<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/NCT01727167</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00031899</org_study_id>
    <nct_id>NCT01727167</nct_id>
  </id_info>
  <brief_title>CO as a Stimulant for Mitochondrial Biogenesis in Human Cardiac Muscle</brief_title>
  <official_title>Effects of Low Level Carbon Monoxide Preconditioning on Human Mitochondrial Biogenesis in Aortic Valve Surgery Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>John J Freiberger</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will test if inhalation of Carbon Monoxide (CO) will increase the numbers of&#xD;
      mitochondria in heart muscle. Mitochondria are the small components of muscle and other cells&#xD;
      that convert fuel and oxygen to the easily usable forms of energy (ATP) that power all cell's&#xD;
      activities. Adequate numbers of healthy mitochondria are essential to heart cell function.&#xD;
      From animal and other studies we have reason to believe that breathing small amounts of CO&#xD;
      will signal the body to increase the numbers of mitochondria in heart cells. We propose to&#xD;
      test this theory in heart valve surgery patients by examining a small sample of heart tissue&#xD;
      (from the right atrial appendage) that is routinely cut out during the preparation of the&#xD;
      patient for cardio-pulmonary bypass and that would otherwise be discarded by the surgeon.&#xD;
      Muscle samples from two groups of subjects will be compared. One group will breath CO and the&#xD;
      other group will breath room air. If CO is effective, we should notice an increase in the&#xD;
      numbers of mitochondria in the group that was exposed to CO compared to the group that&#xD;
      breathed room air.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PURPOSE AND OBJECTIVE: Endogenously produced carbon monoxide (CO) is known to act as a&#xD;
      physiologic signaling molecule to induce mitochondrial biogenesis. This study will test if&#xD;
      low-level CO preconditioning induces myocardial biogenesis in humans and if clinical benefit&#xD;
      is derived from it. STUDY ACTIVITIES AND POPULATION: The study is an interventional,&#xD;
      prospective, randomized, double-blinded trial with a 2-week follow up period. Forty subjects&#xD;
      will be recruited from the population of patients scheduled to undergo elective aortic valve&#xD;
      replacement. For safety purposes patients with coronary disease will be excluded. Subjects&#xD;
      meeting the inclusion criteria will be randomized to receive either air or air containing CO&#xD;
      @ 200ppm as a one-hour inhalational treatment per day over the course of the three days&#xD;
      immediately prior to their scheduled operation. Biochemical markers for mitochondrial&#xD;
      biogenesis (blood and right atrial tissue) and clinical outcome parameters ( BUN/creatinine,&#xD;
      and left ventricular function measured by 2D echo) will be measured in all patients pre and&#xD;
      post-operatively. Right atrial tissue samples will be collected from tissue that is routinely&#xD;
      excised during placement of venous cannulas for cardiopulmonary bypass. RISK/SAFETY &amp; DATA&#xD;
      ANALYSIS: Risks will be those of CO inhalation and blood drawing. The 200ppm dose chosen is&#xD;
      within OSHA work place exposure limits and has been used safely in human subjects previously.&#xD;
      Data will be analyzed by comparing biogenetic marker levels and clinical parameters pre and&#xD;
      post intervention and control to CO treatment group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Lack of funding and low accrual.&#xD;
  </why_stopped>
  <start_date>February 2014</start_date>
  <completion_date type="Actual">March 2016</completion_date>
  <primary_completion_date type="Actual">January 2016</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Biochemical Markers for Mitochondrial Biogenesis (Blood and Right Atrial Tissue)</measure>
    <time_frame>2 weeks</time_frame>
    <description>Right atrial biochemical markers will be measured one time only, intra-operatively. Blood Biochemical markers will be measured before CO exposure and at intervals up to one week post-operatively</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Compare Blood to Right Atrial Tissue Biochemical Markers of Mitochondrial Biogenesis</measure>
    <time_frame>on week</time_frame>
    <description>Biochemical markers in both right atrial tissue and blood will be measured and compared to see if the more easily obtained blood markers accurately describe changes expected in the heart.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Cardiac Disease</condition>
  <condition>Mitochondrial Biogenesis</condition>
  <condition>Carbon Monoxide</condition>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CO group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>200ppm CO for one hour</intervention_name>
    <description>This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.</description>
    <arm_group_label>CO group</arm_group_label>
    <other_name>CO exposure</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Control</intervention_name>
    <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
    <arm_group_label>Control Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able to consent&#xD;
&#xD;
          2. Competent adult&#xD;
&#xD;
          3. Scheduled to undergo aortic or mitral valve surgery only, not combined valve /&#xD;
             revascularization procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unable to consent&#xD;
&#xD;
          2. Tobacco use&#xD;
&#xD;
          3. Unanticipated medical diagnoses made at the time of surgery which require further&#xD;
             procedures lengthening OR time and complexity above that of AVR alone.&#xD;
&#xD;
          4. Concomitant coronary artery disease.&#xD;
&#xD;
          5. Renal dialysis&#xD;
&#xD;
          6. Hemodynamic instability&#xD;
&#xD;
          7. End stage COPD defined as requiring home oxygen&#xD;
&#xD;
          8. By history any significant exposure to second hand smoke including living with a&#xD;
             smoker who smokes indoors or working in a high smoking environment for 8 hours a day&#xD;
             or more (i.e. factory or bar) will exclude subject from the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Duke Hospital</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2016</verification_date>
  <study_first_submitted>November 12, 2012</study_first_submitted>
