<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04487678</url>
  </required_header>
  <id_info>
    <org_study_id>KEsupplements</org_study_id>
    <nct_id>NCT04487678</nct_id>
  </id_info>
  <brief_title>Exogenous Ketones in People With Type 1 Diabetes</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this pilot study is to investigate the metabolic effects of exogenous ketone ester&#xD;
      food supplements, by assessing the change in blood acid-base balance, and the level of blood&#xD;
      beta-hydroxy-butyrate in people with type 1 diabetes during resting conditions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The ketone bodies acetoacetate, β-hydroxybutyrate (βHB) and acetone are small lipid-derived&#xD;
      molecules that are produced in the liver under certain conditions such as starvation, very&#xD;
      low carbohydrate intake and prolonged glycogen-depleting exercise. Ketone bodies serve as an&#xD;
      alternative energy substrate for the brain and other metabolically active tissues under&#xD;
      periods of low glucose availability, and can modulate carbohydrate and lipid metabolism.&#xD;
      Previously, controlled physiological ketosis required a low carbohydrate diet, starvation or&#xD;
      administration of acetoacetate (AcAc) salts which were all unpleasant or potentially harmful.&#xD;
      The development of ketone esters provides an alternative method to increase βHB levels, and&#xD;
      has been shown to be well tolerated in rodents and humans. Two examples are the&#xD;
      R,S-1,3-butanediol acetoacetate diester and the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate&#xD;
      ketone monoester. Ingestion of either have been shown to result in short-term (0.5-6 hours)&#xD;
      nutritional ketosis (βHB &gt;1mM). Nutritional ketosis can therefore be achieved without the&#xD;
      need for the impracticality of ketogenic dieting or fasting.&#xD;
&#xD;
      In recent years there has been considerable interest in ketone body food supplements due to&#xD;
      their potential for improved exercise performance and therapeutic glucose lowering effects in&#xD;
      people with type 2 diabetes. Exogenous ketone supplements may be of particular interest for&#xD;
      individuals living with type 1 diabetes by serving as an alternative fuel substrate to reduce&#xD;
      the reliance on glucose utilisation and spare endogenous glycogen and reduce the risk of&#xD;
      hypoglycaemia in certain situations, such as exercise. Stubbs et al. (2017) found that drinks&#xD;
      containing exogenous ketones were a practical and efficacious way to raise blood βHB levels&#xD;
      with only a modest change in acid-base balance in healthy individuals without diabetes (after&#xD;
      60 min, blood pH declined from 7.41 to 7.31 following a ketone ester drink). To date, no&#xD;
      studies have investigated the metabolic effects of ketone in people with type 1 diabetes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Prioritization of other projects&#xD;
  </why_stopped>
  <start_date type="Anticipated">August 2023</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">November 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Single-centre, randomised, single blinded, crossover study in 6 individuals with type 1 diabetes (see inclusion/exclusion criteria)</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>There will be two intervention arms that will take place in a randomised, single blinded fashion so that participants are not aware of which dose of ketone esters they receive</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in venous blood pH</measure>
    <time_frame>Over a 3 hour period from baseline following ingestion of a ketone ester drink in people with type 1 diabetes.</time_frame>
    <description>Change in blood pH over a 3 hour period from baseline following ingestion of a ketone ester drink</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood total ketone level /beta hydroxy butyrate level</measure>
    <time_frame>3 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood glucose concentration</measure>
    <time_frame>3 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio)</measure>
    <time_frame>3 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastro-intestinal distress symptoms via a questionnaire</measure>
    <time_frame>3 hours</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Ketosis, Diabetic</condition>
  <arm_group>
    <arm_group_label>Low-dose KE</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>141 mg/kg bodyweight of ketone esters</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High-dose KE</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>282 mg/kg bodyweight of ketone esters</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Ketone ester supplement</intervention_name>
    <description>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.</description>
    <arm_group_label>High-dose KE</arm_group_label>
    <arm_group_label>Low-dose KE</arm_group_label>
    <other_name>H.V.M.N Ketone Ester food supplement</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 1 diabetes for &gt;1 year&#xD;
&#xD;
          -  Male and female aged 18-45 years old&#xD;
&#xD;
          -  HbA1c &lt;8.5% (69 mmol/mol) based on analysis from the central laboratory unit of Bern&#xD;
             University Hospital&#xD;
&#xD;
          -  Using either continuous subcutaneous insulin infusion or multiple daily injections&#xD;
&#xD;
          -  Wearing a continuous glucose monitor (CGM) or flash glucose monitor (fGM)&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Physical or psychological disease likely to interfere with the normal conduct of the&#xD;
