<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/NCT01725061</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00014152</org_study_id>
    <nct_id>NCT01725061</nct_id>
  </id_info>
  <brief_title>Study of the Function of Cells Involved in Inflammation in the Lungs of Those With Acute Lung Injury and Sepsis</brief_title>
  <acronym>AMFAS</acronym>
  <official_title>Alveolar Macrophage Function in ALI and Sepsis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Emory University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acute lung injury (ALI) is an often deadly form of respiratory failure caused by&#xD;
      inflammation. The widespread injury to the lungs involves a build-up of fluid in the lungs&#xD;
      that results in damage to the lungs and a decreased ability of the lungs to function&#xD;
      properly. There is currently no specific treatment for ALI; and of the 200,000 cases reported&#xD;
      in the US yearly, about 40% will die.&#xD;
&#xD;
      Some patients may have other conditions that could change the risk of developing ALI. For&#xD;
      example, it has been reported that patients who have septic shock have a lower chance of&#xD;
      developing ALI if they also have diabetes mellitus (diabetes). Septic shock is a type of&#xD;
      infection that causes overwhelming inflammation to occur throughout the body; it increases&#xD;
      the chances that a person will develop ALI.&#xD;
&#xD;
      The reason diabetics are less likely to develop ALI is unclear and deserves further&#xD;
      investigation. The investigators believe that it may be explained by differences in the way&#xD;
      certain cells that are involved in inflammation function in the lungs. The investigators plan&#xD;
      on looking at the relationship between the wide-spread inflammation that occurs within the&#xD;
      bodies of diabetic and non-diabetic patients with an increased chance of developing ALI&#xD;
      [sepsis].&#xD;
&#xD;
      To study this relationship, we will identify patients who fit the requirements of the study.&#xD;
      The investigators will obtain blood samples and lung washings from these patients. The lung&#xD;
      washings will be obtained by injecting clean salt water into the lungs through a tube and&#xD;
      then pulling the water back out. When the sterile water is removed, some cells from the lungs&#xD;
      also are removed and they can then be used for further lab studies. Determining how diabetes&#xD;
      may change a patient's chance of developing ALI may uncover useful information that may help&#xD;
      prevent or treat ALI in all patients at risk.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute lung injury (ALI) is a common and lethal form of respiratory failure, occurring in&#xD;
      200,000 people each year and in as many as 25% of mechanically ventilated patients. Despite&#xD;
      multiple clinical studies, there are presently no effective medical therapies for ALI, and&#xD;
      its mortality remains unacceptably high at about 40%. Common co-morbid conditions that can&#xD;
      alter the susceptibility to ALI are chronic alcohol abuse and diabetes mellitus (DM). The&#xD;
      incidence and severity of ALI is increased in critically ill patients with a history of&#xD;
      chronic alcohol abuse. With respect to DM, the group has previously reported that a history&#xD;
      of diabetes mellitus is associated with a decreased incidence of ALI in patients with septic&#xD;
      shock. As the biological mechanism for this association was unknown, a cross-sectional&#xD;
      epidemiological study was conducted by broadly examining the role of diabetes in the&#xD;
      development of respiratory failure associated with sepsis. Using national hospitalization&#xD;
      data, it was found that diabetics with sepsis were less likely to develop any form of acute&#xD;
      respiratory failure than non-diabetics.&#xD;
&#xD;
      ALI occurs through a common pathway of oxidant stress and inflammation, injuring the lungs&#xD;
      and rendering them dysfunctional for gas exchange. The alveolar macrophage (AM) is an&#xD;
      important mediator of the inflammatory response, with roles such as phagocytosis and&#xD;
      secretion of inflammatory cytokines that are key components of lung injury and repair. While&#xD;
      more than one mechanism may explain the previous observations of a decreased incidence of ALI&#xD;
      in diabetics, the data in chronic alcoholics suggests that AM dysfunction may play a role in&#xD;
      the in the development of ALI leading us to hypothesize that DM may similarly alter the&#xD;
      pulmonary microenvironment, thereby decreasing the susceptibility to ALI. Furthermore, early&#xD;
      preliminary data suggests that the AM activity of peroxisome proliferator-activated receptor&#xD;
      gamma (PPARγ), a transcription factor with anti-inflammatory properties, may be increased in&#xD;
      diabetics. In addition, evidence suggests that macrophage activation into a pro-inflammatory&#xD;
