A single-centre, cross-over trial evaluating the metabolic effects of a ketone ester food supplement in intensive care patients

ISRCTN	ISRCTN13903536
DOI	https://doi.org/10.1186/ISRCTN13903536
Secondary identifying numbers	S67928

Submission date: 24/10/2023
Registration date: 27/10/2023
Last edited: 23/01/2025

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

Background and study aims
The majority of long-term critically ill patients develop muscle weakness and muscle wasting during their stay in intensive care, which hampers recovery and leads to increased complications and a greater risk of death. In animal experiments administering a nutritional supplement, namely ketone esters, can improve muscle weakness during disease. The next step in this research is to see if this supplement can be used to prevent or improve muscle weakness in critically ill patients. The first step is to determine a well-tolerated and effective dose of the dietary supplement (ketone esters) in critically ill patients.

Who can participate?
Adults over the age of 18 years who are admitted to the intensive care unit in UZ Leuven

What does the study involve?
This pilot study will test three doses (25 g, 50 g and 75 g) of ketone esters in adult critically ill patients. Participants are randomly allocated to receive the product or a placebo through a nasogastric feeding tube on 2 consecutive days. Frequent blood samples are scheduled to determine at which dose there is an effective increase in ketones in the blood without any adverse side effects.

What are the possible benefits and risks of participating?
There are no known interactions of ketone esters with drugs. Still, it is possible that nausea or abdominal pain, for example, may occur if the dietary supplement is not well tolerated.

Where is the study run from?
University Hospitals Leuven (Belgium)

When is the study starting and how long is it expected to run for?
January 2023 to December 2026

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 33 05 24
Email	lies.langouche@kuleuven.be

Mrs Liese Mebis
Public

Herestraat
Leuven
3000
Belgium

ORCID ID	0000-0002-6941-3044
Phone	+32 (0)16 343125
Email	liese.mebis@uzleuven.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

Study information

Study design	Single-center placebo-controlled cross-over randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised cross over trial
Study setting(s)	Hospital
Study type	Safety, Efficacy
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	A single-centre, placebo-controlled, cross-over randomized controlled trial evaluating the metabolic effects of a ketone ester food supplement in intensive care patients: the KETOCARE RCT
Study acronym	KETOCARE RCT
Study hypothesis	To study the feasibility, safety and tolerability of enteral ketone ester supplementation to increase circulating ketone levels in adult critically ill patients.
Ethics approval(s)	Approved 12/09/2023, Ethics Committee Research UZ/KU Leuven (Herestraat 49, Leuven, 3000, Belgium; +32 (0)16 34 86 00; ec@uzleuven.be), ref: S67928
Condition	Adult critically ill patients
Intervention	A blocked randomization scheme with blocks of 4 patients will be used in this study. The code for randomization blinding is stored in the randomization tool, developed in FilemakerPro with restricted access to the database administrators. Randomization will be carried out by dedicated research staff members using a role-based user access. With a cross-over design, patients will receive in random order on 2 consecutive days ketone ester (3HHB) and a placebo (5% glucose). The ketone esters will be supplied by TDeltaS Ltd (UK). Patients will receive the investigational product between ICU days 4 and 10. The investigational product (3HHB) or placebo will be delivered through the enteral feeding tube via repeated small boluses. The researchers will first perform this trial with a 25 g dose of 3HHB divided over 6 boluses of 3,9 ml. Next, they will assess the primary and secondary endpoints in this cohort of patients. If the dose of 25 g is found safe but ineffective for increasing plasma 3-hydroxybutyrate at least with 0.22 mmol/l, a second cohort of patients will be tested with the same cross-over study design but with a higher 3HHB dose (50 g of 3HHB, divided over 6 boluses of 7,8 ml). If this dose is again safe but ineffective, a third cohort of patients will be tested with the same cross-over study design with an increased dose of 75 g of 3HHB, divided over 6 doses of 11.7ml. For each cohort of patients tested (cohort 1 to test 25 g, cohort 2 to test 50 g and cohort 3 to test 75 g), 16 patients will be included.
Intervention type	Supplement
Primary outcome measure	Increase in plasma 3-hydroxybutyrate by at least 0.22 mmol/l following administration of enteral 3HHB, measured by LC-MS/MS
Secondary outcome measures	1. Plasma levels of 3HHB and metabolites 3-hydroxybutyrate and 1,3-butanediol measured over time during (6-hour period) and after the intervention (12-hour period), measured by LC-MS/MS 2. Urine levels of 3HHB and metabolites 3-hydroxybutyrate and 1,3-butanediol over time during (6-hour period) and after the intervention (12-hour period), measured by LC-MS/MS 3. Plasma levels of cholesterol (HDL, LDL, total), triglycerides and free fatty acids over time during (6-hour period) and after the intervention (12-hour period), measured by commercial kits 4. Blood glucose concentrations during the 48 h study period, measured by blood-gas-analyzer 5. Incidence of severe (<40 mg/dl) hypoglycemia during the intervention window and until 12 h after stopping study infusion (3HHB or placebo), measured with a blood gas analyser in the ICU 6. Incidence of ketoacidosis during the intervention window and until 12 h after stopping the study infusion, measured with a ketone stick test on arterial blood in the ICU 7. Intolerance for the supplement (including abdominal discomfort or vomiting) during the intervention up until 48 hours after the last intervention, as reported by the patient or observed by the attending (study) nurse
Overall study start date	25/01/2023
Overall study end date	31/12/2026

