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Mechanisms of Benefit of IL4RA Inhibition in Aspirin-Exacerbated Respiratory Disease (MARINER)

Primary Purpose

Nasal Polyps, Asthma, Aspirin-Induced, Aspirin-Exacerbated Respiratory Disease

Status
Not yet recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dupilumab
Placebo
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nasal Polyps

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

  1. A Body Mass Index (BMI) of >18.0 kg/m2
  2. History of AERD, defined as meeting the diagnostic triad with:

    1. History of physician-diagnosed asthma and
    2. History of physician-diagnosed nasal polyposis and
    3. History of pathognomonic reactions to aspirin or other nonselective COX inhibitors.
  3. Visible nasal polyps bilaterally on rhinoscopy at the time of Screening, with a Total Polyp Score (TPS) 1 of >2 on each side, for a minimum total score of 4 (out of 8 maximum).
  4. Evidence of sense of smell impairment, with a University of Pennsylvania Smell Identification Test (UPSIT) score of <34.
  5. Stable asthma (pre-bronchodilator FEV1 of >60% predicted, no glucocorticoid burst for at least 4 weeks prior to Visit 1, and no hospitalizations or ER visits for asthma for at least the prior 6 months).
  6. Consistent (daily) use of an intranasal steroid for at least 4 weeks prior to Screening.
  7. No current smoking (not more than one instance of smoking in the last 3 months).
  8. For females: Practicing FDA-approved methods of birth control for the duration of the study. Female participants of childbearing potential must have a negative pregnancy test upon study entry.
  9. For males: Practicing FDA-approved methods of birth control for the duration of the study.

Key Exclusion Criteria:

  1. Use of investigational drugs within 12 weeks of Screening.
  2. Use of any biologic agent within 4 months prior to Screening.
  3. Use of systemic (enteral or injected) glucocorticoids within 4 weeks prior to randomization/Visit 1
  4. History of any sinonasal surgery within 4 months prior to Screening
  5. Current use of zileuton
  6. Current use of high-dose aspirin therapy (no more than 325 mg aspirin per day will be allowed)
  7. Pregnant, nursing, or planning to become pregnant

Note: Other inclusion and exclusion criteria apply.

Sites / Locations

  • Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Dupilumab

Placebo

Arm Description

Subjects will be randomized to receive dupilumab (300mg every-other-week for 8 weeks).

Subjects will be randomized to receive placebo (every-other-week for 8 weeks).

Outcomes

Primary Outcome Measures

Nasal fluid levels of LTE4
The nasal fluid levels of LTE4 will be measured at week 8 and will serve as a surrogate biomarker of respiratory mast cell activation or burden, compared between the dupilumab group and the placebo group.

Secondary Outcome Measures

Nasal fluid levels of albumin
The nasal fluid levels of albumin will be measured at week 8 and serve as a surrogate biomarker of nasal epithelial cell integrity, compared between the dupilumab group and the placebo group.
Sense of smell - University of Pennsylvania Smell Identification Test (UPSIT)
Patients' sense of smell will be assessed at week 8 using the UPSIT, compared between the dupilumab group and the placebo group.
Rhinoscopic Total Polyp Score (TPS)
The extent of patients' nasal polyps will be assessed at week 8 using a TPS, compared between the dupilumab group and the placebo group.
Peak Nasal Inspiratory Flow (PNIF)
Patients' nasal congestion will be assessed at week 8 by a PNIF, compared between the dupilumab group and the placebo group.
Quality of life - 22-Item Sino-Nasal Outcome Test (SNOT-22)
Quality of life will be assessed at week 8 with a SNOT-22, compared between the dupilumab group and the placebo group.
Lung function - Forced Expiratory Volume 1 (FEV1)
Patients' lung function will be assessed at week 8 with an FEV1, compared between the dupilumab group and the placebo group.
Asthma control - Asthma Control Questionnaire-6 (ACQ-6)
Asthma control will be measured at week 8 with an ACQ-6, compared between the dupilumab group and the placebo group.
Number of treatment-related adverse events (AEs) and serious adverse events (SAEs) leading to study drug discontinuation
Safety will be measured by the number of treatment-related AEs and SAEs leading to study drug (dupilumab) discontinuation.

Full Information

First Posted
October 7, 2022
Last Updated
October 7, 2022
Sponsor
Brigham and Women's Hospital
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT05575037
Brief Title
Mechanisms of Benefit of IL4RA Inhibition in Aspirin-Exacerbated Respiratory Disease
Acronym
MARINER
Official Title
Mechanisms of Benefit of IL4RA Inhibition in Aspirin-Exacerbated Respiratory Disease: MARINER
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 2022 (Anticipated)
Primary Completion Date
November 2026 (Anticipated)
Study Completion Date
November 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

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
Yes

5. Study Description

Brief Summary
The overall aim of the study is to determine the clinical efficacy and mechanisms of action of anti-IL-4a (dupilumab) as treatment for patients with Aspirin-Exacerbated Respiratory Disease (AERD).
Detailed Description
The protocol involves an 8-week, double-blind, placebo-controlled parallel-design trial of dupilumab in patients with AERD. Participants will have 4 total doses of dupilumab or placebo administered, with each dose administered every 2 weeks. There will be full clinical assessments and biospecimen collections at Baseline (Visit 1), Week 2 (Visit 2), and Week 8 (Visit 3).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nasal Polyps, Asthma, Aspirin-Induced, Aspirin-Exacerbated Respiratory Disease, Aspirin-Sensitive Asthma With Nasal Polyps