      versus an anti-inflammatory state may be tissue specific and altered by obesity and insulin&#xD;
      resistance (i.e. compartmentalized in the lung). However, the effect of DM on the pulmonary&#xD;
      inflammatory response and specifically AM function is as yet unknown. PPARγ is highly&#xD;
      expressed in AMs, and thus PPARγ ligands have direct affects on AMs to influence lung&#xD;
      inflammation by inhibiting oxidative burst and enhancing AM phagocytic function. PPARγ and&#xD;
      its ligands influence AM differentiation into M1 (pro-inflammatory) and M2&#xD;
      (anti-inflammatory) phenotypes and a recent preclinical study demonstrated effective&#xD;
      prevention of ALI by pretreatment with a PPARγ ligand. However, the effect that DM and PPARγ&#xD;
      ligands have on AM phenotypic differentiation, PPARγ expression, oxidative stress and AM&#xD;
      phagocytic function has not been well investigated. To our knowledge, there is no data on AM&#xD;
      PPARγ activity in DM, and little is known about how this disease state may alter the&#xD;
      pulmonary inflammatory milieu. The investigators hypothesize that DM reduces the risk of ALI&#xD;
      by modulating AM differentiation and function via PPARγ expression, oxidative stress and AM&#xD;
      phagocytic function, which may be positively influenced by exposure to a PPARγ ligand.&#xD;
      Examining the impact of DM and PPARγ on AM phenotype and function may identify mechanisms&#xD;
      responsible for the decreased incidence of ALI in diabetics; improve our understanding of the&#xD;
      pathogenesis of a common and lethal disease, and lead to novel therapies for both diabetic&#xD;
      and non-diabetic critically ill patients&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2009</start_date>
  <completion_date type="Actual">September 2012</completion_date>
  <primary_completion_date type="Actual">September 2012</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Development of acute lung injury</measure>
    <time_frame>within 7 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>mortality</measure>
    <time_frame>28 day</time_frame>
  </secondary_outcome>
  <enrollment type="Actual">80</enrollment>
  <condition>Sepsis</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma and bronchoalveolar lavage fluid&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients in the ICU with severe sepsis ot septic shock that are on mechanical ventilation.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients within the first 72 hours of development of severe sepsis or septic shock&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. No informed consent&#xD;
&#xD;
          2. Pregnancy&#xD;
&#xD;
          3. Expected survival ≤ 72 hours&#xD;
&#xD;
          4. Not mechanically ventilated&#xD;
&#xD;
          5. Age &lt; 18 years&#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>Annette Esper, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Grady Memorial Hospital</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2014</verification_date>
  <study_first_submitted>November 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 12, 2012</study_first_posted>
  <last_update_submitted>December 17, 2014</last_update_submitted>
  <last_update_submitted_qc>December 17, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 18, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Emory University</investigator_affiliation>
    <investigator_full_name>Annette Esper, MD</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
  </condition_browse>
  <!-- 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/NCT01725061
org study id: IRB00014152
nct id: NCT01725061
lead sponsor: 
has dmc: No
Acute lung injury (ALI) is an often deadly form of respiratory failure caused by
      inflammation. The widespread injury to the lungs involves a build-up of fluid in the lungs
      that results in damage to the lungs and a decreased ability of the lungs to function
      properly. There is currently no specific treatment for ALI; and of the 200,000 cases reported
      in the US yearly, about 40% will die.

      Some patients may have other conditions that could change the risk of developing ALI. For
      example, it has been reported that patients who have septic shock have a lower chance of
      developing ALI if they also have diabetes mellitus (diabetes). Septic shock is a type of
      infection that causes overwhelming inflammation to occur throughout the body; it increases
      the chances that a person will develop ALI.

      The reason diabetics are less likely to develop ALI is unclear and deserves further
      investigation. The investigators believe that it may be explained by differences in the way
      certain cells that are involved in inflammation function in the lungs. The investigators plan
      on looking at the relationship between the wide-spread inflammation that occurs within the
      bodies of diabetic and non-diabetic patients with an increased chance of developing ALI
      [sepsis].