             study and interpretation of the results as judged by the investigator&#xD;
&#xD;
          -  Current treatment with drugs known to interfere with metabolism e.g. systemic&#xD;
             corticosteroids, statins, SGLT2 inhibitors, GLP1 agonists&#xD;
&#xD;
          -  Relevant diabetic complications as judged by the investigator&#xD;
&#xD;
          -  Body mass index &gt; 30 kg/m2&#xD;
&#xD;
          -  Uncontrolled hypertension (&gt;180/100 mmHg)&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Males</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christoph Stettler, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Bern</affiliation>
  </overall_official>
  <removed_countries>
    <country>Switzerland</country>
  </removed_countries>
  <reference>
    <citation>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.</citation>
    <PMID>2656155</PMID>
  </reference>
  <reference>
    <citation>Clarke 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.</citation>
    <PMID>22561291</PMID>
  </reference>
  <reference>
    <citation>Cox 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.</citation>
    <PMID>25379174</PMID>
  </reference>
  <reference>
    <citation>Cox 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.</citation>
    <PMID>27475046</PMID>
  </reference>
  <reference>
    <citation>Egan 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.</citation>
    <PMID>29473164</PMID>
  </reference>
  <reference>
    <citation>Egan 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.</citation>
    <PMID>27626197</PMID>
  </reference>
  <reference>
    <citation>Evans 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.</citation>
    <PMID>27861911</PMID>
  </reference>
  <reference>
    <citation>Flint 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.</citation>
    <PMID>10702749</PMID>
  </reference>
  <reference>
    <citation>Kesl 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.</citation>
    <PMID>26855664</PMID>
  </reference>
  <reference>
    <citation>Myette-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. Erratum In: J Physiol. 2019 Nov;597(22):5515. Abstract corrected.</citation>
    <PMID>29446830</PMID>
  </reference>
  <reference>
    <citation>Pinckaers 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.</citation>
    <PMID>27430501</PMID>
  </reference>
  <reference>
    <citation>Robinson 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.</citation>
    <PMID>6986618</PMID>
  </reference>
  <reference>
    <citation>Stubbs 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.</citation>
    <PMID>29163194</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>August 30, 2023</last_update_submitted>
  <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetic Ketoacidosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04487678
org study id: KEsupplements
nct id: NCT04487678
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Single-centre, randomised, single blinded, crossover study in 6 individuals with type 1 diabetes (see inclusion/exclusion criteria)
primary purpose: Prevention
masking: Single (Participant)
masking description: There will be two intervention arms that will take place in a randomised, single blinded fashion so that participants are not aware of which dose of ketone esters they receive
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.
description: Change in blood pH over a 3 hour period from baseline following ingestion of a ketone ester drink
measure: Blood total ketone level /beta hydroxy butyrate level
time frame: 3 hours
measure: Blood glucose concentration
time frame: 3 hours
measure: Substrate oxidation rates determined using indirect calorimetry, via RER (respiratory exchange ratio)
time frame: 3 hours
measure: Gastro-intestinal distress symptoms via a questionnaire
time frame: 3 hours
arm group label: Low-dose KE
arm group type: Experimental
description: 141 mg/kg bodyweight of ketone esters
arm group label: High-dose KE
arm group type: Experimental
description: 282 mg/kg bodyweight of ketone esters
intervention type: Dietary Supplement
intervention name: Ketone ester supplement
description: 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.
arm group label: High-dose KE
arm group label: Low-dose KE
other name: H.V.M.N Ketone Ester food supplement
criteria: 
gender: Male
gender based: Yes
gender description: Males
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Christoph Stettler, MD
role: Principal Investigator
affiliation: University of Bern
country: Switzerland
citation: 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.
PMID: 2656155
citation: Clarke 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.
PMID: 22561291
citation: Cox 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.
PMID: 25379174
citation: Cox 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.
PMID: 27475046
citation: Egan 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.
PMID: 29473164
citation: Egan 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.
PMID: 27626197
citation: Evans 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.
PMID: 27861911
citation: Flint 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.
PMID: 10702749
citation: Kesl 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.
PMID: 26855664
citation: Myette-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. Erratum In: J Physiol. 2019 Nov;597(22):5515. Abstract corrected.
PMID: 29446830
citation: Pinckaers 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.
PMID: 27430501
citation: Robinson 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.
PMID: 6986618
citation: Stubbs 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.
PMID: 29163194
responsible party type: Sponsor
mesh term: Diabetic Ketoacidosis
sharing ipd: No