<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/NCT03797404</url>
  </required_header>
  <id_info>
    <org_study_id>P180501J</org_study_id>
    <secondary_id>2018-002591-40</secondary_id>
    <nct_id>NCT03797404</nct_id>
  </id_info>
  <brief_title>Airway Remodeling During Mepolizumab Treatment</brief_title>
  <acronym>REMOMEPO</acronym>
  <official_title>Airway Remodeling Changes Induced by Mepolizumab in Severe Eosinophil Asthma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</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>
      Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular basement&#xD;
      membrane (RBM) thickening, goblet cells hyperplasia characterize severe asthma. Chronic&#xD;
      inflammation, and especially eosinophilia and T2 cytokines are involved in these structural&#xD;
      changes. The aim of this prospective observational study is to assess airway changes,&#xD;
      assessed by bronchial biopsies before treatment, then after 6 months and 12 months, induced&#xD;
      by mepolizumab in 40 severe asthma patients who will receive the treatment as part of their&#xD;
      standard care. Changes in RBM thickening, in airway smooth muscle (ASM) area, in the number&#xD;
      of PGP9 sections will be assessed on bronchial biopsies after 6 months and 12 months of&#xD;
      mepolizumab treatment. Bronchoalveolar lavage (BAL) levels of inflammatory and remodeling&#xD;
      mediators and of extra-cellular matrix (ECM) components will be measured after 6 months and&#xD;
      12 months of mepolizumab treatment. Relationship between clinical response to mepolizumab and&#xD;
      remodeling changes after 6 months and 12 months will be assessed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Scientific Rationale &amp; Hypothesis:&#xD;
&#xD;
           Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular&#xD;
           basement membrane thickening, goblet cells hyperplasia characterize severe asthma.&#xD;
           Chronic inflammation, and especially eosinophilia and T2 cytokines are involved in these&#xD;
           structural changes. Increased ASM layer has been associated with eosinophilia for&#xD;
           example, but not RBM thickening, suggesting that differential patterns of remodeling can&#xD;
           be observed according to inflammatory patterns. Omalizumab, an anti IgE therapy, can&#xD;
           reduce some features of airway remodeling, especially RBM and some parameters related to&#xD;
           ASM. No data are available on potential changes in airway remodeling induced by&#xD;
           mepolizumab.&#xD;
&#xD;
           The aim of the study is to assess airway changes, assessed by bronchial biopsies,&#xD;
           induced by mepolizumab in severe asthma patients who will receive the treatment as part&#xD;
           of their standard care.&#xD;
&#xD;
           All asthma patients refered to the asthma clinic are proposed to participate to the&#xD;
           COBRA cohort (French national asthma cohort). Serum and DNA are collected at inclusion&#xD;
           and every 6 months. Fiberoptic bronchoscopy (FOB) is routinely performed as part of the&#xD;
           standard care for difficult-to-severe asthma in our centre for many years, to assess&#xD;
           differential diagnosis and inflammatory pattern since Fractional exhaled nitric oxide&#xD;
           (FeNO) is not routinely performed in France. BAL and 4 to 6 bronchial biopsies are&#xD;
           performed.&#xD;
&#xD;
        2. Study Population:&#xD;
&#xD;
           Severe asthma patients, refered to Severe Asthma Centre in Bichat and Bicetre Hospitals,&#xD;
           receiving mepolizumab according to French recommendations (eos &gt;300mm3 in the previous&#xD;
           year, &gt;2 exacerbations, despite optimal step 4-5 therapy, including daily use of&#xD;
           steroids).&#xD;
&#xD;
        3. Study Design &amp; Methods:&#xD;
&#xD;
             -  General study design Prospective, observational study in one Severe Asthma Centre :&#xD;
                Bichat Hospital (Prof C.Taillé).&#xD;
&#xD;
                40 patients will be prospectively included during a 32 months period.&#xD;
&#xD;
      This study aims to assess :&#xD;
&#xD;
        -  Changes in RBM thickening, in ASM area after 6 months and 12 months of mepolizumab&#xD;
           treatment&#xD;
&#xD;
        -  Changes in BAL levels of inflammatory and remodeling mediators and of ECM components&#xD;
           after 6 months and 12 months of mepolizumab treatment&#xD;
&#xD;
        -  Changes in the number of PGP9 sections in the bronchial wall after 6 months and 12&#xD;
           months of mepolizumab treatment&#xD;
&#xD;
        -  Relationship between clinical response to mepolizumab and remodeling changes after 6&#xD;
           months and 12 months of mepolizumab treatment&#xD;
&#xD;
        -  Demographic and clinical characteristics of asthma (atopy, level of asthma control,&#xD;
           FEV1…) will be available at inclusion and follow up, to assess clinical effect of&#xD;
           mepolizumab treatment.&#xD;
&#xD;
