<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/NCT01716494</url>
  </required_header>
  <id_info>
    <org_study_id>201206102</org_study_id>
    <nct_id>NCT01716494</nct_id>
  </id_info>
  <brief_title>Washington University Severe Asthma Research Program III</brief_title>
  <acronym>WU SARPIII</acronym>
  <official_title>Severe Asthma Research Program (SARP)-Washington University</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall goal of this proposal is to better understand the basis of airway remodeling in&#xD;
      severe asthma and how remodeling changes over time. The investigators propose to study a&#xD;
      well-characterized cohort of adult and pediatric subjects with severe asthma using a&#xD;
      multidisciplinary state-of-the-art approach.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The overall goal of this proposal is to better understand the molecular basis and structural&#xD;
      and physiologic consequences of airway remodeling in severe asthma and how remodeling changes&#xD;
      over time. In that context, the investigators propose to study a well-characterized cohort of&#xD;
      adult and pediatric subjects with severe asthma using a multidisciplinary approach that&#xD;
      includes state-of-the-art morphometric, imaging, and physiologic measurements of airways. The&#xD;
      investigators will contrast these findings to those in groups with well-controlled asthma,&#xD;
      normal controls, and diseased controls (chronic bronchitis) to identify features that can&#xD;
      provide biologic targets unique to severe asthma. The investigators have demonstrated that&#xD;
      epithelial hyperplasia, goblet cell metaplasia and mucin production are features of airway&#xD;
      remodeling in subjects with severe asthma, and that epithelial remodeling was due to&#xD;
      increased epithelial proliferation and decreased cell death. The investigators propose that&#xD;
      individuals with severe asthma, in comparison to well controlled asthma, have: (I) increased&#xD;
      airway remodeling as evidenced by goblet cell metaplasia and mucin production, (II) greater&#xD;
      airway thickness by multidetector-row CT of the chest (MDCT) leading to ventilation defects&#xD;
      demonstrated by hyperpolarized helium (3He) MRI and air trapping demonstrated by MDCT, and&#xD;
      (III) airway remodeling associated with more severe and progressive airflow obstruction. The&#xD;
      investigators hypothesize that the goblet cell metaplasia and increased mucin The&#xD;
      investigators have observed in severe asthma are being driven by an IL-13- and EGFR-dependent&#xD;
      mechanism that inhibits epithelial cell apoptosis and allows IL-13 differentiation of the&#xD;
      airway epithelium into goblet cells (Aim I). The investigators further hypothesize that this&#xD;
      remodeling of segmental airways in severe asthma leads to distal ventilation defects and air&#xD;
      trapping (Aim II). In an effort to define potential predictors of subsequent decline in lung&#xD;
      function in severe asthma, the investigators hypothesize that baseline airway remodeling as&#xD;
      reflected by MDCT airway wall area (AWA%) is predictive of FEV1&#xD;
      (post-corticosteroid/bronchodilator FEV1) decline (Aim III). The identification of potential&#xD;
      variables associated with remodeling and severe asthma will help identify individuals at risk&#xD;
      whom would benefit from specific targeted therapy. The concerted efforts of this project&#xD;
      together with the SARP will lead to new insights on the mechanistic basis for severe asthma,&#xD;
      further elucidate how it differs from mild-moderate asthma, identify potential targets for&#xD;
      intervention, and will provide imaging metrics to objectively evaluate outcomes for new&#xD;
      treatments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 2012</start_date>
  <completion_date type="Anticipated">March 2021</completion_date>
  <primary_completion_date type="Anticipated">March 2021</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>Lung function</measure>
    <time_frame>3 yrs</time_frame>
    <description>decline in lung function (FEV1) over 3 yrs</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Asthma Control Questionnaire</measure>
    <time_frame>3 yrs</time_frame>
    <description>asthma control score (ACQ)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health care utilization</measure>
    <time_frame>3 yrs</time_frame>
    <description>Health care utilization including ED visits and hospitalizations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exacerbation</measure>
    <time_frame>3 yrs</time_frame>
    <description>Exacerbations requiring systemic steroids</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CT quantification</measure>
    <time_frame>3 yrs</time_frame>
    <description>CT airway wall thickness, lung density</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRI</measure>
    <time_frame>3 yrs</time_frame>
    <description>Ventilation defects on hyperpolarized gas MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Morphometric biopsy</measure>
    <time_frame>3 yrs</time_frame>
    <description>Morphometric analysis of airway biopsies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gene expression</measure>
    <time_frame>3 yrs</time_frame>
    <description>Gene expression studies of airway epithelial cells</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">121</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Severe Asthma</arm_group_label>
    <description>Subjects with severe asthma (SARP protocol definition)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Well controlled asthma</arm_group_label>
    <description>Subjects with well controlled asthma</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal control</arm_group_label>
    <description>Subjects that are healthy normals</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      whole blood, serum, plasma, DNA, RNA, sputum, urine, bronchial tissue, bronchoalveolar&#xD;
      lavage, bronchial brushings, exhaled breath condensate&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Subjects with asthma (severe asthma, well controlled asthma) and healthy normal controls&#xD;
        from St. Louis region&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Physician diagnosis of asthma,&#xD;
&#xD;
          2. Age 6 years and older&#xD;
&#xD;
          3. Evidence of historical reversibility, including either:&#xD;
&#xD;
               1. FEV1 bronchodilator reversibility ≥ 12%, or&#xD;
&#xD;
               2. Airway hyperresponsiveness reflected by a methacholine PC20 ≤16 mg/mL.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. No primary medical caregiver,&#xD;
&#xD;
