<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/NCT03817749</url>
  </required_header>
  <id_info>
    <org_study_id>H18-02930</org_study_id>
    <nct_id>NCT03817749</nct_id>
  </id_info>
  <brief_title>Ketone Supplementation, Glucose Control, and Cardiovascular Function</brief_title>
  <official_title>The Effects of Exogenous Ketone Supplementation on Cardiovascular Function and Glucose Control</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of British Columbia</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>
      Post-prandial hyperglycemic excursions induce a cascade of deleterious effects on the body,&#xD;
      including increased inflammation, production of reactive oxygen species, and impaired&#xD;
      cardiovascular function. Ingestion of an exogenous oral ketone supplement blunts&#xD;
      hyperglycemia in response to an oral glucose tolerance test. Accordingly, it is hypothesized&#xD;
      that exogenous ketone supplement ingestion prior to a meal could be an effective strategy for&#xD;
      blunting postprandial hyperglycemia. Therefore, the purpose of this study is to investigate&#xD;
      the effect of short-term (14-days) pre-meal exogenous ketone supplementation on glucose&#xD;
      control, cardiovascular function, inflammation, and oxidative stress in individuals at an&#xD;
      elevated risk of type 2 diabetes.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 6, 2019</start_date>
  <completion_date type="Actual">December 31, 2020</completion_date>
  <primary_completion_date type="Actual">March 1, 2020</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>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Glucose control</measure>
    <time_frame>2 hours after a meal</time_frame>
    <description>Post-prandial glucose excursions will be measured by continuous glucose monitoring using the iPro2 CGM by Medtronic in both the active and placebo supplement conditions. Post-prandial glucose following breakfast, lunch, and dinner will be averaged together.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline flow mediated dilation at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Vascular function will be assessed by flow mediated dilation of the brachial artery using vascular ultrasound. A cuff will affixed on the forearm, distal to the brachial artery and will be inflated for 5 minutes. Flow mediation dilation will be measured over a 3-minute period following cuff release.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline histone acetylation at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Histone H3 acetylation status will be quantified by flow cytometry using conjugated acetyl-histone H3 antibody specific for Lys9 (Pacific Blue 445) and the conjugated acetyl-histone H3 antibody specific for Lys14 (Alexa Fluor 488).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline mitochondrial superoxide production at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Oxidative Stress will be measured by mitochondrial superoxide production in blood lymphocytes, monocytes, and neutrophils by flow cytometry using the MitoSOX red assay (ThermoFisher #M36008) and total intracellular ROS via the DCFDA assay (Sigma #D6883)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline cognition (executive functions) at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Cognition will be assessed using a customized battery of psychometrically validated tests within the domain of executive functions using the iPad-based app BrainBaseline. The tests will be the Stroop test, task-switching test, digit-symbol substitution test, and the n-back test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline plasma glucose at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Venous blood samples will be taken and plasma glucose will be measured using a hexokinase method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline plasma insulin at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Venous blood samples will be taken and plasma insulin will be measured using a high-sensitivity human insulin ELISA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline plasma free fatty acids at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Venous blood samples will be taken and free fatty acids will be measured by colorimetric assay.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline interleukin-1(IL)-1beta at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Mature IL-1beta secretion will be quantified by ELISA run in duplicate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline caspase-1 activation at 14 days</measure>
    <time_frame>Day 0 (Pre-intervention) and Day 14 (post-intervention)</time_frame>
    <description>Caspase-1 activation will be quantified by flow cytometry. The fluorescent inhibitor probe FAM-YVAD-FMK binds covalently to activated caspase-1 and emits at 530nm</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Hyperglycemia, Postprandial</condition>
  <condition>Overweight and Obesity</condition>
  <condition>Diabetes Mellitus Risk</condition>
  <arm_group>
    <arm_group_label>Experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will consume 20 g of an active oral exogenous ketone monoester supplement 15 minutes prior to each meal of the day for a 14-day period.&#xD;
Pre-intervention (baseline) and post-intervention measurements will be obtained before and immediately after the 14-day period.&#xD;
All meals will be provided throughout the supplementation period&#xD;
Participants will wear a continuous glucose monitor for 6 consecutive days during the supplementation period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will consume a flavor matched placebo drink and undergo the same procedures described in the Experimental Arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Exogenous ketone monoester</intervention_name>
    <description>Participants will consume 20g of the oral ketone monoester supplement 15 minutes prior to each meal of the day for 14 days. All meals will be provided throughout the 14-day supplementation period.</description>
    <arm_group_label>Experimental</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>HVMN ketone monoester supplement</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Elevated waist circumference (&gt;102 cm for males, &gt;88 cm for females) and/or Obesity&#xD;
             (BMI &gt; 30 kg/m2) and/or Diagnoses of prediabetes based on A1C (5.7-6.4%) and/or&#xD;
             fasting plasma glucose (5.6-6.9 mmol/l) using ADA criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Competitively trained endurance athlete&#xD;
&#xD;
          -  Actively attempting to lose weight&#xD;
&#xD;
          -  History of mental illness or existing neurological disease(s)&#xD;
&#xD;
          -  Previous cardiovascular events (i.e., heart attack, stroke)&#xD;
&#xD;