      The following will perform at inclusion, 6 months and 12 months after initiating mepolizumab:&#xD;
&#xD;
        -  clinical evaluation (age, BMI, atopic status, chronic rhinosinusitis, daily doses of&#xD;
           steroids, exacerbations…)&#xD;
&#xD;
        -  benefit of mepolizumab will be evaluated according to the physician's Global Evaluation&#xD;
           of Treatment Effectiveness (GETE)&#xD;
&#xD;
        -  asthma control test&#xD;
&#xD;
        -  lung function test (FEV1, FEV1/VC, TLC, RV, pre/post salbutamol)&#xD;
&#xD;
        -  FOB with BAL and 6 biopsies at inclusion, 6 months and 12 months&#xD;
&#xD;
        -  Blood test for eosinophil count and serum conservation.&#xD;
&#xD;
             -  Study groups/arms Group 1 (prospective) : patients initiating a mepolizumab&#xD;
                treatment. Group 2 (retrospective): to assess airway changes that can&#xD;
                &quot;spontaneously&quot; occur during a 12 month-period, a retrospective &quot;historical group&quot;&#xD;
                of patients included in the previous ASMATHERM study who had 2 sets of biopsies and&#xD;
                BAL within a 6 to 12 month-interval, without exposure to mepolizumab and without&#xD;
                change in their treatment during this interval, will be studied as a control group&#xD;
                . Clinical data are available at inclusion and after 12 months.&#xD;
&#xD;
             -  Main tests or procedures All biopsies, BAL and serum analysis will be performed in&#xD;
                the UMR1152 lab unit (Head: Dr Marina Pretolani).&#xD;
&#xD;
      Biopsies are fixed in formaldehyde and processed to paraffin wax for immunohistochemical&#xD;
      (IHC) and morphometric studies. One biopsy will be stored at -80°C for further RNAseq&#xD;
      analyses.&#xD;
&#xD;
      RBM thickening (morphometry), ASM area and the rate of ASM-proliferating cells (PCNA&#xD;
      immuno-staining) will be measured. PGP9 staining can assess the number of nerves in the&#xD;
      bronchial wall.&#xD;
&#xD;
      The number of inflammatory cells (eosinophils, neutrophils, mast cells, T-lymphocytes&#xD;
      evaluated respectively by MBP, elastase, tryptase, CD4 expression) and vascular sections will&#xD;
      also be enumerated after IHC. Eosinophils localization in the airway will be described.&#xD;
&#xD;
      Cytospin preparations from BAL cell pellets will be used to assess the proportion of&#xD;
      eosinophils and neutrophils.&#xD;
&#xD;
      In parallel, the levels of different pro-inflammatory and remodeling mediators will be&#xD;
      measured in BAL aliquots concentrated x 10, by specific Elisa and Luminex assays.&#xD;
&#xD;
      • Trial plan&#xD;
&#xD;
      V0: screening visit&#xD;
&#xD;
      V1: inclusion visit&#xD;
&#xD;
        -  clinical evaluation&#xD;
&#xD;
        -  Asthma control test&#xD;
&#xD;
        -  Lung function test&#xD;
&#xD;
        -  Fiber optic fibroscopy with BAL and bronchial biopsies (note that if a fiber optic&#xD;
           fibroscopy with BAL and bronchial biopsies has already been performed in the month prior&#xD;
           to inclusion, it will not be repeated at inclusion and the tissue and BAL samples will&#xD;
           be retrieved for analysis)&#xD;
&#xD;
        -  Blood sampling&#xD;
&#xD;
        -  first treatment by Mepolizumab is administrated in the hospital.&#xD;
&#xD;
        -  Patient injection training if this prescription is chosen&#xD;
&#xD;
        -  Prescription for Mepolizumab, given at home for the next 6 months&#xD;
&#xD;
      V2: 6-month visit&#xD;
&#xD;
        -  Clinical response assessment by GETE and ACT, clinical evaluation&#xD;
&#xD;
        -  Lung function test&#xD;
&#xD;
        -  Fiber optic fibroscopy with BAL and bronchial biopsies&#xD;
&#xD;
        -  Blood sampling&#xD;
&#xD;
        -  If responders, continuation of Mepolizumab treatment&#xD;
&#xD;
        -  Compliance evaluation (file signed by the nurse or patient after each injection)&#xD;
&#xD;
      V3: 12-month visit&#xD;
&#xD;
        -  clinical response assessment by GETE and ACT, clinical evaluation&#xD;
&#xD;
        -  Lung function test&#xD;
&#xD;
        -  Fiber optic fibroscopy with BAL and bronchial biopsies&#xD;
&#xD;
        -  Blood sampling&#xD;
&#xD;
        -  Compliance evaluation (file signed by the nurse or patient after each injection)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 24, 2019</start_date>
  <completion_date type="Actual">June 21, 2022</completion_date>
  <primary_completion_date type="Actual">June 21, 2022</primary_completion_date>
  <study_type>Observational [Patient Registry]</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>
  <target_duration>12 Months</target_duration>
  <primary_outcome>
    <measure>Changes in reticular basement membrane (RBM) thickening</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>The absolute variation in RBM thickening (µm, morphometry measurement on bronchial biopsies) over 12 months is defined as the difference between month twelve and baseline (V1).&#xD;
