma levels of 3HB and 3HHB (metabolites).
Intervention type	Supplement
Primary outcome measure(s)	Percentage of plasma 3-hydroxybutyrate concentrations above 1 mmol/L during the 16-hour treatment interval (from first bolus to the expected complete clearance of 3HB, 4h post last bolus), measured by LC-MS/MS
Key secondary outcome measure(s)	1. Plasma 3-hydroxybutyrate levels during the 6 day intervention window (E), measured by LC-MS/MS 2. Plasma levels of 3HHB and metabolite 1,3-butanediol during the 6 day intervention window (E), measured by LC-MS/MS 3. Urine levels of 3HHB, 3-hydroxybutyrate and 1,3-butanediol during the 6 day intervention window (E), measured by LC-MS/MS 4. Blood glucose concentrations during the 6 day intervention window (E), measured by blood-gas-analyzer on ICU 5. Incidence of severe (<40 mg/dl) hypoglycemia during the 6 day intervention window (S), measured by blood-gas-analyzer on ICU 6. Incidence of ketoacidosis during the 6 day intervention window, defined as a new onset metabolic acidosis with arterial pH less than 7.25 and serum bicarbonate less than 15 mmol/L occurring simultaneously with a 3HB level of at least 10 mmol/L (S), measured by blood-gas-analyzer on ICU 7. Incidence of 3HB levels exceeding 10 mmol/L at any time, without concomitant acidosis, during the 6 day intervention window (S), measured with a ketone stick test on arterial blood in the ICU 8. Incidence of accumulation (pre-administration trough levels exceeding 5 mmol/L) without ketoacidosis during the 6 day intervention window (S), measured with a ketone stick test on arterial blood in the ICU 9. Plasma levels of cholesterol (HDL, LDL, total), triglycerides, free fatty acids over time during the 6 day intervention window (E), measured by commercial kits 10. Plasma levels of bilirubine, gamma-glutamyltransferase, aspartate transaminase and alanine transaminase over time during the 6 day intervention window (S), measured by commercial kits
Completion date	13/08/2027

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	99 Years
Sex	All
Target sample size at registration	10
Key inclusion criteria	1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained 2. At least 18 years of age at the time of signing the Informed Consent Form (ICF) 3. Patient expected to stay at the ICU for at least 6 days after start of the first 3HHB administration 4. The presence of a gastric feeding tube
Key exclusion criteria	1. Therapy restriction code 2. Patients refusing blood transfusion upon ICU admission will be considered as having a therapy restriction upon admission and will not be included 3. Expected to die within 48 hours after screening (= moribund patients) 4. No arterial and central venous line, or expected to have one of these lines removed before the end of the study period (= not critically ill enough to be representative for the future target population, and no possibility to take blood samples without additional venapuncture) 5. Contraindication for enteral drug administration 6. Readmission to the ICU after previous inclusion in the RCT 7. Inborn metabolic disease 8. Clinical need for a ketogenic diet in ICU 9. Underweight (BMI< 18.5 kg/m²) or admitted with complications due to anorexia nervosa 10. Known to be pregnant or lactating 11. ICU admission with diabetic ketoacidosis or hyperosmolar hyperglycemic state 12. Acute or acute on chronic liver failure 13. High intravenous glucose need to prevent spontaneous hypoglycemia 14. Metabolic acidosis (pH <7.30 and bicarbonate <18 mmol/l)
Date of first enrolment	27/10/2025
Date of final enrolment	27/10/2026

Locations

Countries of recruitment

Belgium

Study participating centre

UZ Leuven

Herestraat 49
Leuven
3000
Belgium

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in publicly available repository
IPD sharing plan	The datasets generated during and/or analysed during the current study will be stored in a publicly available repository (name: RDR; https://rdr.kuleuven.be/)

Editorial Notes

14/10/2025: Trial's existence confirmed by UZ Leuven.