      To study this relationship, we will identify patients who fit the requirements of the study.
      The investigators will obtain blood samples and lung washings from these patients. The lung
      washings will be obtained by injecting clean salt water into the lungs through a tube and
      then pulling the water back out. When the sterile water is removed, some cells from the lungs
      also are removed and they can then be used for further lab studies. Determining how diabetes
      may change a patient's chance of developing ALI may uncover useful information that may help
      prevent or treat ALI in all patients at risk.
Acute lung injury (ALI) is a common and lethal form of respiratory failure, occurring in
      200,000 people each year and in as many as 25% of mechanically ventilated patients. Despite
      multiple clinical studies, there are presently no effective medical therapies for ALI, and
      its mortality remains unacceptably high at about 40%. Common co-morbid conditions that can
      alter the susceptibility to ALI are chronic alcohol abuse and diabetes mellitus (DM). The
      incidence and severity of ALI is increased in critically ill patients with a history of
      chronic alcohol abuse. With respect to DM, the group has previously reported that a history
      of diabetes mellitus is associated with a decreased incidence of ALI in patients with septic
      shock. As the biological mechanism for this association was unknown, a cross-sectional
      epidemiological study was conducted by broadly examining the role of diabetes in the
      development of respiratory failure associated with sepsis. Using national hospitalization
      data, it was found that diabetics with sepsis were less likely to develop any form of acute
      respiratory failure than non-diabetics.

      ALI occurs through a common pathway of oxidant stress and inflammation, injuring the lungs
      and rendering them dysfunctional for gas exchange. The alveolar macrophage (AM) is an
      important mediator of the inflammatory response, with roles such as phagocytosis and
      secretion of inflammatory cytokines that are key components of lung injury and repair. While
      more than one mechanism may explain the previous observations of a decreased incidence of ALI
      in diabetics, the data in chronic alcoholics suggests that AM dysfunction may play a role in
      the in the development of ALI leading us to hypothesize that DM may similarly alter the
      pulmonary microenvironment, thereby decreasing the susceptibility to ALI. Furthermore, early
      preliminary data suggests that the AM activity of peroxisome proliferator-activated receptor
      gamma (PPARγ), a transcription factor with anti-inflammatory properties, may be increased in
      diabetics. In addition, evidence suggests that macrophage activation into a pro-inflammatory
      versus an anti-inflammatory state may be tissue specific and altered by obesity and insulin
      resistance (i.e. compartmentalized in the lung). However, the effect of DM on the pulmonary
      inflammatory response and specifically AM function is as yet unknown. PPARγ is highly
      expressed in AMs, and thus PPARγ ligands have direct affects on AMs to influence lung
      inflammation by inhibiting oxidative burst and enhancing AM phagocytic function. PPARγ and
      its ligands influence AM differentiation into M1 (pro-inflammatory) and M2
      (anti-inflammatory) phenotypes and a recent preclinical study demonstrated effective
      prevention of ALI by pretreatment with a PPARγ ligand. However, the effect that DM and PPARγ
      ligands have on AM phenotypic differentiation, PPARγ expression, oxidative stress and AM
      phagocytic function has not been well investigated. To our knowledge, there is no data on AM
      PPARγ activity in DM, and little is known about how this disease state may alter the
      pulmonary inflammatory milieu. The investigators hypothesize that DM reduces the risk of ALI
      by modulating AM differentiation and function via PPARγ expression, oxidative stress and AM
      phagocytic function, which may be positively influenced by exposure to a PPARγ ligand.
      Examining the impact of DM and PPARγ on AM phenotype and function may identify mechanisms
      responsible for the decreased incidence of ALI in diabetics; improve our understanding of the
      pathogenesis of a common and lethal disease, and lead to novel therapies for both diabetic
      and non-diabetic critically ill patients
observational model: Cohort
time perspective: Prospective
measure: Development of acute lung injury
time frame: within 7 days
measure: mortality
time frame: 28 day
Plasma and bronchoalveolar lavage fluid
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Annette Esper, MD, MSc
role: Principal Investigator
affiliation: Emory University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Emory University
investigator full name: Annette Esper, MD
investigator title: Assistant Professor
mesh term: Sepsis
mesh term: Toxemia