The absolute variation in RBM thickening over 6 months is defined as the difference between month six and baseline (V1).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in airway smooth muscle (ASM) area</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured in morphometry in µm2 and expressed as a percentage of smooth muscle surface area relative to the biopsy surface.&#xD;
The absolute variation in ASM area over 12 months is defined as the difference between month twelve and baseline (V1).&#xD;
The absolute variation in ASM area over 6 months is defined as the difference between month six and baseline (V1).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of proliferating muscle cells</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Evaluated by anti proliferating cell nuclear antigen (PCNA) antibodies, expressed as the number of positive cells per muscle surface.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of nerve endings</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Evaluated by PGP9 and expressed as number of positive cells per biopsy surface in mm2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of vascular sections</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured with an anti-CD31 antibody, expressed in number of sections per mm2.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of infiltrating inflammatory cells in the biopsies</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Number of infiltrating inflammatory cells (infiltrating neutrophils, lymphocytes and eosinophils) expressed as number of positive cells per biopsy surface in mm2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of inflammatory cells in the BAL</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Number of inflammatory cells (neutrophils, lymphocytes and eosinophils) expressed as % of total cells in the BAL</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of eosinophils expressing MBP/IL3R</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured on bronchial biopsies, expressed as number of cells per biopsy surface in mm2</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Interferon-gamma concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Interferon-gamma (Th1 cytokine) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-13 concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>IL-13 (Th2 cytokine) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Periostin concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Periostin (Th2 cytokine) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-17A concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>IL-17A (Th17 cytokine) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-22 concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>IL-22 (Th17 cytokine) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-33 concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>IL-33 (innate immune cytokines) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thymic Stromal Lymphopoietin (TSLP) concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>TSLP (innate immune cytokines) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fibronectin concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Fibronectin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tenascin concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Tenascin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fibulin-1 concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Fibulin-1 (soluble hallmarks of ECM remodeling) will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monocyte chemoattractant protein-1 (CCL/MCP-1) concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EGF concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>bFGF concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PDGF-BB concentration</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Will be measured in BAL and serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total score at Asthma Control Test</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured using the Asthma Control Test (ACT) scale (range: 5 to 25). ACT assesses the frequency of shortness of breath and general asthma symptoms, use of rescue medications, the effect of asthma on daily functioning, and overall self-assessment of asthma control.&#xD;
5 items, with 4-week recall (on symptoms and daily functioning)&#xD;
each item is evaluated by a 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled).&#xD;
The total score ranges from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score &gt;19 indicates well-controlled asthma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Global evaluation of mepolizumab benefit</measure>
    <time_frame>6 and 12 months</time_frame>
    <description>Benefit of mepolizumab will be evaluated by patient and by physician according to the physician's Global Evaluation of Treatment Effectiveness (GETE).&#xD;
