<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/NCT04442256</url>
  </required_header>
  <id_info>
    <org_study_id>2019-004889-18</org_study_id>
    <nct_id>NCT04442256</nct_id>
  </id_info>
  <brief_title>Effect of Dupilumab on Aspirin Intolerance</brief_title>
  <official_title>Effect of Dupilumab on ASS Intolerance and Its Mechanisms in Patients With Aspirin-exacerbated Respiratory Disease (AERD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Vienna</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      To test the efficacy of dupilumab in patients with AERD regarding the intolerance to&#xD;
      salicylic acid after 6 months. This will be evaluated by oral drug provocation testing with&#xD;
      low dose salicylic acid after 6 months of dupilumab treatment.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      After 6 months of therapy, patients will tolerate aspirin dose levels as tested with&#xD;
      different dosages (125mg, 250mg and 500 mg).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      30 patients suffering from AERD will be included in this single-center, prospective,&#xD;
      explorative study for treatment with dupilumab. Before study initiation, informed consent&#xD;
      will be obtained from all subjects. All patients with AERD can be included according to&#xD;
      inclusion- and exclusion criteria.&#xD;
&#xD;
      AERD patients who had already obtained a monoclonal antibody for the treatment of asthma or&#xD;
      polyps will also be included if at least a wash out period of 5 half -lives or 3 months has&#xD;
      passed. The first visit will be performed at screening (day 0, V1/before dupilumab therapy).&#xD;
      Clinically significant abnormal laboratory values will be ruled out prior to the first dose.&#xD;
&#xD;
      All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.&#xD;
&#xD;
      For several reasons comparison with placebo will not be performed:&#xD;
&#xD;
        -  All patients included are in urgent need for an effective treatment.&#xD;
&#xD;
        -  The only currently available alternative treatment option is a functional endoscopic&#xD;
           sinus surgery (FESS). Usually there is a high recurrence rate after surgery.&#xD;
&#xD;
        -  All included patients have a long medical history concerning AERD. The rate of a&#xD;
           spontaneous improvement or resolution in this patient population is negligible.&#xD;
&#xD;
      Spirometry (peak-flow and FEV1) and an asthma control test will be performed prior to&#xD;
      dupilumab therapy, after 1, 3 and 6 months. In addition, the sinonasal outcome test-22 and&#xD;
      the total nasal endoscopic polyps score as well as nasal congestion score, disease severity&#xD;
      (by visual analogue scale=VAS), total symptom score (TSS) will be performed at baseline,&#xD;
      after 1,3 and 6 months. To further evaluate the polyp size, a nasal CT will be performed at&#xD;
      screening visit. To evaluate the sense of smell we will perform UPSIT testing before and&#xD;
      after 6 months dupilumab.&#xD;
&#xD;
      All patients will have routine laboratory testing (blood chemistry, hematology) before and&#xD;
      after 6 months of therapy. Adverse events will be recorded at each visit. Biological activity&#xD;
      will be evaluated based on peripheral blood eosinophil counts, serum total Immunoglobulin E&#xD;
      (IgE) levels and measurement of eosinophilic cationic protein in patients' sera at baseline&#xD;
      and after 6 months.&#xD;
&#xD;
      To assess local changes in the nose caused by dupilumab treatment, nasal secretions, nasal&#xD;
      mucosa samples (nasal curette), nasal microbiome as well as nasal biopsies will be collected.&#xD;
&#xD;
      After the end of study, treatment will be continued in all patients with significant&#xD;
      improvement in asthmatic symptoms, nasal symptoms as well as a reduction of polyps.&#xD;
&#xD;
      For patients who did not experience clinical improvement, dupilumab treatment will be&#xD;
      discontinued after 6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Only one group</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximally tolerated aspirin dose level (stages 125mg, 250mg and 500mg)</measure>
    <time_frame>6 months</time_frame>
    <description>Changes in the maximal ASS dose level tolerations (no toleration, 125mg, 250mg and 500mg) at baseline and after 6 months.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of nasal polyps (TPS)</measure>
    <time_frame>6 months</time_frame>
    <description>A secondary endpoint is the change of polyps after 6 months of treatment with dupilumab, which will be evaluated by an ENT specialist. The polyps will be evaluated on each side by means of nasal endoscopy and graded based on polyp size, resulting in scores of 0 to 4 (TPSs).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of allergic asthma (Spirometry)</measure>
