xml: <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/NCT06022588</url>
    </required_header>
    <id_info>
      <org_study_id>NL72878.078.20</org_study_id>
      <nct_id>NCT06022588</nct_id>
    </id_info>
    <brief_title>Chronic Mesenteric Ischemia Breath Testing</brief_title>
    <official_title>Heavy Isotope-labeled-butyrate and Glucose in Breath Testing to Detect Mesenteric Ischemia, a Proof-of-concept Study in Healthy Volunteers.</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Erasmus Medical Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Erasmus Medical Center</source>
    <oversight_info>
      <has_dmc>Yes</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>
        Background and aims:&#xD;
  &#xD;
        A gold standard diagnostic test to diagnose chronic mesenteric ischemia is currently lacking.&#xD;
        Isotope labelled-butyrate and glucose breath testing could theoretically quantify mucosal&#xD;
        oxygen consumption and thereby detect ischemia, since oxygen is needed to absorb and&#xD;
        metabolize butyrate and glucose, and distinguish aerobic/anaerobic intestinal epithelial&#xD;
        metabolism. Here we aim to test this notion and compare results to conventional biomarkers.&#xD;
  &#xD;
        Methods:&#xD;
  &#xD;
        Healthy volunteers were randomized into two control groups and two intervention groups, each&#xD;
        consisting of five volunteers receiving either oral 13C -butyrate or 13C -glucose. The&#xD;
        control groups performed breath tests without any physical exercise. The intervention groups&#xD;
        performed a 30 minutes standardized bicycle exercise test, which has been proven to elicit&#xD;
        mesenteric ischemia. Breath samples of expired 13CO2 were collected during a period of 4&#xD;
        hours and results were contrasted to measurements of biomarkers in peripheral blood.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Even as chronic mesenteric ischemia (CMI) is the most common vascular disorder involving the&#xD;
        mesenteric arteries, accounting for 2% of all revascularization procedures, it remains an&#xD;
        underdiagnosed condition. CMI is an invalidating disease that causes severe complaints of&#xD;
        post-prandial abdominal pain, food fear and weight loss. Diagnosis of CMI remains difficult&#xD;
        since no gold standard diagnostic test exists, the presumptive diagnosis of CMI is currently&#xD;
        confirmed when a patient experiences relief of symptoms after revascularization. For making&#xD;
        treatment decisions, clinicians rely on a consensus diagnosis, based on clinical history,&#xD;
        presence of mesenteric artery stenosis on abdominal imaging, and, in dedicated centers, the&#xD;
        outcome of a functional test, such as visible light spectroscopy (VLS) or tonometry. The&#xD;
        diagnostic accuracy of this consensus diagnosis is unstatisfactory, since clinical&#xD;
        improvement is achieved in only 73% of patients with a consensus diagnosis of CMI based on a&#xD;
        single mesenteric artery stenosis. Per extenso in the remaining 27% treatment was initiated&#xD;
        in patients not suffering from CMI. Stressing the need for a reliable diagnostic test to&#xD;
        identify patients with CMI.&#xD;
  &#xD;
        In the intestinal epithelium the most important substrate for mitochondrion-dependent ATP&#xD;
        production, and by consequence as the source for CO2 release is butyrate, a small chain fatty&#xD;
        acid produced by the intestinal microflora. Under ischemic conditions, butyrate can no longer&#xD;
        be metabolized. The most straight forward biochemical pathway to cope with this situation is&#xD;
        a switch in cellular metabolism to anaerobic glycolysis. In this process glucose is&#xD;
        metabolized to pyruvate, producing two ATP molecules, providing an oxygen independent pathway&#xD;
        for maintaining ATP production, but also resulting in the reduction of NAD+ molecules into&#xD;
        NADH+. To maintain ATP production, pyruvate will undergo a process called fermentation&#xD;
        resulting in the production of lactate in which NADH+ is recycled back to NAD+ so that&#xD;
        glycolysis can continue. Upon subsequent transport via the blood, lactate is cleared in the&#xD;
        liver and the resulting CO2 will leave the body via the lungs. Hence theoretically measuring&#xD;
        the shift from butyrate towards glucose metabolism, which occurs in enterocytes under&#xD;
        anaerobic conditions, could be a method to detect mucosal ischemia.&#xD;
  &#xD;
        This multi-center randomized interventional proof of principal study explored the possibility&#xD;
        to quantify mucosal oxygen content by labeled-butyrate and labelled-glucose breath testing as&#xD;
        a potential test to diagnose CMI. Since both substrates are dependent on oxygen to be&#xD;
        metabolized, it is expected that subjects with low mucosal oxygen concentrations will&#xD;
        metabolize less butyrate and glucose compared to subjects with normal mucosal oxygen&#xD;
        concentrations.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Completed</overall_status>
    <start_date type="Actual">March 1, 2021</start_date>
    <completion_date type="Actual">August 1, 2021</completion_date>
    <primary_completion_date type="Actual">April 1, 2021</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>Single Group Assignment</intervention_model>
      <primary_purpose>Diagnostic</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>The median concentrations of measured 13CO2</measure>
      <time_frame>At the following time points; baseline, 0.5, 1, 1.25 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5 and 4 hours (total of 12 time points) after ingestion of 13C-butyrate or 13C-glucose.</time_frame>
      <description>The median concentrations of measured 13CO2 at each time point where compared within the four groups and statistically tested with a Mann - Whitney U test.</description>