Patients will be considered as &quot;responders&quot; if classified as &quot;excellent response&quot; or &quot;good response&quot; by their physician.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced expiratory volume (FEV1)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in ml.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced expiratory volume (FEV1)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced expiratory volume/Vital capacity (FEV1/VC)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in %</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total lung capacity (TLC)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in ml.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total lung capacity (TLC)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Residual volume (RV)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in ml.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Residual volume (RV)</measure>
    <time_frame>0, 6 and 12 months</time_frame>
    <description>Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with pre-bronchodilator FEV1 greater than 80%</measure>
    <time_frame>6 and 12 months</time_frame>
    <description>In order to assess functional response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with an increase from baseline in pre-bronchodilator FEV1 greater than 20%</measure>
    <time_frame>6 and 12 months</time_frame>
    <description>In order to assess functional response to treatment</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">37</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Mepolizumab</arm_group_label>
    <description>Patients receiving mepolizumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients w/o mepolizumab (retrospective)</arm_group_label>
    <description>Retrospective control group of patients not exposed to mepolizumab, included in the COBRA cohort and the ASMATHERM protocol, who had 2 sets of biopsies and BAL within a 6 to 12 month-interval, without change in their treatment. Clinical data for this patients are available at inclusion and after 12 months.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with severe uncontrolled eosinophil asthma with an indication for mepolizumab&#xD;
        according to French recommandations (eos &gt;300mm3 in the previous year, &gt;2 exacerbations,&#xD;
        despite optimal step 4-5 therapy, including daily use of steroids).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  adult &gt;18 years,&#xD;
&#xD;
          -  severe uncontrolled asthma, defined as eosinophil blood count &gt;300/mm3 in the previous&#xD;
             12 months and at least 2 exacerbations in the previous 12 months or requiring oral&#xD;
             steroids for more than half of the previous year,&#xD;
&#xD;
          -  indication for mepolizumab decided by an asthma specialist,&#xD;
&#xD;
          -  efficient contraception, for women of reproductive age&#xD;
&#xD;
        Exclusion criteria :&#xD;
&#xD;
          -  pregnancy,&#xD;
&#xD;
          -  smokers or ex smokers &gt;10 pack/yr,&#xD;
&#xD;
          -  contra indication for fiberoptic bronchoscopy (allergy to xylocain, antiaggregant or&#xD;
             anticoagulant treatment...),&#xD;
&#xD;
          -  contra indication for mepolizumab,&#xD;
&#xD;
          -  patient who previously received mepolizumab or already received mepolizumab at&#xD;
             inclusion,&#xD;
&#xD;
          -  participation in another interventional trial&#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>Camille TAILLE, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bichat hospital</name>
      <address>
        <city>Paris</city>
        <zip>75018</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>January 19, 2023</last_update_submitted>
  <last_update_submitted_qc>January 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Eosinophil</keyword>
  <keyword>Bronchial biopsies</keyword>
  <keyword>Mepolizumab</keyword>
  <keyword>Severe</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
    <mesh_term>Airway Remodeling</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03797404
org study id: P180501J
secondary id: 2018-002591-40
nct id: NCT03797404
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular basement
      membrane (RBM) thickening, goblet cells hyperplasia characterize severe asthma. Chronic
      inflammation, and especially eosinophilia and T2 cytokines are involved in these structural
      changes. The aim of this prospective observational study is to assess airway changes,
      assessed by bronchial biopsies before treatment, then after 6 months and 12 months, induced
      by mepolizumab in 40 severe asthma patients who will receive the treatment as part of their
      standard care. Changes in RBM thickening, in airway smooth muscle (ASM) area, in the number
      of PGP9 sections will be assessed on bronchial biopsies after 6 months and 12 months of
      mepolizumab treatment. Bronchoalveolar lavage (BAL) levels of inflammatory and remodeling
      mediators and of extra-cellular matrix (ECM) components will be measured after 6 months and
      12 months of mepolizumab treatment. Relationship between clinical response to mepolizumab and
      remodeling changes after 6 months and 12 months will be assessed.
1. Scientific Rationale & Hypothesis:

           Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular
           basement membrane thickening, goblet cells hyperplasia characterize severe asthma.
           Chronic inflammation, and especially eosinophilia and T2 cytokines are involved in these
           structural changes. Increased ASM layer has been associated with eosinophilia for
           example, but not RBM thickening, suggesting that differential patterns of remodeling can
           be observed according to inflammatory patterns. Omalizumab, an anti IgE therapy, can
           reduce some features of airway remodeling, especially RBM and some parameters related to
           ASM. No data are available on potential changes in airway remodeling induced by
           mepolizumab.

           The aim of the study is to assess airway changes, assessed by bronchial biopsies,
           induced by mepolizumab in severe asthma patients who will receive the treatment as part
           of their standard care.

           All asthma patients refered to the asthma clinic are proposed to participate to the
           COBRA cohort (French national asthma cohort). Serum and DNA are collected at inclusion
           and every 6 months. Fiberoptic bronchoscopy (FOB) is routinely performed as part of the
           standard care for difficult-to-severe asthma in our centre for many years, to assess
           differential diagnosis and inflammatory pattern since Fractional exhaled nitric oxide
           (FeNO) is not routinely performed in France. BAL and 4 to 6 bronchial biopsies are
           performed.

        2. Study Population:

           Severe asthma patients, refered to Severe Asthma Centre in Bichat and Bicetre Hospitals,
           receiving mepolizumab according to French recommendations (eos >300mm3 in the previous
           year, >2 exacerbations, despite optimal step 4-5 therapy, including daily use of
           steroids).

        3. Study Design & Methods:

             -  General study design Prospective, observational study in one Severe Asthma Centre :
                Bichat Hospital (Prof C.Taillé).

                40 patients will be prospectively included during a 32 months period.

      This study aims to assess :

        -  Changes in RBM thickening, in ASM area after 6 months and 12 months of mepolizumab
           treatment

        -  Changes in BAL levels of inflammatory and remodeling mediators and of ECM components
           after 6 months and 12 months of mepolizumab treatment

        -  Changes in the number of PGP9 sections in the bronchial wall after 6 months and 12
           months of mepolizumab treatment

        -  Relationship between clinical response to mepolizumab and remodeling changes after 6
           months and 12 months of mepolizumab treatment

        -  Demographic and clinical characteristics of asthma (atopy, level of asthma control,
           FEV1…) will be available at inclusion and follow up, to assess clinical effect of
           mepolizumab treatment.

      The following will perform at inclusion, 6 months and 12 months after initiating mepolizumab:

        -  clinical evaluation (age, BMI, atopic status, chronic rhinosinusitis, daily doses of
           steroids, exacerbations…)

        -  benefit of mepolizumab will be evaluated according to the physician's Global Evaluation
           of Treatment Effectiveness (GETE)

        -  asthma control test

        -  lung function test (FEV1, FEV1/VC, TLC, RV, pre/post salbutamol)

        -  FOB with BAL and 6 biopsies at inclusion, 6 months and 12 months

        -  Blood test for eosinophil count and serum conservation.

             -  Study groups/arms Group 1 (prospective) : patients initiating a mepolizumab
                treatment. Group 2 (retrospective): to assess airway changes that can
                "spontaneously" occur during a 12 month-period, a retrospective "historical group"
                of patients included in the previous ASMATHERM study who had 2 sets of biopsies and
                BAL within a 6 to 12 month-interval, without exposure to mepolizumab and without
                change in their treatment during this interval, will be studied as a control group
                . Clinical data are available at inclusion and after 12 months.

             -  Main tests or procedures All biopsies, BAL and serum analysis will be performed in
                the UMR1152 lab unit (Head: Dr Marina Pretolani).

