Ketosis, DiabeticNCT04487678
Exogenous Ketones in People With Type 1 Diabetes
A study testing Ketone ester supplement in people with Ketosis, Diabetic, run by Insel Gruppe AG, University Hospital Bern.
Trial summary
The aim of this pilot study is to investigate the metabolic effects of exogenous ketone ester food supplements, by assessing the change in blood acid-base balance, and the level of blood beta-hydroxy-butyrate in people with type 1 diabetes during resting conditions. Read more about this study
- Who is it for?
- Ages 18 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Ketosis, Diabetic
- What is being tested?
- Ketone ester supplement
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Aug 2023to Dec 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Type 1 diabetes for >1 year
- Male and female aged 18-45 years old
- HbA1c <8.5% (69 mmol/mol) based on analysis from the central laboratory unit of Bern University Hospital
- Using either continuous subcutaneous insulin infusion or multiple daily injections
- Wearing a continuous glucose monitor (CGM) or flash glucose monitor (fGM)
- Written informed consent
Who cannot join
- Physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the results as judged by the investigator
- Current treatment with drugs known to interfere with metabolism e.g. systemic corticosteroids, statins, SGLT2 inhibitors, GLP1 agonists
- Relevant diabetic complications as judged by the investigator
- Body mass index > 30 kg/m2
- Uncontrolled hypertension (>180/100 mmHg)
About this study
Official title: A Single-centre, Randomised, Single-blinded Crossover Study Evaluating the Metabolic Effects of a Ketone Ester Food Supplement in People With Type 1 Diabetes
The aim of this pilot study is to investigate the metabolic effects of exogenous ketone ester food supplements, by assessing the change in blood acid-base balance, and the level of blood beta-hydroxy-butyrate in people with type 1 diabetes during resting conditions.
Read the detailed description
The ketone bodies acetoacetate, β-hydroxybutyrate (βHB) and acetone are small lipid-derived molecules that are produced in the liver under certain conditions such as starvation, very low carbohydrate intake and prolonged glycogen-depleting exercise. Ketone bodies serve as an alternative energy substrate for the brain and other metabolically active tissues under periods of low glucose availability, and can modulate carbohydrate and lipid metabolism. Previously, controlled physiological ketosis required a low carbohydrate diet, starvation or administration of acetoacetate (AcAc) salts which were all unpleasant or potentially harmful. The development of ketone esters provides an alternative method to increase βHB levels, and has been shown to be well tolerated in rodents and humans. Two examples are the R,S-1,3-butanediol acetoacetate diester and the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester. Ingestion of either have been shown to result in short-term (0.5-6 hours) nutritional ketosis (βHB >1mM). Nutritional ketosis can therefore be achieved without the need for the impracticality of ketogenic dieting or fasting.
In recent years there has been considerable interest in ketone body food supplements due to their potential for improved exercise performance and therapeutic glucose lowering effects in people with type 2 diabetes. Exogenous ketone supplements may be of particular interest for individuals living with type 1 diabetes by serving as an alternative fuel substrate to reduce the reliance on glucose utilisation and spare endogenous glycogen and reduce the risk of hypoglycaemia in certain situations, such as exercise. Stubbs et al. (2017) found that drinks containing exogenous ketones were a practical and efficacious way to raise blood βHB levels with only a modest change in acid-base balance in healthy individuals without diabetes (after 60 min, blood pH declined from 7.41 to 7.31 following a ketone ester drink). To date, no studies have investigated the metabolic effects of ketone in people with type 1 diabetes.
- Conditions
- Ketosis, Diabetic
- Being tested
- Ketone ester supplement
- Medical subject headings
- Diabetic Ketoacidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketone ester supplementDietary supplement
Also called H.V.M.N Ketone Ester food supplement
Participants taking part in this study will receive a drink containing either 141 or 282 mg/kg bodyweight of ketone esters in a randomised order. These doses are in line with recommendations by the company HVMN from which the supplements for this study will be obtained.
| Study group | Role | What they receive |
|---|---|---|
| Low-dose KE | Experimental | 141 mg/kg bodyweight of ketone esters Receives: Dietary Supplement: Ketone ester supplement |
| High-dose KE | Experimental | 282 mg/kg bodyweight of ketone esters Receives: Dietary Supplement: Ketone ester supplement |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in venous blood pH
Change in blood pH over a 3 hour period from baseline following ingestion of a ketone ester drink
Measured: Over a 3 hour period from baseline following ingestion of a ketone ester drink in people with type 1 diabetes.