    </primary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Actual">20</enrollment>
    <condition>Chronic Mesenteric Ischemia</condition>
    <arm_group>
      <arm_group_label>13C -butyrate control group</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>5 healthy volunteers performed the breath test without any psychical exercise</description>
    </arm_group>
    <arm_group>
      <arm_group_label>13C -butyrate intervention group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>5 healthy volunteers performed the breath test with psychical exercise - bicycle test</description>
    </arm_group>
    <arm_group>
      <arm_group_label>13C -glucose control group</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>5 healthy volunteers performed the breath test without any psychical exercise</description>
    </arm_group>
    <arm_group>
      <arm_group_label>13C -glucose intervention group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>5 healthy volunteers performed the breath test with psychical exercise - bicycle test</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sodium butyrate, 1-13C, 99%, Cambridge Isotope Laboratories, Inc.USA</intervention_name>
      <description>a solution containing butyrate of which 12C of the last 4 carbon positions of butyrate were replaced by 13C butyrate. Participants received 0.80 gram 13C-butyrate (7.3 mMol butyrate / 29 mMol 13C) dissolved in 50 mL water at baseline</description>
      <arm_group_label>13C -butyrate control group</arm_group_label>
      <arm_group_label>13C -butyrate intervention group</arm_group_label>
      <other_name>13C butyrate</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>U-13C6, 99%; Cambridge Isotope Laboratories, Inc.USA</intervention_name>
      <description>a glucose solution in which all six 12C carbons were replaced by 13C D-Glucose. Participants received 0.75 gram 13C-glucose (4.2 mMol D-glucose/ 25 mMol 13C) dissolved in 50 mL water at baseline</description>
      <arm_group_label>13C -glucose control group</arm_group_label>
      <arm_group_label>13C -glucose intervention group</arm_group_label>
      <other_name>13C glucose</other_name>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Breath test</intervention_name>
      <description>Breath tests were performed at the following time points baseline, 0.5, 1, 1.25 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5 and 4 hours after ingestion of 13C-butyrate and 13C-glucose. Breath samples were obtained by blowing a single breath of air through a straw into a test tube. Two breath samples were collected at all mentioned time points. Measurement of 13CO2 is performed using mass spectrometry (IDMicro Breath, Compact Science Systems, Newcastle-Under-Lyme, United Kingdom) using procedures described earlier for galactose and methacetin breath tests, and expressed as an absolute increase in the 13CO2-to-12CO2 ratio in delta permil (δ‰).</description>
      <arm_group_label>13C -butyrate control group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Exercise + breath test</intervention_name>
      <description>The intervention groups performed a standardized bicycle ergometer exercise test of 30 minutes and semi-continuous peripheral blood lactate monitoring. The bicycle ergometer protocol consists of three phases. The first 10 minutes of exercise was used to gradually increase the workload until submaximal exercise intensity was reached which is defined as a circulating blood lactate level between 3 and 5.5 mmol/L. From minute 10 to 20 submaximal exercise intensity was maintained by adjusting the workload based on lactate measurements. Minute 20 to 30 was used to reach maximal exercise intensity, the workload was increased by 10% of the submaximal workload until exhaustion</description>
      <arm_group_label>13C -butyrate intervention group</arm_group_label>
      <arm_group_label>13C -glucose control group</arm_group_label>
      <arm_group_label>13C -glucose intervention group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  healthy volunteers without any gastrointestinal complaints&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  pregnant woman&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>N/A</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Marco Bruno, prof.</last_name>
      <role>Principal Investigator</role>
      <affiliation>Erasmus Medical Center</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>Erasmus Medical Center - Department of Gastroenterology</name>
        <address>
          <city>Rotterdam</city>
          <country>Netherlands</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Netherlands</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 26, 2023</study_first_submitted>
    <study_first_submitted_qc>August 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 5, 2023</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 5, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Erasmus Medical Center</investigator_affiliation>
      <investigator_full_name>Marco J. Bruno</investigator_full_name>
      <investigator_title>Gastroenterologist</investigator_title>
    </responsible_party>
    <keyword>Chronic mesenteric ischemia</keyword>
    <keyword>Diagnostic</keyword>
    <keyword>Breath test</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Mesenteric Ischemia</mesh_term>
      <mesh_term>Ischemia</mesh_term>
      <mesh_term>Chronic Disease</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Butyric Acid</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <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 8, 2020</document_date>
        <document_url>https://ClinicalTrials.gov/ProvidedDocs/88/NCT06022588/Prot_SAP_000.pdf</document_url>
      </provided_document>
    </provided_document_section>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06022588
  org study id: NL72878.078.20
  nct id: NCT06022588
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Background and aims:
  
        A gold standard diagnostic test to diagnose chronic mesenteric ischemia is currently lacking.