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	16 patients for each cohort, 3 cohorts maximum. Total maximum target number: 48.
Participant inclusion criteria	1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained 2. Age >= 18 years 3. Patient expected to stay at the ICU for at least 5 days 4. The presence of a nasogastric feeding tube
Participant 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). 5. Contraindication for enteral feeding 6. Readmission to the ICU after previous inclusion in the RCT 7. Inborn metabolic disease 8. Receiving ketogenic diet in ICU 9. Underweigt (BMI<20) 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 chronic liver failure 13. High glucose need to prevent spontaneous hypoglycemia 14. Metabolic acidosis (pH <7.30 and bicarbonate <18 mmol/l)
Recruitment start date	08/01/2024
Recruitment end date	01/12/2025

Locations

Countries of recruitment

Belgium

Study participating centre

UZ Leuven

Herestraat 49
Leuven
3000
Belgium

Sponsor information

Universitair Ziekenhuis Leuven
Hospital/treatment centre

Herestraat 49
Leuven
3000
Belgium

Phone	+32 (0)16 344021
Email	intensieve_geneeskunde@uzleuven.be
Website	https://www.uzleuven.be/en
"ROR"	https://ror.org/0424bsv16

Funders

Funder type

Research council

European Research Council
Government organisation / National government

Alternative name(s): ERC

Vlaamse regering (Methusalem Program)
Government organisation / National government

Alternative name(s): Flanders, Flemish Government, Flandre, Flandern, Vlaanderen
Location: Belgium

Results and Publications

Intention to publish date	01/12/2027
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in publicly available repository
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal
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/).

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file	version 1.3	17/04/2024	24/04/2024	No	No

Additional files

ISRCTN13903536_PROTOCOL_V1.3_17Apr24.pdf

Editorial Notes

23/01/2025: The following changes were made to the study record:
1. The recruitment end date was changed from 07/01/2025 to 01/12/2025.
2. The overall study end date was changed from 31/12/2025 to 31/12/2026.
3. The intention to publish date was changed from 01/12/2026 to 01/12/2027.
24/04/2024: Protocol uploaded.
12/12/2023: The following changes were made to the trial record:
1. The recruitment start date was changed from 15/12/2023 to 08/01/2024.
2. The recruitment end date was changed from 15/12/2025 to 07/01/2025.
16/11/2023: The following has been changed:
1. The recruitment start date was changed from 01/11/2023 to 15/12/2023.
2. The recruitment end date was changed from 01/11/2025 to 15/12/2025.
27/10/2023: Study's existence confirmed by the Ethics Committee Research UZ/KU Leuven.