    <time_frame>6 months</time_frame>
    <description>Changes in spirometry (FEV1%)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of T and B cell subsets in nasal polyp tissues of patients treated with dupilumab as assessed with confocal microscopy</measure>
    <time_frame>6 months</time_frame>
    <description>Biopisies of nasal polyps will be taken at baseline and after 6 months of treatment with Dupilumab. RNA will be isolated from part of the biopsy and subjected to bulk RNA sequencing. Genes up or downregulated upon treatment will be calculated by bioinformaticians. Biopsies will also be assessed by confocal microscopy upon staining for surface specific markers identifiying various T (T mem, reg T cells) and B (Plasma cell, memory cells) as well as other immune cell subpopulations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of allergic asthma (Asthma control test)</measure>
    <time_frame>6 months</time_frame>
    <description>Change from baseline in allergic asthma on the asthma control test at 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of nasal polyps (SNOT-22)</measure>
    <time_frame>6 months</time_frame>
    <description>Changes in sinus nasal outcome test-22 (SNOT 22) between baseline and 6 months.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>AERD - Aspirin Exacerbated Respiratory Disease</condition>
  <arm_group>
    <arm_group_label>Dupilumab</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>All patients will be administered subcutaneous doses of dupilumab in a monthly fashion. Observation period will be 30 minutes after injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dupilumab</intervention_name>
    <description>All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.</description>
    <arm_group_label>Dupilumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Dupilumab treatment group:&#xD;
&#xD;
          -  Signed and dated informed consent has been obtained&#xD;
&#xD;
          -  Age 18 - 70 years&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  Diagnosed with AERD (nasal polyps, allergic asthma, aspirin intolerance)&#xD;
&#xD;
          -  Chronic rhinosinusitis with nasal polyps (CRSwNP) (according to the European Position&#xD;
             Paper on Rhinosinusitis and Nasal Polyps Guidelines)8&#xD;
&#xD;
          -  Documented aspirin intolerance&#xD;
&#xD;
          -  Asthma bronchial diagnosed by a respiratory physician (based on Global -Initiative for&#xD;
             Asthma guidelines)9&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Clinically significant abnormal laboratory values and active infection (Tbc, HIV,&#xD;
             hepatitis A/B/C)&#xD;
&#xD;
          -  History of malignancy or immunodeficiency&#xD;
&#xD;
          -  Chronic obstructive lung disorders (COPD), other obstructive lung disorders&#xD;
             (bronchiolitis)&#xD;
&#xD;
          -  Need for systemic corticosteroid therapy 1 month prior to screening visit Eosinophilic&#xD;
             pneumonia and Churg-Strauss Syndrome&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christine Bangert, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical University of Vienna</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Christine Bangert, M.D</last_name>
    <phone>004314040025310</phone>
    <email>christine.bangert@meduniwien.ac.at</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tamara Quint, M.D</last_name>
    <email>tamara.quint@meduniwien.ac.at</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical University of Vienna</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christine Bangert, M.D</last_name>
    </contact>
    <investigator>
      <last_name>Tamara Quint, M.D</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sven Schneider, M.D</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Julia Eckl-Dorna, M.D</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dariga Ramazanova</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 22, 2020</study_first_posted>
  <last_update_submitted>April 5, 2022</last_update_submitted>
  <last_update_submitted_qc>April 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Tamara Quint</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>AERD</keyword>
  <keyword>Asthma</keyword>
  <keyword>Morbus Widal</keyword>
  <keyword>chronic rhinosinusitis with nasal polyps</keyword>
  <keyword>dupilumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Tract Diseases</mesh_term>
    <mesh_term>Respiration Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</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/NCT04442256
org study id: 2019-004889-18
nct id: NCT04442256
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
To test the efficacy of dupilumab in patients with AERD regarding the intolerance to
      salicylic acid after 6 months. This will be evaluated by oral drug provocation testing with
      low dose salicylic acid after 6 months of dupilumab treatment.