        Isotope labelled-butyrate and glucose breath testing could theoretically quantify mucosal
        oxygen consumption and thereby detect ischemia, since oxygen is needed to absorb and
        metabolize butyrate and glucose, and distinguish aerobic/anaerobic intestinal epithelial
        metabolism. Here we aim to test this notion and compare results to conventional biomarkers.
  
        Methods:
  
        Healthy volunteers were randomized into two control groups and two intervention groups, each
        consisting of five volunteers receiving either oral 13C -butyrate or 13C -glucose. The
        control groups performed breath tests without any physical exercise. The intervention groups
        performed a 30 minutes standardized bicycle exercise test, which has been proven to elicit
        mesenteric ischemia. Breath samples of expired 13CO2 were collected during a period of 4
        hours and results were contrasted to measurements of biomarkers in peripheral blood.
  Even as chronic mesenteric ischemia (CMI) is the most common vascular disorder involving the
        mesenteric arteries, accounting for 2% of all revascularization procedures, it remains an
        underdiagnosed condition. CMI is an invalidating disease that causes severe complaints of
        post-prandial abdominal pain, food fear and weight loss. Diagnosis of CMI remains difficult
        since no gold standard diagnostic test exists, the presumptive diagnosis of CMI is currently
        confirmed when a patient experiences relief of symptoms after revascularization. For making
        treatment decisions, clinicians rely on a consensus diagnosis, based on clinical history,
        presence of mesenteric artery stenosis on abdominal imaging, and, in dedicated centers, the
        outcome of a functional test, such as visible light spectroscopy (VLS) or tonometry. The
        diagnostic accuracy of this consensus diagnosis is unstatisfactory, since clinical
        improvement is achieved in only 73% of patients with a consensus diagnosis of CMI based on a
        single mesenteric artery stenosis. Per extenso in the remaining 27% treatment was initiated
        in patients not suffering from CMI. Stressing the need for a reliable diagnostic test to
        identify patients with CMI.
  
        In the intestinal epithelium the most important substrate for mitochondrion-dependent ATP
        production, and by consequence as the source for CO2 release is butyrate, a small chain fatty
        acid produced by the intestinal microflora. Under ischemic conditions, butyrate can no longer
        be metabolized. The most straight forward biochemical pathway to cope with this situation is
        a switch in cellular metabolism to anaerobic glycolysis. In this process glucose is
        metabolized to pyruvate, producing two ATP molecules, providing an oxygen independent pathway
        for maintaining ATP production, but also resulting in the reduction of NAD+ molecules into
        NADH+. To maintain ATP production, pyruvate will undergo a process called fermentation
        resulting in the production of lactate in which NADH+ is recycled back to NAD+ so that
        glycolysis can continue. Upon subsequent transport via the blood, lactate is cleared in the
        liver and the resulting CO2 will leave the body via the lungs. Hence theoretically measuring
        the shift from butyrate towards glucose metabolism, which occurs in enterocytes under
        anaerobic conditions, could be a method to detect mucosal ischemia.
