<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/NCT04443426</url>
  </required_header>
  <id_info>
    <org_study_id>KETO- CHF 1-10-72-362-18</org_study_id>
    <nct_id>NCT04443426</nct_id>
  </id_info>
  <brief_title>Modulation of Circulating Levels of the Ketone Body 3-hydroxybutyrate in Patients With Chronic Heart Failure: Cardiovascular Effects</brief_title>
  <acronym>KETO-KINETICS1</acronym>
  <official_title>Modulation of Circulating Levels of the Ketone Body 3-hydroxybutyrate in Patients With Chronic Heart Failure: Cardiovascular Effects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aarhus</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 ketone body 3-hydroxybutyrate (3-OHB) is a naturally occurring energy substrate, and is&#xD;
      associated with increased life span and improved health. We have previously shown that&#xD;
      intravenous 3-OHB treatment increases myocardial blood flow &gt; 70% in healthy humans and data&#xD;
      from our group show that 3-OHB increases cardiac output by 40 % in patients with heart&#xD;
      failure.&#xD;
&#xD;
      In this study the investigators aim to investigate:&#xD;
&#xD;
        1. If this effect is reproducible with a commercially available oral ketone supplements&#xD;
&#xD;
        2. The safety of commercially available ketone supplements in heart failure patients&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Heart Failure (HF) is a major public health issue because the disease affects 1-2% of the&#xD;
      Western population and the lifetime risk of HF is 20%. HF is responsible for 1-2% of all&#xD;
      healthcare expenditures. Despite major improvements in the management and care of patients&#xD;
      with HF, the 1-year mortality in patients with HF is 13 % and &gt;50% of HF-patients is admitted&#xD;
      during a 2.5 year period. Furthermore patients with HF have markedly decreased physical&#xD;
      capacity and quality of life. Thus, there is a need for new treatment modalities in this&#xD;
      group of patients.&#xD;
&#xD;
      Ketone bodies are produced in the liver and are of vital importance in the human body for&#xD;
      energy generation in the heart and brain during fasting, exercise and severe illness. Ketosis&#xD;
      can be safely obtained using dietary supplements and can increase exercise capacity in&#xD;
      athletes. The most important ketone bodies are 3-hydroxybutyrate (3-OHB) and acetoacetate.&#xD;
      Recently, it was demonstrated that patients with severe HF have increased myocardial&#xD;
      utilization of the ketone body 3-hydroxybutyrate.&#xD;
&#xD;
      We have shown, using positron emission tomography, that ketone body infusion reduces&#xD;
      myocardial glucose uptake and increases myocardial blood flow in healthy subjects. Data from&#xD;
      another study conducted by our group show a 40% increase in cardiac output during infusion of&#xD;
      3-OHB.&#xD;
&#xD;
      Presently there are no data on the clinical cardiovascular and metabolic effects of long-term&#xD;
      oral ketone-supplementation in patients with chronic HF.&#xD;
&#xD;
      In this study the investigators will whether ketosis obtained by oral ketone supplements&#xD;
      affects hemodynamics and contractile function.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 25, 2019</start_date>
  <completion_date type="Anticipated">November 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">November 1, 2022</primary_completion_date>
  <phase>Phase 2</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>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cardiac Output (L/min)</measure>
    <time_frame>5 hours - Area under the curve</time_frame>
    <description>Right Heart Catherization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Left Ventricle Ejection Fraction (%)</measure>
    <time_frame>5 Hours - Area under the curve</time_frame>
    <description>Echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricular filling pressure (mmHg)</measure>
    <time_frame>5 hours - Area under the curve</time_frame>
    <description>Right Heart Catherization</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Heart Failure</condition>
  <condition>Ketosis</condition>
  <condition>Ketonemia</condition>
  <arm_group>
    <arm_group_label>Single dose oral 3-hydroxybutyrate monoester</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cross-over study in 8 patients receiving single-dose oral 3-hydroxybutyrate monoester, 3-OHB salt and placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Single dose oral 3-hydroxybutyrate Salt</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Single dose oral placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>maltodextrin-based, isocaloric to ketone dosis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Oral 3-hydroxybutyrate salts</intervention_name>
    <description>Comercially available 3-hydroxybutyrate salts with 36 grams of 3-OHB salts three times daily.</description>
    <arm_group_label>Single dose oral 3-hydroxybutyrate Salt</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Carbohydrate Placebo</intervention_name>
    <description>Comercially available carbohydrate sports drink. The placebo dose is isocaloric to the 3-hydroxy butyrate dose.</description>
    <arm_group_label>Single dose oral placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Ketone Monoester</intervention_name>
    <description>Commercially available ketone monoester in a dosage isocaloric to 3-OHB salts.</description>
    <arm_group_label>Single dose oral 3-hydroxybutyrate monoester</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Chronic Heart Failure;&#xD;
&#xD;
          -  NYHA class II-III&#xD;
&#xD;
          -  Left Ventricular Ejection Fraction &lt;40%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diabetes or HbA1c &gt; 48 mmol/mol&#xD;
&#xD;
          -  Significant cardiac valve disease,&#xD;
&#xD;
          -  Severe stable angina pectoris&#xD;
&#xD;
          -  Severe comorbidity as judged by investigator,&#xD;
&#xD;
          -  Inability to give informed consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristian H Christensen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Aarhus Universitetshospital - Department of Cardiology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Aarhus University Hospital</name>
      <address>
        <city>Aarhus</city>
        <zip>8200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>May 20, 2019</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>August 16, 2022</last_update_submitted>
  <last_update_submitted_qc>August 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Metabolism</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Ketosis</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 15, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/26/NCT04443426/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04443426
org study id: KETO- CHF 1-10-72-362-18
nct id: NCT04443426
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The ketone body 3-hydroxybutyrate (3-OHB) is a naturally occurring energy substrate, and is
      associated with increased life span and improved health. We have previously shown that
      intravenous 3-OHB treatment increases myocardial blood flow > 70% in healthy humans and data
      from our group show that 3-OHB increases cardiac output by 40 % in patients with heart
      failure.

