xml: <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/NCT05964465</url>
    </required_header>
    <id_info>
      <org_study_id>Pro00125142</org_study_id>
      <nct_id>NCT05964465</nct_id>
    </id_info>
    <brief_title>Mechanisms of Smell Improvement With Dupilumab.</brief_title>
    <official_title>Mechanisms of Smell Improvement With Dupilumab</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Medical University of South Carolina</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Medical University of South Carolina</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>Yes</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This study seeks to explore the mechanism through which dupilumab improves olfactory cleft&#xD;
        inflammation in patients with chronic sinusitis with nasal polyps (CRSwNP). The investigators&#xD;
        expect this study to provide convincing evidence that dupilumab improves clinical olfaction&#xD;
        via direct reduction in olfactory cleft inflammation.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Post-marketed administration of dupilumab (FDA approved medication for CRSwNP) in patients&#xD;
        with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) will result in significant improvement&#xD;
        in objective measures of olfactory cleft inflammation and psychophysical olfaction. The&#xD;
        investigators seek to explore the mechanism through which dupilumab improves olfactory cleft&#xD;
        inflammation in patients with CRSwNP. The investigators also want to determine whether change&#xD;
        in olfactory cleft inflammation correlates with improvement in olfaction (one of the cardinal&#xD;
        symptoms of CRSwNP) at 3 months. The investigators hypothesize that after 3 months of&#xD;
        treatment with dupilumab, non-inflammatory factors will explain a significant degree of&#xD;
        variation in residual clinical olfaction. Additionally, the investigators want to explore the&#xD;
        determinants of ongoing olfactory loss after 3 months of treatment with attention to&#xD;
        non-inflammatory factors. The investigators expect this study to provide convincing evidence&#xD;
        that dupilumab improves clinical olfaction via direct reduction in olfactory cleft&#xD;
        inflammation. Specifically, the investigators expect to show that reduction in olfactory&#xD;
        cleft inflammation is the result of reduction in IL13 levels in olfactory cleft mucus.&#xD;
        Finally, the investigators expect to show that most of the variation in post-treatment&#xD;
        olfaction can be explained by non-inflammatory measures that are independent of CRSwNP.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 10, 2023</start_date>
    <completion_date type="Anticipated">June 30, 2025</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2025</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>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Change in volumetric olfactory cleft opacification based on CT.</measure>
      <time_frame>3 months post-treatment</time_frame>
      <description>Non-contrast sinus computed tomography (CT) scans will be obtained at baseline and 3 month follow-up to provide 1mm cuts that can be formatted in coronal, sagittal, and axial planes. Volumetric analysis of the OC will be performed utilizing equally spaced coronal CT images per our previously described protocols. Total volume of the segmented 3-D olfactory cleft space will be calculated, as well as the volume of air within that space. The percent opacification will be defined as [1-(total volume of air/total volume of olfactory cleft)] multiplied by 100. Sinus opacification will be quantified using the Lund-Mackay CT scale.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in olfactory cleft endoscopy score based on nasalendoscopy.</measure>
      <time_frame>3 months post-treatment</time_frame>
      <description>Subjects will have sinonasal endoscopy at baseline and every follow up visit. This procedure allows visual inspection of the sinus mucosal lining and grading of polyps, including the olfactory cleft. Results for each side will be recorded separately and combined for a final Olfactory Cleft Endoscopy Scale (OCES) that ranges from 0-20, with higher scores representing increased disease severity.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in olfactory cleft mucus cytokine levels</measure>
      <time_frame>3 months post-treatment</time_frame>