      Biopsies are fixed in formaldehyde and processed to paraffin wax for immunohistochemical
      (IHC) and morphometric studies. One biopsy will be stored at -80°C for further RNAseq
      analyses.

      RBM thickening (morphometry), ASM area and the rate of ASM-proliferating cells (PCNA
      immuno-staining) will be measured. PGP9 staining can assess the number of nerves in the
      bronchial wall.

      The number of inflammatory cells (eosinophils, neutrophils, mast cells, T-lymphocytes
      evaluated respectively by MBP, elastase, tryptase, CD4 expression) and vascular sections will
      also be enumerated after IHC. Eosinophils localization in the airway will be described.

      Cytospin preparations from BAL cell pellets will be used to assess the proportion of
      eosinophils and neutrophils.

      In parallel, the levels of different pro-inflammatory and remodeling mediators will be
      measured in BAL aliquots concentrated x 10, by specific Elisa and Luminex assays.

      • Trial plan

      V0: screening visit

      V1: inclusion visit

        -  clinical evaluation

        -  Asthma control test

        -  Lung function test

        -  Fiber optic fibroscopy with BAL and bronchial biopsies (note that if a fiber optic
           fibroscopy with BAL and bronchial biopsies has already been performed in the month prior
           to inclusion, it will not be repeated at inclusion and the tissue and BAL samples will
           be retrieved for analysis)

        -  Blood sampling

        -  first treatment by Mepolizumab is administrated in the hospital.

        -  Patient injection training if this prescription is chosen

        -  Prescription for Mepolizumab, given at home for the next 6 months

      V2: 6-month visit

        -  Clinical response assessment by GETE and ACT, clinical evaluation

        -  Lung function test

        -  Fiber optic fibroscopy with BAL and bronchial biopsies

        -  Blood sampling

        -  If responders, continuation of Mepolizumab treatment

        -  Compliance evaluation (file signed by the nurse or patient after each injection)