          2. Pregnancy (if undergoing methacholine challenge or bronchoscopy),&#xD;
&#xD;
          3. Current smoking&#xD;
&#xD;
          4. Smoking history &gt; 10 pack years if ≥ 30 years of age or smoking history &gt; 5 pack years&#xD;
             if &lt; 30 years of age (Note: If a subject has a smoking history, no smoking within the&#xD;
             past year)&#xD;
&#xD;
          5. Other chronic pulmonary disorders associated with asthma-like symptoms,including (but&#xD;
             not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic&#xD;
             bronchitis, vocal cord dysfunction that is the sole cause of asthma symptoms, severe&#xD;
             scoliosis or chest wall deformities that affect lung function, or congenital disorders&#xD;
             of the lungs or airways,&#xD;
&#xD;
          6. History of premature birth before 35 weeks gestation,&#xD;
&#xD;
          7. Evidence that the participant or family may be unreliable or poorly adherent to their&#xD;
             asthma treatment or study procedures,&#xD;
&#xD;
          8. Planning to relocate from the clinical center area before study completion, or&#xD;
&#xD;
          9. Any other criteria that place the subject at unnecessary risk according to the&#xD;
             judgment of the Principal Investigator and/or attending physician(s) of record.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kaharu Sumino, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.severeasthma.org</url>
    <description>SARP website</description>
  </link>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>October 25, 2012</study_first_submitted>
  <study_first_submitted_qc>October 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 29, 2012</study_first_posted>
  <last_update_submitted>October 5, 2020</last_update_submitted>
  <last_update_submitted_qc>October 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>asthma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</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/NCT01716494
org study id: 201206102
nct id: NCT01716494
lead sponsor: 
has dmc: Yes
The overall goal of this proposal is to better understand the basis of airway remodeling in
      severe asthma and how remodeling changes over time. The investigators propose to study a
      well-characterized cohort of adult and pediatric subjects with severe asthma using a
      multidisciplinary state-of-the-art approach.
The overall goal of this proposal is to better understand the molecular basis and structural
      and physiologic consequences of airway remodeling in severe asthma and how remodeling changes
      over time. In that context, the investigators propose to study a well-characterized cohort of
      adult and pediatric subjects with severe asthma using a multidisciplinary approach that
      includes state-of-the-art morphometric, imaging, and physiologic measurements of airways. The
      investigators will contrast these findings to those in groups with well-controlled asthma,
      normal controls, and diseased controls (chronic bronchitis) to identify features that can
      provide biologic targets unique to severe asthma. The investigators have demonstrated that
      epithelial hyperplasia, goblet cell metaplasia and mucin production are features of airway
      remodeling in subjects with severe asthma, and that epithelial remodeling was due to
      increased epithelial proliferation and decreased cell death. The investigators propose that
      individuals with severe asthma, in comparison to well controlled asthma, have: (I) increased
      airway remodeling as evidenced by goblet cell metaplasia and mucin production, (II) greater
      airway thickness by multidetector-row CT of the chest (MDCT) leading to ventilation defects
      demonstrated by hyperpolarized helium (3He) MRI and air trapping demonstrated by MDCT, and
      (III) airway remodeling associated with more severe and progressive airflow obstruction. The
      investigators hypothesize that the goblet cell metaplasia and increased mucin The
      investigators have observed in severe asthma are being driven by an IL-13- and EGFR-dependent
      mechanism that inhibits epithelial cell apoptosis and allows IL-13 differentiation of the
      airway epithelium into goblet cells (Aim I). The investigators further hypothesize that this
      remodeling of segmental airways in severe asthma leads to distal ventilation defects and air
      trapping (Aim II). In an effort to define potential predictors of subsequent decline in lung
      function in severe asthma, the investigators hypothesize that baseline airway remodeling as
      reflected by MDCT airway wall area (AWA%) is predictive of FEV1
      (post-corticosteroid/bronchodilator FEV1) decline (Aim III). The identification of potential
      variables associated with remodeling and severe asthma will help identify individuals at risk
      whom would benefit from specific targeted therapy. The concerted efforts of this project
      together with the SARP will lead to new insights on the mechanistic basis for severe asthma,
      further elucidate how it differs from mild-moderate asthma, identify potential targets for
      intervention, and will provide imaging metrics to objectively evaluate outcomes for new
      treatments.
observational model: Cohort
time perspective: Prospective
measure: Lung function
time frame: 3 yrs
description: decline in lung function (FEV1) over 3 yrs
measure: Asthma Control Questionnaire
time frame: 3 yrs
description: asthma control score (ACQ)
measure: Health care utilization
time frame: 3 yrs
description: Health care utilization including ED visits and hospitalizations.
measure: Exacerbation
time frame: 3 yrs
description: Exacerbations requiring systemic steroids
measure: CT quantification
time frame: 3 yrs
description: CT airway wall thickness, lung density
measure: MRI
time frame: 3 yrs
description: Ventilation defects on hyperpolarized gas MRI
measure: Morphometric biopsy
time frame: 3 yrs
description: Morphometric analysis of airway biopsies
measure: Gene expression
time frame: 3 yrs
description: Gene expression studies of airway epithelial cells
arm group label: Severe Asthma
description: Subjects with severe asthma (SARP protocol definition)
arm group label: Well controlled asthma
description: Subjects with well controlled asthma
arm group label: Normal control
description: Subjects that are healthy normals
whole blood, serum, plasma, DNA, RNA, sputum, urine, bronchial tissue, bronchoalveolar
      lavage, bronchial brushings, exhaled breath condensate
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 6 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Kaharu Sumino, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
url: http://www.severeasthma.org
description: SARP website
responsible party type: Sponsor
mesh term: Asthma