      <description>Under endoscopic guidance, a 1 × 2-cm Leukosorb filter paper (Pall Scientific, Port Washington, NY) strip will be placed into the olfactory cleft of each side, and kept in place for 3 minutes, as described in earlier studies. This will be done at baseline, 2 weeks, and 3 months. Olfactory cleft mucus inflammatory cytokine levels will be detected using commercially available LegendPlex Th2 Cytometric Bead Array (BioLegend, San Diego, CA) following the manufacturer's recommended protocol. This panel will include IL4, IL13, IL5 cytokines (among others). The assay will be carried out according to manufacturers' instructions and as previously described. The samples will be read on a Guava easyCyte 8HT flow cytometer (EMD Millipore) and analysis performed with LegendPlex software. Total IgE will be quantified via ELISA (GenWay Biotech. Inc, San Diego, CA).</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in Lund-Kennedy endoscopy score.</measure>
      <time_frame>3 months post-treatment</time_frame>
      <description>Subjects will have sinonasal endoscopy at baseline and every follow up visit. This procedure allows visual inspection of the sinus mucosal lining and grading of polyps, including the olfactory cleft. Results for each side will be recorded separately and combined for a final Lund-Kennedy endoscopy score (LKES) that ranges from 0-20, with higher scores representing increased disease severity.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in overall polyp score from sinonasal endoscopy</measure>
      <time_frame>3 months post-treatment.</time_frame>
      <description>Overall polyp score on a 0-4 scale for each nostril (summed 0-8).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Correlation between change in olfactory cleft mucus IL13 level and Sniffin Sticks TDI</measure>
      <time_frame>3 months post-treatment</time_frame>
      <description>Quantitative psychophysical olfactory testing will be performed using the &quot;Sniffin' Sticks&quot; test (Burghardt, Wedel, Germany). Testing will be performed by trained clinical research coordinators who routinely perform objective olfactory testing and will be done in a blinded fashion. This commercially available test battery measures odor threshold (OT), odor discrimination (OD) and odor identification (OI). The results will be combined for an overall TDI score. TDI will be correlated with OC IL13 levels.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Correlation between change in IL13 level and QOD-NS score</measure>
      <time_frame>3 months post-treatment</time_frame>
      <description>Olfactory-specific QOL will be assessed using the previously validated, short, modified version of the Questionnaire of Olfactory Disorders (QOD-NS) survey. This instrument was validated by Mattos and Soler and has been found to have criterion validity, internal consistency, and excellent reproducibility.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">50</enrollment>
    <condition>Chronic Rhinosinusitis With Nasal Polyps</condition>
    <arm_group>
      <arm_group_label>Treatment</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>The treatment group will receive dupilumab at 300mg SC Q2weeks. The first dose will be administered via subcutaneous injection in clinic at baseline. Subjects will self-administer study drug (dupilumab 300 mg) subcutaneous every 2 weeks after initial dosing at visit 2.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Dupilumab</intervention_name>
      <description>Monoclonal antibody blocking interleukin 4 and interleukin 13</description>
      <arm_group_label>Treatment</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Adults ≥18 years of age&#xD;
  &#xD;
            -  Meet criteria for CRSwNP as defined by ICAR-21&#xD;
  &#xD;
            -  2 out of 4 cardinal symptoms for ≥12 weeks&#xD;
  &#xD;
            -  Visible evidence of inflammation on endoscopy or imaging&#xD;
  &#xD;
            -  Bilateral visible nasal polyps ≥1 in each nasal cavity (0-4 scale each side)&#xD;
  &#xD;
            -  Olfaction score ≥1 (0-3 scale)&#xD;
  &#xD;
            -  Candidate for treatment with dupilumab for CRSwNP&#xD;
  &#xD;
            -  Elected to proceed with dupilumab for treatment of CRSwNP&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Prior use of dupilumab&#xD;
  &#xD;
            -  Previous treatment with another biologic medication for CRSwNP or asthma within 6&#xD;
               months&#xD;
  &#xD;
            -  Any nasal or sinus surgery within the last 3 months&#xD;
  &#xD;
            -  Oral corticosteroid use within the last 1 month&#xD;
  &#xD;
            -  Current pregnancy, breast-feeding, or plan to become pregnant during next 3 months&#xD;
  &#xD;
            -  Presence of antrochoanal nasal polyps; acute rhinosinusitis; upper respiratory&#xD;
               infection;&#xD;