Secondary outcomes (4)
Blood total ketone level /beta hydroxy butyrate level
Measured: 3 hours
Blood glucose concentration
Measured: 3 hours
Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio)
Measured: 3 hours
Gastro-intestinal distress symptoms via a questionnaire
Measured: 3 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2020
- Study startAug 2023 (estimated)
- Primary completionNov 2023 (estimated)
- Study completionDec 2023 (estimated)
Why it stopped: Prioritization of other projects
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Ketosis, DiabeticStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Single-centre, randomised, single blinded, crossover study in 6 individuals with type 1 diabetes (see inclusion/exclusion criteria)
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Christoph Stettler, MD, Principal investigator, University of Bern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04487678
- Sponsor's protocol ID
- KEsupplements
- Status last verified
- Aug 2023
- First submitted
- 22 Jul 2020
- Last updated
- 1 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Balasse EO, Fery F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989 May;5(3):247-70. doi: 10.1002/dmr.5610050304.
PubMed 2656155Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3.
PubMed 22561291Cox PJ, Clarke K. Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem Physiol Med. 2014 Oct 29;3:17. doi: 10.1186/2046-7648-3-17. eCollection 2014.
PubMed 25379174Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27.
PubMed 27475046Egan B. The glucose-lowering effects of exogenous ketones: is there therapeutic potential? J Physiol. 2018 Apr 15;596(8):1317-1318. doi: 10.1113/JP275938. Epub 2018 Mar 24. No abstract available.
PubMed 29473164Egan B, D'Agostino DP. Fueling Performance: Ketones Enter the Mix. Cell Metab. 2016 Sep 13;24(3):373-375. doi: 10.1016/j.cmet.2016.08.021.
PubMed 27626197Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol. 2017 May 1;595(9):2857-2871. doi: 10.1113/JP273185. Epub 2016 Dec 7.
PubMed 27861911Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord. 2000 Jan;24(1):38-48. doi: 10.1038/sj.ijo.0801083.
PubMed 10702749Kesl SL, Poff AM, Ward NP, Fiorelli TN, Ari C, Van Putten AJ, Sherwood JW, Arnold P, D'Agostino DP. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Nutr Metab (Lond). 2016 Feb 4;13:9. doi: 10.1186/s12986-016-0069-y. eCollection 2016.
PubMed 26855664Myette-Cote E, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018 Apr 15;596(8):1385-1395. doi: 10.1113/JP275709. Epub 2018 Mar 2.
PubMed 29446830Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Sports Med. 2017 Mar;47(3):383-391. doi: 10.1007/s40279-016-0577-y.
PubMed 27430501Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980 Jan;60(1):143-87. doi: 10.1152/physrev.1980.60.1.143. No abstract available.
PubMed 6986618Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K. On the Metabolism of Exogenous Ketones in Humans. Front Physiol. 2017 Oct 30;8:848. doi: 10.3389/fphys.2017.00848. eCollection 2017.
PubMed 29163194
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single-centre, Randomised, Single-blinded Crossover Study Evaluating the Metabolic Effects of a Ketone Ester Food Supplement in People With Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT04487678
- Acronym / sponsor ID
- KEsupplements
- Conditions
- Ketosis, Diabetic
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Prioritization of other projects
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Study start
- Aug 2023 (estimated)
- Primary completion
- Nov 2023 (estimated)
- Study completion
- Dec 2023 (estimated)
- First posted
- 27 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of this pilot study is to investigate the metabolic effects of exogenous ketone ester food supplements, by assessing the change in blood acid-base balance, and the level of blood beta-hydroxy-butyrate in people with type 1 diabetes during resting conditions.
Detailed description
The ketone bodies acetoacetate, β-hydroxybutyrate (βHB) and acetone are small lipid-derived molecules that are produced in the liver under certain conditions such as starvation, very low carbohydrate intake and prolonged glycogen-depleting exercise. Ketone bodies serve as an alternative energy substrate for the brain and other metabolically active tissues under periods of low glucose availability, and can modulate carbohydrate and lipid metabolism. Previously, controlled physiological ketosis required a low carbohydrate diet, starvation or administration of acetoacetate (AcAc) salts which were all unpleasant or potentially harmful. The development of ketone esters provides an alternative method to increase βHB levels, and has been shown to be well tolerated in rodents and humans. Two examples are the R,S-1,3-butanediol acetoacetate diester and the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester. Ingestion of either have been shown to result in short-term (0.5-6 hours) nutritional ketosis (βHB >1mM). Nutritional ketosis can therefore be achieved without the need for the impracticality of ketogenic dieting or fasting.