      In this study the investigators aim to investigate:

        1. If this effect is reproducible with a commercially available oral ketone supplements

        2. The safety of commercially available ketone supplements in heart failure patients
Heart Failure (HF) is a major public health issue because the disease affects 1-2% of the
      Western population and the lifetime risk of HF is 20%. HF is responsible for 1-2% of all
      healthcare expenditures. Despite major improvements in the management and care of patients
      with HF, the 1-year mortality in patients with HF is 13 % and >50% of HF-patients is admitted
      during a 2.5 year period. Furthermore patients with HF have markedly decreased physical
      capacity and quality of life. Thus, there is a need for new treatment modalities in this
      group of patients.

      Ketone bodies are produced in the liver and are of vital importance in the human body for
      energy generation in the heart and brain during fasting, exercise and severe illness. Ketosis
      can be safely obtained using dietary supplements and can increase exercise capacity in
      athletes. The most important ketone bodies are 3-hydroxybutyrate (3-OHB) and acetoacetate.
      Recently, it was demonstrated that patients with severe HF have increased myocardial
      utilization of the ketone body 3-hydroxybutyrate.

      We have shown, using positron emission tomography, that ketone body infusion reduces
      myocardial glucose uptake and increases myocardial blood flow in healthy subjects. Data from
      another study conducted by our group show a 40% increase in cardiac output during infusion of
      3-OHB.

      Presently there are no data on the clinical cardiovascular and metabolic effects of long-term
      oral ketone-supplementation in patients with chronic HF.

      In this study the investigators will whether ketosis obtained by oral ketone supplements
      affects hemodynamics and contractile function.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Cardiac Output (L/min)
time frame: 5 hours - Area under the curve
description: Right Heart Catherization
measure: Left Ventricle Ejection Fraction (%)
time frame: 5 Hours - Area under the curve
description: Echocardiography
measure: Left Ventricular filling pressure (mmHg)
time frame: 5 hours - Area under the curve
description: Right Heart Catherization
arm group label: Single dose oral 3-hydroxybutyrate monoester
arm group type: Experimental
description: Cross-over study in 8 patients receiving single-dose oral 3-hydroxybutyrate monoester, 3-OHB salt and placebo.
arm group label: Single dose oral 3-hydroxybutyrate Salt
arm group type: Experimental
arm group label: Single dose oral placebo
arm group type: Placebo Comparator
description: maltodextrin-based, isocaloric to ketone dosis.
intervention type: Dietary Supplement
intervention name: Oral 3-hydroxybutyrate salts
description: Comercially available 3-hydroxybutyrate salts with 36 grams of 3-OHB salts three times daily.
arm group label: Single dose oral 3-hydroxybutyrate Salt
intervention type: Dietary Supplement
intervention name: Carbohydrate Placebo
description: Comercially available carbohydrate sports drink. The placebo dose is isocaloric to the 3-hydroxy butyrate dose.
arm group label: Single dose oral placebo
intervention type: Dietary Supplement
intervention name: Ketone Monoester
description: Commercially available ketone monoester in a dosage isocaloric to 3-OHB salts.
arm group label: Single dose oral 3-hydroxybutyrate monoester
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kristian H Christensen, MD
role: Principal Investigator
affiliation: Aarhus Universitetshospital - Department of Cardiology
facility: 
country: Denmark
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Ketosis
provided document: 