  &#xD;
            -  Allergic granulomatous angiitis/eosinophilic granulomatosis with polyangiitis;&#xD;
  &#xD;
            -  Granulomatosis with polyangiitis; cystic fibrosis; Young syndrome;&#xD;
  &#xD;
            -  Kartagener syndrome; or dyskinetic cilia syndrome&#xD;
  &#xD;
            -  Poorly controlled asthma&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Medical University of South Carolina</name>
        <address>
          <city>Charleston</city>
          <state>South Carolina</state>
          <zip>29425</zip>
          <country>United States</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Shaun Nguyen, MD</last_name>
        <phone>843-792-1356</phone>
        <email>nguyensh@musc.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>University of Virginia</name>
        <address>
          <city>Charlottesville</city>
          <state>Virginia</state>
          <zip>22904</zip>
          <country>United States</country>
        </address>
      </facility>
      <status>Not yet recruiting</status>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>February 15, 2023</study_first_submitted>
    <study_first_submitted_qc>July 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 28, 2023</study_first_posted>
    <last_update_submitted>September 6, 2023</last_update_submitted>
    <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Medical University of South Carolina</investigator_affiliation>
      <investigator_full_name>Shaun A. Nguyen, MD</investigator_full_name>
      <investigator_title>Professor and Director of Clinical Research</investigator_title>
    </responsible_party>
    <keyword>Chronic Rhinosinusitis</keyword>
    <keyword>Nasal Polyps</keyword>
    <keyword>dupilumab</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Nasal Polyps</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05964465
  org study id: Pro00125142
  nct id: NCT05964465
  lead sponsor: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  This study seeks to explore the mechanism through which dupilumab improves olfactory cleft
        inflammation in patients with chronic sinusitis with nasal polyps (CRSwNP). The investigators
        expect this study to provide convincing evidence that dupilumab improves clinical olfaction
        via direct reduction in olfactory cleft inflammation.
  Post-marketed administration of dupilumab (FDA approved medication for CRSwNP) in patients
        with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) will result in significant improvement
        in objective measures of olfactory cleft inflammation and psychophysical olfaction. The
        investigators seek to explore the mechanism through which dupilumab improves olfactory cleft
        inflammation in patients with CRSwNP. The investigators also want to determine whether change
        in olfactory cleft inflammation correlates with improvement in olfaction (one of the cardinal
        symptoms of CRSwNP) at 3 months. The investigators hypothesize that after 3 months of
        treatment with dupilumab, non-inflammatory factors will explain a significant degree of
        variation in residual clinical olfaction. Additionally, the investigators want to explore the
        determinants of ongoing olfactory loss after 3 months of treatment with attention to
        non-inflammatory factors. The investigators expect this study to provide convincing evidence
        that dupilumab improves clinical olfaction via direct reduction in olfactory cleft
        inflammation. Specifically, the investigators expect to show that reduction in olfactory
        cleft inflammation is the result of reduction in IL13 levels in olfactory cleft mucus.
        Finally, the investigators expect to show that most of the variation in post-treatment
        olfaction can be explained by non-inflammatory measures that are independent of CRSwNP.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Change in volumetric olfactory cleft opacification based on CT.
  time frame: 3 months post-treatment
  description: Non-contrast sinus computed tomography (CT) scans will be obtained at baseline and 3 month follow-up to provide 1mm cuts that can be formatted in coronal, sagittal, and axial planes. Volumetric analysis of the OC will be performed utilizing equally spaced coronal CT images per our previously described protocols. Total volume of the segmented 3-D olfactory cleft space will be calculated, as well as the volume of air within that space. The percent opacification will be defined as [1-(total volume of air/total volume of olfactory cleft)] multiplied by 100. Sinus opacification will be quantified using the Lund-Mackay CT scale.