  <study_first_submitted_qc>November 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 15, 2012</study_first_posted>
  <results_first_submitted>May 18, 2016</results_first_submitted>
  <results_first_submitted_qc>May 18, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">May 19, 2016</results_first_posted>
  <last_update_submitted>May 18, 2016</last_update_submitted>
  <last_update_submitted_qc>May 18, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 19, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Duke University</investigator_affiliation>
    <investigator_full_name>John J Freiberger</investigator_full_name>
    <investigator_title>Associate Professor of Anesthesiology</investigator_title>
  </responsible_party>
  <keyword>cardiac disease</keyword>
  <keyword>mitochondrial biogenesis</keyword>
  <keyword>carbon monoxide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Only one subject was recruited. Funding was not obtained. The study was cancelled with the Duke IRB 3/16.</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Control Group</title>
          <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.&#xD;
Control: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
        </group>
        <group group_id="P2">
          <title>CO Group</title>
          <description>This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.&#xD;
200ppm CO for one hour: This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Collected demographic and clinical characteristics are not reported to protect patient anonymity.</population>
      <group_list>
        <group group_id="B1">
          <title>Control Group</title>
          <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.&#xD;
Control: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
        </group>
        <group group_id="B2">
          <title>CO Group</title>
          <description>This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.&#xD;
200ppm CO for one hour: This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="0"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="0"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>&lt;=18 years</title>
            </class>
            <class>
              <title>Between 18 and 65 years</title>
            </class>
            <class>
              <title>&gt;=65 years</title>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Female</title>
            </class>
            <class>
              <title>Male</title>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Biochemical Markers for Mitochondrial Biogenesis (Blood and Right Atrial Tissue)</title>
        <description>Right atrial biochemical markers will be measured one time only, intra-operatively. Blood Biochemical markers will be measured before CO exposure and at intervals up to one week post-operatively</description>
        <time_frame>2 weeks</time_frame>
        <population>Molecular data was not collected for the single enrolled participant.</population>
        <group_list>
          <group group_id="O1">
            <title>Control Group</title>
            <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.&#xD;
Control: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
          </group>
          <group group_id="O2">
            <title>CO Group</title>
            <description>This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.&#xD;
200ppm CO for one hour: This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Biochemical Markers for Mitochondrial Biogenesis (Blood and Right Atrial Tissue)</title>
          <description>Right atrial biochemical markers will be measured one time only, intra-operatively. Blood Biochemical markers will be measured before CO exposure and at intervals up to one week post-operatively</description>
          <population>Molecular data was not collected for the single enrolled participant.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Compare Blood to Right Atrial Tissue Biochemical Markers of Mitochondrial Biogenesis</title>
        <description>Biochemical markers in both right atrial tissue and blood will be measured and compared to see if the more easily obtained blood markers accurately describe changes expected in the heart.</description>
        <time_frame>on week</time_frame>
        <population>Molecular data was not collected for the single enrolled participant.</population>
        <group_list>
          <group group_id="O1">
            <title>Control Group</title>
            <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.&#xD;
Control: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
          </group>
          <group group_id="O2">
            <title>CO Group</title>
            <description>This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.&#xD;
200ppm CO for one hour: This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Compare Blood to Right Atrial Tissue Biochemical Markers of Mitochondrial Biogenesis</title>
          <description>Biochemical markers in both right atrial tissue and blood will be measured and compared to see if the more easily obtained blood markers accurately describe changes expected in the heart.</description>
          <population>Molecular data was not collected for the single enrolled participant.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Control Group</title>
          <description>This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.&#xD;
Control: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.</description>
        </group>
        <group group_id="E2">
          <title>CO Group</title>
          <description>This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.&#xD;
200ppm CO for one hour: This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Terminated study due to low accrual.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>John J. Freiberger, M.D.</name_or_title>
      <organization>Duke University Medical Center</organization>
      <phone>919-684-6726</phone>
      <email>john.freiberger@duke.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01727167
org study id: Pro00031899
nct id: NCT01727167
lead sponsor: 
has dmc: No
This study will test if inhalation of Carbon Monoxide (CO) will increase the numbers of
      mitochondria in heart muscle. Mitochondria are the small components of muscle and other cells
      that convert fuel and oxygen to the easily usable forms of energy (ATP) that power all cell's
      activities. Adequate numbers of healthy mitochondria are essential to heart cell function.
