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Mechanisms of Smell Improvement With Dupilumab.

Primary Purpose

Chronic Rhinosinusitis With Nasal Polyps

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Dupilumab
Sponsored by
Medical University of South Carolina
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Rhinosinusitis With Nasal Polyps focused on measuring Chronic Rhinosinusitis, Nasal Polyps, dupilumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Adults ≥18 years of age Meet criteria for CRSwNP as defined by ICAR-21 2 out of 4 cardinal symptoms for ≥12 weeks Visible evidence of inflammation on endoscopy or imaging Bilateral visible nasal polyps ≥1 in each nasal cavity (0-4 scale each side) Olfaction score ≥1 (0-3 scale) Candidate for treatment with dupilumab for CRSwNP Elected to proceed with dupilumab for treatment of CRSwNP Exclusion Criteria: Prior use of dupilumab Previous treatment with another biologic medication for CRSwNP or asthma within 6 months Any nasal or sinus surgery within the last 3 months Oral corticosteroid use within the last 1 month Current pregnancy, breast-feeding, or plan to become pregnant during next 3 months Presence of antrochoanal nasal polyps; acute rhinosinusitis; upper respiratory infection; Allergic granulomatous angiitis/eosinophilic granulomatosis with polyangiitis; Granulomatosis with polyangiitis; cystic fibrosis; Young syndrome; Kartagener syndrome; or dyskinetic cilia syndrome Poorly controlled asthma

Sites / Locations

  • Medical University of South CarolinaRecruiting
  • University of Virginia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm 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.

Outcomes

Primary Outcome Measures

Change in volumetric olfactory cleft opacification based on CT.
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.
Change in olfactory cleft endoscopy score based on nasalendoscopy.
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.
Change in olfactory cleft mucus cytokine levels
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).
Change in Lund-Kennedy endoscopy score.
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.
Change in overall polyp score from sinonasal endoscopy
Overall polyp score on a 0-4 scale for each nostril (summed 0-8).

Secondary Outcome Measures

Correlation between change in olfactory cleft mucus IL13 level and Sniffin Sticks TDI
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.
Correlation between change in IL13 level and QOD-NS score
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.

Full Information

First Posted
February 15, 2023
Last Updated
September 6, 2023
Sponsor
Medical University of South Carolina
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1. Study Identification

Unique Protocol Identification Number
NCT05964465
Brief Title
Mechanisms of Smell Improvement With Dupilumab.
Official Title
Mechanisms of Smell Improvement With Dupilumab
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 10, 2023 (Actual)
Primary Completion Date
June 30, 2025 (Anticipated)
Study Completion Date
June 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of South Carolina

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Rhinosinusitis With Nasal Polyps
Keywords
Chronic Rhinosinusitis, Nasal Polyps, dupilumab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment
Arm Type
Experimental
Arm 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(s)
Dupilumab
Intervention Description
Monoclonal antibody blocking interleukin 4 and interleukin 13
Primary Outcome Measure Information:
Title
Change in volumetric olfactory cleft opacification based on CT.
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.
Time Frame
3 months post-treatment
Title
Change in olfactory cleft endoscopy score based on nasalendoscopy.
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.
Time Frame
3 months post-treatment
Title
Change in olfactory cleft mucus cytokine levels
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).
Time Frame
3 months post-treatment
Title
Change in Lund-Kennedy endoscopy score.
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.
Time Frame
3 months post-treatment
Title
Change in overall polyp score from sinonasal endoscopy
Description
Overall polyp score on a 0-4 scale for each nostril (summed 0-8).
Time Frame
3 months post-treatment.
Secondary Outcome Measure Information:
Title
Correlation between change in olfactory cleft mucus IL13 level and Sniffin Sticks TDI
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.
Time Frame
3 months post-treatment
Title
Correlation between change in IL13 level and QOD-NS score
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.
Time Frame
3 months post-treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adults ≥18 years of age Meet criteria for CRSwNP as defined by ICAR-21 2 out of 4 cardinal symptoms for ≥12 weeks Visible evidence of inflammation on endoscopy or imaging Bilateral visible nasal polyps ≥1 in each nasal cavity (0-4 scale each side) Olfaction score ≥1 (0-3 scale) Candidate for treatment with dupilumab for CRSwNP Elected to proceed with dupilumab for treatment of CRSwNP Exclusion Criteria: Prior use of dupilumab Previous treatment with another biologic medication for CRSwNP or asthma within 6 months Any nasal or sinus surgery within the last 3 months Oral corticosteroid use within the last 1 month Current pregnancy, breast-feeding, or plan to become pregnant during next 3 months Presence of antrochoanal nasal polyps; acute rhinosinusitis; upper respiratory infection; Allergic granulomatous angiitis/eosinophilic granulomatosis with polyangiitis; Granulomatosis with polyangiitis; cystic fibrosis; Young syndrome; Kartagener syndrome; or dyskinetic cilia syndrome Poorly controlled asthma
Facility Information:
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shaun Nguyen, MD
Phone
843-792-1356
Email
nguyensh@musc.edu
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22904
Country
United States
Individual Site Status
Not yet recruiting

12. IPD Sharing Statement

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Mechanisms of Smell Improvement With Dupilumab.

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