  measure: Change in olfactory cleft endoscopy score based on nasalendoscopy.
  time frame: 3 months post-treatment
  description: Subjects will have sinonasal endoscopy at baseline and every follow up visit. This procedure allows visual inspection of the sinus mucosal lining and grading of polyps, including the olfactory cleft. Results for each side will be recorded separately and combined for a final Olfactory Cleft Endoscopy Scale (OCES) that ranges from 0-20, with higher scores representing increased disease severity.
  measure: Change in olfactory cleft mucus cytokine levels
  time frame: 3 months post-treatment
  description: Under endoscopic guidance, a 1 × 2-cm Leukosorb filter paper (Pall Scientific, Port Washington, NY) strip will be placed into the olfactory cleft of each side, and kept in place for 3 minutes, as described in earlier studies. This will be done at baseline, 2 weeks, and 3 months. Olfactory cleft mucus inflammatory cytokine levels will be detected using commercially available LegendPlex Th2 Cytometric Bead Array (BioLegend, San Diego, CA) following the manufacturer's recommended protocol. This panel will include IL4, IL13, IL5 cytokines (among others). The assay will be carried out according to manufacturers' instructions and as previously described. The samples will be read on a Guava easyCyte 8HT flow cytometer (EMD Millipore) and analysis performed with LegendPlex software. Total IgE will be quantified via ELISA (GenWay Biotech. Inc, San Diego, CA).
  measure: Change in Lund-Kennedy endoscopy score.
  time frame: 3 months post-treatment
  description: Subjects will have sinonasal endoscopy at baseline and every follow up visit. This procedure allows visual inspection of the sinus mucosal lining and grading of polyps, including the olfactory cleft. Results for each side will be recorded separately and combined for a final Lund-Kennedy endoscopy score (LKES) that ranges from 0-20, with higher scores representing increased disease severity.
  measure: Change in overall polyp score from sinonasal endoscopy
  time frame: 3 months post-treatment.
  description: Overall polyp score on a 0-4 scale for each nostril (summed 0-8).
  measure: Correlation between change in olfactory cleft mucus IL13 level and Sniffin Sticks TDI
  time frame: 3 months post-treatment
  description: Quantitative psychophysical olfactory testing will be performed using the "Sniffin' Sticks" test (Burghardt, Wedel, Germany). Testing will be performed by trained clinical research coordinators who routinely perform objective olfactory testing and will be done in a blinded fashion. This commercially available test battery measures odor threshold (OT), odor discrimination (OD) and odor identification (OI). The results will be combined for an overall TDI score. TDI will be correlated with OC IL13 levels.
  measure: Correlation between change in IL13 level and QOD-NS score
  time frame: 3 months post-treatment
  description: Olfactory-specific QOL will be assessed using the previously validated, short, modified version of the Questionnaire of Olfactory Disorders (QOD-NS) survey. This instrument was validated by Mattos and Soler and has been found to have criterion validity, internal consistency, and excellent reproducibility.
  arm group label: Treatment
  arm group type: Experimental
  description: The treatment group will receive dupilumab at 300mg SC Q2weeks. The first dose will be administered via subcutaneous injection in clinic at baseline. Subjects will self-administer study drug (dupilumab 300 mg) subcutaneous every 2 weeks after initial dosing at visit 2.
  intervention type: Drug
  intervention name: Dupilumab
  description: Monoclonal antibody blocking interleukin 4 and interleukin 13
  arm group label: Treatment
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  facility: 
  status: Recruiting
  contact: 
  facility: 
  status: Not yet recruiting
  country: United States
  responsible party type: Principal Investigator
  investigator affiliation: Medical University of South Carolina
  investigator full name: Shaun A. Nguyen, MD
  investigator title: Professor and Director of Clinical Research
  mesh term: Nasal Polyps