          -  Diagnoses of diabetes&#xD;
&#xD;
          -  Hypoglycemia&#xD;
&#xD;
          -  Irritable bowel syndrome or inflammatory bowel disease&#xD;
&#xD;
          -  Taking medication that may interfere with insulin sensitivity&#xD;
&#xD;
          -  Currently following a ketogenic diet or taking ketone supplements&#xD;
&#xD;
          -  Unable to commit for 2 separate 14-day trials and unable to follow a controlled diet&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>69 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of British Columbia, Okanagan.</name>
      <address>
        <city>Kelowna</city>
        <state>British Columbia</state>
        <zip>V1V 1V7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>April 26, 2021</last_update_submitted>
  <last_update_submitted_qc>April 26, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 28, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Jonathan Little</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Flow mediated dilation</keyword>
  <keyword>Glucose control</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Immune cell function</keyword>
  <keyword>Cognition</keyword>
  <keyword>Oxidative stress</keyword>
  <keyword>Cardiovascular function</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Overweight</mesh_term>
    <mesh_term>Hyperglycemia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>The investigators will share individual patient data (de-identified) with researchers upon request.</ipd_description>
  </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/NCT03817749
org study id: H18-02930
nct id: NCT03817749
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Post-prandial hyperglycemic excursions induce a cascade of deleterious effects on the body,
      including increased inflammation, production of reactive oxygen species, and impaired
      cardiovascular function. Ingestion of an exogenous oral ketone supplement blunts
      hyperglycemia in response to an oral glucose tolerance test. Accordingly, it is hypothesized
      that exogenous ketone supplement ingestion prior to a meal could be an effective strategy for
      blunting postprandial hyperglycemia. Therefore, the purpose of this study is to investigate
      the effect of short-term (14-days) pre-meal exogenous ketone supplementation on glucose
      control, cardiovascular function, inflammation, and oxidative stress in individuals at an
      elevated risk of type 2 diabetes.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Glucose control
time frame: 2 hours after a meal
description: Post-prandial glucose excursions will be measured by continuous glucose monitoring using the iPro2 CGM by Medtronic in both the active and placebo supplement conditions. Post-prandial glucose following breakfast, lunch, and dinner will be averaged together.
measure: Change from baseline flow mediated dilation at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Vascular function will be assessed by flow mediated dilation of the brachial artery using vascular ultrasound. A cuff will affixed on the forearm, distal to the brachial artery and will be inflated for 5 minutes. Flow mediation dilation will be measured over a 3-minute period following cuff release.
measure: Change from baseline histone acetylation at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Histone H3 acetylation status will be quantified by flow cytometry using conjugated acetyl-histone H3 antibody specific for Lys9 (Pacific Blue 445) and the conjugated acetyl-histone H3 antibody specific for Lys14 (Alexa Fluor 488).
measure: Change from baseline mitochondrial superoxide production at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Oxidative Stress will be measured by mitochondrial superoxide production in blood lymphocytes, monocytes, and neutrophils by flow cytometry using the MitoSOX red assay (ThermoFisher #M36008) and total intracellular ROS via the DCFDA assay (Sigma #D6883)
measure: Change from baseline cognition (executive functions) at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Cognition will be assessed using a customized battery of psychometrically validated tests within the domain of executive functions using the iPad-based app BrainBaseline. The tests will be the Stroop test, task-switching test, digit-symbol substitution test, and the n-back test.
measure: Change from baseline plasma glucose at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Venous blood samples will be taken and plasma glucose will be measured using a hexokinase method.
measure: Change from baseline plasma insulin at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Venous blood samples will be taken and plasma insulin will be measured using a high-sensitivity human insulin ELISA.
measure: Change from baseline plasma free fatty acids at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Venous blood samples will be taken and free fatty acids will be measured by colorimetric assay.
measure: Change from baseline interleukin-1(IL)-1beta at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Mature IL-1beta secretion will be quantified by ELISA run in duplicate
measure: Change from baseline caspase-1 activation at 14 days
time frame: Day 0 (Pre-intervention) and Day 14 (post-intervention)
description: Caspase-1 activation will be quantified by flow cytometry. The fluorescent inhibitor probe FAM-YVAD-FMK binds covalently to activated caspase-1 and emits at 530nm
arm group label: Experimental
arm group type: Experimental
description: Participants will consume 20 g of an active oral exogenous ketone monoester supplement 15 minutes prior to each meal of the day for a 14-day period.
Pre-intervention (baseline) and post-intervention measurements will be obtained before and immediately after the 14-day period.
All meals will be provided throughout the supplementation period
Participants will wear a continuous glucose monitor for 6 consecutive days during the supplementation period.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will consume a flavor matched placebo drink and undergo the same procedures described in the Experimental Arm
intervention type: Dietary Supplement
intervention name: Exogenous ketone monoester
description: Participants will consume 20g of the oral ketone monoester supplement 15 minutes prior to each meal of the day for 14 days. All meals will be provided throughout the 14-day supplementation period.
arm group label: Experimental
arm group label: Placebo
other name: HVMN ketone monoester supplement
criteria: 
gender: All
minimum age: 30 Years
maximum age: 69 Years
healthy volunteers: No
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Jonathan Little
investigator title: Assistant Professor
mesh term: Overweight
mesh term: Hyperglycemia
sharing ipd: Undecided
ipd description: The investigators will share individual patient data (de-identified) with researchers upon request.