      Hypothesis:

      After 6 months of therapy, patients will tolerate aspirin dose levels as tested with
      different dosages (125mg, 250mg and 500 mg).
30 patients suffering from AERD will be included in this single-center, prospective,
      explorative study for treatment with dupilumab. Before study initiation, informed consent
      will be obtained from all subjects. All patients with AERD can be included according to
      inclusion- and exclusion criteria.

      AERD patients who had already obtained a monoclonal antibody for the treatment of asthma or
      polyps will also be included if at least a wash out period of 5 half -lives or 3 months has
      passed. The first visit will be performed at screening (day 0, V1/before dupilumab therapy).
      Clinically significant abnormal laboratory values will be ruled out prior to the first dose.

      All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.

      For several reasons comparison with placebo will not be performed:

        -  All patients included are in urgent need for an effective treatment.

        -  The only currently available alternative treatment option is a functional endoscopic
           sinus surgery (FESS). Usually there is a high recurrence rate after surgery.

        -  All included patients have a long medical history concerning AERD. The rate of a
           spontaneous improvement or resolution in this patient population is negligible.

      Spirometry (peak-flow and FEV1) and an asthma control test will be performed prior to
      dupilumab therapy, after 1, 3 and 6 months. In addition, the sinonasal outcome test-22 and
      the total nasal endoscopic polyps score as well as nasal congestion score, disease severity
      (by visual analogue scale=VAS), total symptom score (TSS) will be performed at baseline,
      after 1,3 and 6 months. To further evaluate the polyp size, a nasal CT will be performed at
      screening visit. To evaluate the sense of smell we will perform UPSIT testing before and
      after 6 months dupilumab.

      All patients will have routine laboratory testing (blood chemistry, hematology) before and
      after 6 months of therapy. Adverse events will be recorded at each visit. Biological activity
      will be evaluated based on peripheral blood eosinophil counts, serum total Immunoglobulin E
      (IgE) levels and measurement of eosinophilic cationic protein in patients' sera at baseline
      and after 6 months.

      To assess local changes in the nose caused by dupilumab treatment, nasal secretions, nasal
      mucosa samples (nasal curette), nasal microbiome as well as nasal biopsies will be collected.

      After the end of study, treatment will be continued in all patients with significant
      improvement in asthmatic symptoms, nasal symptoms as well as a reduction of polyps.

      For patients who did not experience clinical improvement, dupilumab treatment will be
      discontinued after 6 months.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Only one group
primary purpose: Treatment
masking: None (Open Label)
measure: Maximally tolerated aspirin dose level (stages 125mg, 250mg and 500mg)
time frame: 6 months
description: Changes in the maximal ASS dose level tolerations (no toleration, 125mg, 250mg and 500mg) at baseline and after 6 months.
measure: Change of nasal polyps (TPS)
time frame: 6 months
description: A secondary endpoint is the change of polyps after 6 months of treatment with dupilumab, which will be evaluated by an ENT specialist. The polyps will be evaluated on each side by means of nasal endoscopy and graded based on polyp size, resulting in scores of 0 to 4 (TPSs).
measure: Change of allergic asthma (Spirometry)
time frame: 6 months
description: Changes in spirometry (FEV1%)
measure: Percentage of T and B cell subsets in nasal polyp tissues of patients treated with dupilumab as assessed with confocal microscopy
time frame: 6 months
description: Biopisies of nasal polyps will be taken at baseline and after 6 months of treatment with Dupilumab. RNA will be isolated from part of the biopsy and subjected to bulk RNA sequencing. Genes up or downregulated upon treatment will be calculated by bioinformaticians. Biopsies will also be assessed by confocal microscopy upon staining for surface specific markers identifiying various T (T mem, reg T cells) and B (Plasma cell, memory cells) as well as other immune cell subpopulations.
measure: Change of allergic asthma (Asthma control test)
time frame: 6 months
description: Change from baseline in allergic asthma on the asthma control test at 6 months.
measure: Change of nasal polyps (SNOT-22)
time frame: 6 months
description: Changes in sinus nasal outcome test-22 (SNOT 22) between baseline and 6 months.
arm group label: Dupilumab
arm group type: Other
description: All patients will be administered subcutaneous doses of dupilumab in a monthly fashion. Observation period will be 30 minutes after injection
intervention type: Drug
intervention name: Dupilumab
description: All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.
arm group label: Dupilumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Christine Bangert, M.D.
role: Principal Investigator
affiliation: Medical University of Vienna
last name: Christine Bangert, M.D
phone: 004314040025310
email: christine.bangert@meduniwien.ac.at
last name: Tamara Quint, M.D
email: tamara.quint@meduniwien.ac.at
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Austria
responsible party type: Principal Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Tamara Quint
investigator title: Principal investigator
mesh term: Respiratory Tract Diseases
mesh term: Respiration Disorders
sharing ipd: Yes