In recent years there has been considerable interest in ketone body food supplements due to their potential for improved exercise performance and therapeutic glucose lowering effects in people with type 2 diabetes. Exogenous ketone supplements may be of particular interest for individuals living with type 1 diabetes by serving as an alternative fuel substrate to reduce the reliance on glucose utilisation and spare endogenous glycogen and reduce the risk of hypoglycaemia in certain situations, such as exercise. Stubbs et al. (2017) found that drinks containing exogenous ketones were a practical and efficacious way to raise blood βHB levels with only a modest change in acid-base balance in healthy individuals without diabetes (after 60 min, blood pH declined from 7.41 to 7.31 following a ketone ester drink). To date, no studies have investigated the metabolic effects of ketone in people with type 1 diabetes.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Single-centre, randomised, single blinded, crossover study in 6 individuals with type 1 diabetes (see inclusion/exclusion criteria)
| Arm | Type | Receives |
|---|---|---|
| Low-dose KE | Experimental | Dietary Supplement: Ketone ester supplement141 mg/kg bodyweight of ketone esters |
| High-dose KE | Experimental | Dietary Supplement: Ketone ester supplement282 mg/kg bodyweight of ketone esters |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Type 1 diabetes for >1 year
- Male and female aged 18-45 years old
- HbA1c <8.5% (69 mmol/mol) based on analysis from the central laboratory unit of Bern University Hospital
- Using either continuous subcutaneous insulin infusion or multiple daily injections
- Wearing a continuous glucose monitor (CGM) or flash glucose monitor (fGM)
Key exclusion criteria (5 listed)
- Physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the results as judged by the investigator
- Current treatment with drugs known to interfere with metabolism e.g. systemic corticosteroids, statins, SGLT2 inhibitors, GLP1 agonists
- Relevant diabetic complications as judged by the investigator
- Body mass index > 30 kg/m2
- Uncontrolled hypertension (>180/100 mmHg)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketone ester supplementAlso: H.V.M.N Ketone Ester food supplementParticipants taking part in this study will receive a drink containing either 141 or 282 mg/kg bodyweight of ketone esters in a randomised order. These doses are in line with recommendations by the company HVMN from which the supplements for this study will be obtained. | Dietary supplement | High-dose KE, Low-dose KE |
Primary outcome
Change in venous blood pH
Time frame: Over a 3 hour period from baseline following ingestion of a ketone ester drink in people with type 1 diabetes.
Change in blood pH over a 3 hour period from baseline following ingestion of a ketone ester drink
4 secondary outcomes
Blood total ketone level /beta hydroxy butyrate level
Time frame: 3 hours
Blood glucose concentration
Time frame: 3 hours
Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio)
Time frame: 3 hours
Gastro-intestinal distress symptoms via a questionnaire
Time frame: 3 hours
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2023.
- Background: PubMed 2656155Balasse EO, Fery F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989 May;5(3):247-70. doi: 10.1002/dmr.5610050304.
- Background: PubMed 22561291Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, Ho M, Roberts A, Robertson J, Vanitallie TB, Veech RL. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol. 2012 Aug;63(3):401-8. doi: 10.1016/j.yrtph.2012.04.008. Epub 2012 May 3.
- Background: PubMed 25379174Cox PJ, Clarke K. Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem Physiol Med. 2014 Oct 29;3:17. doi: 10.1186/2046-7648-3-17. eCollection 2014.
- Background: PubMed 27475046Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27.
- Background: PubMed 29473164Egan B. The glucose-lowering effects of exogenous ketones: is there therapeutic potential? J Physiol. 2018 Apr 15;596(8):1317-1318. doi: 10.1113/JP275938. Epub 2018 Mar 24. No abstract available.
- Background: PubMed 27626197Egan B, D'Agostino DP. Fueling Performance: Ketones Enter the Mix. Cell Metab. 2016 Sep 13;24(3):373-375. doi: 10.1016/j.cmet.2016.08.021.
- Background: PubMed 27861911Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol. 2017 May 1;595(9):2857-2871. doi: 10.1113/JP273185. Epub 2016 Dec 7.
- Background: PubMed 10702749Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord. 2000 Jan;24(1):38-48. doi: 10.1038/sj.ijo.0801083.
- Background: PubMed 26855664Kesl SL, Poff AM, Ward NP, Fiorelli TN, Ari C, Van Putten AJ, Sherwood JW, Arnold P, D'Agostino DP. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Nutr Metab (Lond). 2016 Feb 4;13:9. doi: 10.1186/s12986-016-0069-y. eCollection 2016.
- Background: PubMed 29446830Myette-Cote E, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018 Apr 15;596(8):1385-1395. doi: 10.1113/JP275709. Epub 2018 Mar 2.
- Background: PubMed 27430501Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Sports Med. 2017 Mar;47(3):383-391. doi: 10.1007/s40279-016-0577-y.
- Background: PubMed 6986618Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980 Jan;60(1):143-87. doi: 10.1152/physrev.1980.60.1.143. No abstract available.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christoph Stettler, MD principal investigator
University of Bern
Questions about this trial
What is this clinical trial studying?
A study testing Ketone ester supplement in people with Ketosis, Diabetic, run by Insel Gruppe AG, University Hospital Bern.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 1 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in venous blood pH (time frame: Over a 3 hour period from baseline following ingestion of a ketone ester drink in people with type 1 diabetes.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04487678, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2023.