  
        This multi-center randomized interventional proof of principal study explored the possibility
        to quantify mucosal oxygen content by labeled-butyrate and labelled-glucose breath testing as
        a potential test to diagnose CMI. Since both substrates are dependent on oxygen to be
        metabolized, it is expected that subjects with low mucosal oxygen concentrations will
        metabolize less butyrate and glucose compared to subjects with normal mucosal oxygen
        concentrations.
  allocation: Randomized
  intervention model: Single Group Assignment
  primary purpose: Diagnostic
  masking: None (Open Label)
  measure: The median concentrations of measured 13CO2
  time frame: At the following time points; baseline, 0.5, 1, 1.25 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5 and 4 hours (total of 12 time points) after ingestion of 13C-butyrate or 13C-glucose.
  description: The median concentrations of measured 13CO2 at each time point where compared within the four groups and statistically tested with a Mann - Whitney U test.
  arm group label: 13C -butyrate control group
  arm group type: Placebo Comparator
  description: 5 healthy volunteers performed the breath test without any psychical exercise
  arm group label: 13C -butyrate intervention group
  arm group type: Experimental
  description: 5 healthy volunteers performed the breath test with psychical exercise - bicycle test
  arm group label: 13C -glucose control group
  arm group type: Placebo Comparator
  description: 5 healthy volunteers performed the breath test without any psychical exercise
  arm group label: 13C -glucose intervention group
  arm group type: Experimental
  description: 5 healthy volunteers performed the breath test with psychical exercise - bicycle test
  intervention type: Drug
  intervention name: Sodium butyrate, 1-13C, 99%, Cambridge Isotope Laboratories, Inc.USA
  description: a solution containing butyrate of which 12C of the last 4 carbon positions of butyrate were replaced by 13C butyrate. Participants received 0.80 gram 13C-butyrate (7.3 mMol butyrate / 29 mMol 13C) dissolved in 50 mL water at baseline
  arm group label: 13C -butyrate control group
  arm group label: 13C -butyrate intervention group
  other name: 13C butyrate
  intervention type: Drug
  intervention name: U-13C6, 99%; Cambridge Isotope Laboratories, Inc.USA
  description: a glucose solution in which all six 12C carbons were replaced by 13C D-Glucose. Participants received 0.75 gram 13C-glucose (4.2 mMol D-glucose/ 25 mMol 13C) dissolved in 50 mL water at baseline
  arm group label: 13C -glucose control group
  arm group label: 13C -glucose intervention group
  other name: 13C glucose
  intervention type: Diagnostic Test
  intervention name: Breath test
  description: Breath tests were performed at the following time points baseline, 0.5, 1, 1.25 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5 and 4 hours after ingestion of 13C-butyrate and 13C-glucose. Breath samples were obtained by blowing a single breath of air through a straw into a test tube. Two breath samples were collected at all mentioned time points. Measurement of 13CO2 is performed using mass spectrometry (IDMicro Breath, Compact Science Systems, Newcastle-Under-Lyme, United Kingdom) using procedures described earlier for galactose and methacetin breath tests, and expressed as an absolute increase in the 13CO2-to-12CO2 ratio in delta permil (δ‰).
  arm group label: 13C -butyrate control group
  intervention type: Diagnostic Test
  intervention name: Exercise + breath test
  description: The intervention groups performed a standardized bicycle ergometer exercise test of 30 minutes and semi-continuous peripheral blood lactate monitoring. The bicycle ergometer protocol consists of three phases. The first 10 minutes of exercise was used to gradually increase the workload until submaximal exercise intensity was reached which is defined as a circulating blood lactate level between 3 and 5.5 mmol/L. From minute 10 to 20 submaximal exercise intensity was maintained by adjusting the workload based on lactate measurements. Minute 20 to 30 was used to reach maximal exercise intensity, the workload was increased by 10% of the submaximal workload until exhaustion
  arm group label: 13C -butyrate intervention group
  arm group label: 13C -glucose control group
  arm group label: 13C -glucose intervention group
  criteria: 
  gender: All
  minimum age: N/A
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: Marco Bruno, prof.
  role: Principal Investigator
  affiliation: Erasmus Medical Center
  facility: 
  country: Netherlands
  responsible party type: Principal Investigator
  investigator affiliation: Erasmus Medical Center
  investigator full name: Marco J. Bruno
  investigator title: Gastroenterologist
  mesh term: Mesenteric Ischemia
  mesh term: Ischemia
  mesh term: Chronic Disease
  mesh term: Butyric Acid
  sharing ipd: No
  provided document: 