      V3: 12-month visit

        -  clinical response assessment by GETE and ACT, clinical evaluation

        -  Lung function test

        -  Fiber optic fibroscopy with BAL and bronchial biopsies

        -  Blood sampling

        -  Compliance evaluation (file signed by the nurse or patient after each injection)
observational model: Cohort
time perspective: Prospective
measure: Changes in reticular basement membrane (RBM) thickening
time frame: 0, 6 and 12 months
description: The absolute variation in RBM thickening (µm, morphometry measurement on bronchial biopsies) over 12 months is defined as the difference between month twelve and baseline (V1).
The absolute variation in RBM thickening over 6 months is defined as the difference between month six and baseline (V1).
measure: Changes in airway smooth muscle (ASM) area
time frame: 0, 6 and 12 months
description: Measured in morphometry in µm2 and expressed as a percentage of smooth muscle surface area relative to the biopsy surface.
The absolute variation in ASM area over 12 months is defined as the difference between month twelve and baseline (V1).
The absolute variation in ASM area over 6 months is defined as the difference between month six and baseline (V1).
measure: Number of proliferating muscle cells
time frame: 0, 6 and 12 months
description: Evaluated by anti proliferating cell nuclear antigen (PCNA) antibodies, expressed as the number of positive cells per muscle surface.
measure: Number of nerve endings
time frame: 0, 6 and 12 months
description: Evaluated by PGP9 and expressed as number of positive cells per biopsy surface in mm2
measure: Number of vascular sections
time frame: 0, 6 and 12 months
description: Measured with an anti-CD31 antibody, expressed in number of sections per mm2.
measure: Number of infiltrating inflammatory cells in the biopsies
time frame: 0, 6 and 12 months
description: Number of infiltrating inflammatory cells (infiltrating neutrophils, lymphocytes and eosinophils) expressed as number of positive cells per biopsy surface in mm2
measure: Number of inflammatory cells in the BAL
time frame: 0, 6 and 12 months
description: Number of inflammatory cells (neutrophils, lymphocytes and eosinophils) expressed as % of total cells in the BAL
measure: Proportion of eosinophils expressing MBP/IL3R
time frame: 0, 6 and 12 months
description: Measured on bronchial biopsies, expressed as number of cells per biopsy surface in mm2
measure: Interferon-gamma concentration
time frame: 0, 6 and 12 months
description: Interferon-gamma (Th1 cytokine) will be measured in BAL and serum
measure: IL-13 concentration
time frame: 0, 6 and 12 months
description: IL-13 (Th2 cytokine) will be measured in BAL and serum
measure: Periostin concentration
time frame: 0, 6 and 12 months
description: Periostin (Th2 cytokine) will be measured in BAL and serum
measure: IL-17A concentration
time frame: 0, 6 and 12 months
description: IL-17A (Th17 cytokine) will be measured in BAL and serum
measure: IL-22 concentration
time frame: 0, 6 and 12 months
description: IL-22 (Th17 cytokine) will be measured in BAL and serum
measure: IL-33 concentration
time frame: 0, 6 and 12 months
description: IL-33 (innate immune cytokines) will be measured in BAL and serum
measure: Thymic Stromal Lymphopoietin (TSLP) concentration
time frame: 0, 6 and 12 months
description: TSLP (innate immune cytokines) will be measured in BAL and serum
measure: Fibronectin concentration
time frame: 0, 6 and 12 months
description: Fibronectin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum
measure: Tenascin concentration
time frame: 0, 6 and 12 months
description: Tenascin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum
measure: Fibulin-1 concentration
time frame: 0, 6 and 12 months
description: Fibulin-1 (soluble hallmarks of ECM remodeling) will be measured in BAL and serum
measure: Monocyte chemoattractant protein-1 (CCL/MCP-1) concentration
time frame: 0, 6 and 12 months
description: Will be measured in BAL and serum
measure: EGF concentration
time frame: 0, 6 and 12 months
description: Will be measured in BAL and serum
measure: bFGF concentration
time frame: 0, 6 and 12 months
description: Will be measured in BAL and serum
measure: PDGF-BB concentration
time frame: 0, 6 and 12 months
description: Will be measured in BAL and serum
measure: Total score at Asthma Control Test
time frame: 0, 6 and 12 months
description: Measured using the Asthma Control Test (ACT) scale (range: 5 to 25). ACT assesses the frequency of shortness of breath and general asthma symptoms, use of rescue medications, the effect of asthma on daily functioning, and overall self-assessment of asthma control.
5 items, with 4-week recall (on symptoms and daily functioning)
each item is evaluated by a 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled).
The total score ranges from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma.
measure: Global evaluation of mepolizumab benefit
time frame: 6 and 12 months
description: Benefit of mepolizumab will be evaluated by patient and by physician according to the physician's Global Evaluation of Treatment Effectiveness (GETE).
Patients will be considered as "responders" if classified as "excellent response" or "good response" by their physician.
measure: Forced expiratory volume (FEV1)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in ml.
measure: Forced expiratory volume (FEV1)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.
measure: Forced expiratory volume/Vital capacity (FEV1/VC)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in %
measure: Total lung capacity (TLC)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in ml.
measure: Total lung capacity (TLC)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.
measure: Residual volume (RV)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in ml.
measure: Residual volume (RV)
time frame: 0, 6 and 12 months
description: Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.
measure: Proportion of patients with pre-bronchodilator FEV1 greater than 80%
time frame: 6 and 12 months
description: In order to assess functional response to treatment
measure: Proportion of patients with an increase from baseline in pre-bronchodilator FEV1 greater than 20%
time frame: 6 and 12 months
description: In order to assess functional response to treatment
arm group label: Mepolizumab
description: Patients receiving mepolizumab
arm group label: Patients w/o mepolizumab (retrospective)
description: Retrospective control group of patients not exposed to mepolizumab, included in the COBRA cohort and the ASMATHERM protocol, who had 2 sets of biopsies and BAL within a 6 to 12 month-interval, without change in their treatment. Clinical data for this patients are available at inclusion and after 12 months.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Camille TAILLE, MD, PhD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
facility: 
country: France
responsible party type: Sponsor
mesh term: Asthma
mesh term: Airway Remodeling
sharing ipd: Undecided