      From animal and other studies we have reason to believe that breathing small amounts of CO
      will signal the body to increase the numbers of mitochondria in heart cells. We propose to
      test this theory in heart valve surgery patients by examining a small sample of heart tissue
      (from the right atrial appendage) that is routinely cut out during the preparation of the
      patient for cardio-pulmonary bypass and that would otherwise be discarded by the surgeon.
      Muscle samples from two groups of subjects will be compared. One group will breath CO and the
      other group will breath room air. If CO is effective, we should notice an increase in the
      numbers of mitochondria in the group that was exposed to CO compared to the group that
      breathed room air.
PURPOSE AND OBJECTIVE: Endogenously produced carbon monoxide (CO) is known to act as a
      physiologic signaling molecule to induce mitochondrial biogenesis. This study will test if
      low-level CO preconditioning induces myocardial biogenesis in humans and if clinical benefit
      is derived from it. STUDY ACTIVITIES AND POPULATION: The study is an interventional,
      prospective, randomized, double-blinded trial with a 2-week follow up period. Forty subjects
      will be recruited from the population of patients scheduled to undergo elective aortic valve
      replacement. For safety purposes patients with coronary disease will be excluded. Subjects
      meeting the inclusion criteria will be randomized to receive either air or air containing CO
      @ 200ppm as a one-hour inhalational treatment per day over the course of the three days
      immediately prior to their scheduled operation. Biochemical markers for mitochondrial
      biogenesis (blood and right atrial tissue) and clinical outcome parameters ( BUN/creatinine,
      and left ventricular function measured by 2D echo) will be measured in all patients pre and
      post-operatively. Right atrial tissue samples will be collected from tissue that is routinely
      excised during placement of venous cannulas for cardiopulmonary bypass. RISK/SAFETY & DATA
      ANALYSIS: Risks will be those of CO inhalation and blood drawing. The 200ppm dose chosen is
      within OSHA work place exposure limits and has been used safely in human subjects previously.
      Data will be analyzed by comparing biogenetic marker levels and clinical parameters pre and
      post intervention and control to CO treatment group.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Biochemical Markers for Mitochondrial Biogenesis (Blood and Right Atrial Tissue)
time frame: 2 weeks
description: Right atrial biochemical markers will be measured one time only, intra-operatively. Blood Biochemical markers will be measured before CO exposure and at intervals up to one week post-operatively
measure: Compare Blood to Right Atrial Tissue Biochemical Markers of Mitochondrial Biogenesis
time frame: on week
description: Biochemical markers in both right atrial tissue and blood will be measured and compared to see if the more easily obtained blood markers accurately describe changes expected in the heart.
arm group label: Control Group
arm group type: Placebo Comparator
description: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.
arm group label: CO group
arm group type: Experimental
description: This group will breath 200 ppm of CO for one hour per day over the course of the three days immediately prior to surgery.
intervention type: Drug
intervention name: 200ppm CO for one hour
description: This is the study intervention. The treatment group will breath 200 ppm of CO for one hour over the three days immediately prior to surgery.
arm group label: CO group
other name: CO exposure
intervention type: Other
intervention name: Control
description: This group will breath room air for one hour per day over the course of the three days immediately prior to surgery.
arm group label: Control Group
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Duke University
investigator full name: John J Freiberger
investigator title: Associate Professor of Anesthesiology
mesh term: Heart Diseases
sharing ipd: No
ipd description: Only one subject was recruited. Funding was not obtained. The study was cancelled with the Duke IRB 3/16.
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Terminated study due to low accrual.
point of contact: 