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
33 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dupilumab
Arm Type
Active Comparator
Arm Description
Subjects will be randomized to receive dupilumab (300mg every-other-week for 8 weeks).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects will be randomized to receive placebo (every-other-week for 8 weeks).
Intervention Type
Drug
Intervention Name(s)
Dupilumab
Other Intervention Name(s)
Dupilumab Prefilled Syringe [Dupixent]
Intervention Description
8-week, double-blind, placebo-controlled parallel-design trial of dupilumab (an anti-IL-4a) in patients with AERD.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo Injection
Intervention Description
8-week, double-blind, placebo-controlled parallel-design trial of dupilumab (an anti-IL-4a) in patients with AERD.
Primary Outcome Measure Information:
Title
Nasal fluid levels of LTE4
Description
The nasal fluid levels of LTE4 will be measured at week 8 and will serve as a surrogate biomarker of respiratory mast cell activation or burden, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Secondary Outcome Measure Information:
Title
Nasal fluid levels of albumin
Description
The nasal fluid levels of albumin will be measured at week 8 and serve as a surrogate biomarker of nasal epithelial cell integrity, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Sense of smell - University of Pennsylvania Smell Identification Test (UPSIT)
Description
Patients' sense of smell will be assessed at week 8 using the UPSIT, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Rhinoscopic Total Polyp Score (TPS)
Description
The extent of patients' nasal polyps will be assessed at week 8 using a TPS, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Peak Nasal Inspiratory Flow (PNIF)
Description
Patients' nasal congestion will be assessed at week 8 by a PNIF, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Quality of life - 22-Item Sino-Nasal Outcome Test (SNOT-22)
Description
Quality of life will be assessed at week 8 with a SNOT-22, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Lung function - Forced Expiratory Volume 1 (FEV1)
Description
Patients' lung function will be assessed at week 8 with an FEV1, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Asthma control - Asthma Control Questionnaire-6 (ACQ-6)
Description
Asthma control will be measured at week 8 with an ACQ-6, compared between the dupilumab group and the placebo group.
Time Frame
At Week 8 (Visit 3)
Title
Number of treatment-related adverse events (AEs) and serious adverse events (SAEs) leading to study drug discontinuation
Description
Safety will be measured by the number of treatment-related AEs and SAEs leading to study drug (dupilumab) discontinuation.
Time Frame
At Week 8 (Visit 3)
Other Pre-specified Outcome Measures:
Title
Change in sense of smell - University of Pennsylvania Smell Identification Test (UPSIT)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in UPSIT, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in Rhinoscopic Total Polyp Score (TPS)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in TPS, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in Peak Nasal Inspiratory Flow (PNIF)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in PNIF, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in 22-Item Sino-Nasal Outcome Test (SNOT-22)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in SNOT-22, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in lung function - Forced Expiratory Volume 1 (FEV1)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in FEV1, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in Asthma control - Asthma Control Questionnaire-6 (ACQ-6)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in ACQ-6, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in Nasal fluid levels of eicosanoids
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid eicosanoid levels, compared between patients on placebo vs dupilumab.
Time Frame
weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in Nasal fluid levels of albumin
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid albumin levels, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in urinary levels of eicosanoids
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in urinary eicosanoid levels, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in serum tryptase
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in serum tryptase levels, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in IgE levels
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid and plasma levels of IgE, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Title
Change in eosinophilic cationic protein (ECP)
Description
Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid levels of ECP, compared between patients on placebo vs dupilumab.
Time Frame
2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria: A Body Mass Index (BMI) of >18.0 kg/m2 History of AERD, defined as meeting the diagnostic triad with: History of physician-diagnosed asthma and History of physician-diagnosed nasal polyposis and History of pathognomonic reactions to aspirin or other nonselective COX inhibitors. Visible nasal polyps bilaterally on rhinoscopy at the time of Screening, with a Total Polyp Score (TPS) 1 of >2 on each side, for a minimum total score of 4 (out of 8 maximum). Evidence of sense of smell impairment, with a University of Pennsylvania Smell Identification Test (UPSIT) score of <34. Stable asthma (pre-bronchodilator FEV1 of >60% predicted, no glucocorticoid burst for at least 4 weeks prior to Visit 1, and no hospitalizations or ER visits for asthma for at least the prior 6 months). Consistent (daily) use of an intranasal steroid for at least 4 weeks prior to Screening. No current smoking (not more than one instance of smoking in the last 3 months). For females: Practicing FDA-approved methods of birth control for the duration of the study. Female participants of childbearing potential must have a negative pregnancy test upon study entry. For males: Practicing FDA-approved methods of birth control for the duration of the study. Key Exclusion Criteria: Use of investigational drugs within 12 weeks of Screening. Use of any biologic agent within 4 months prior to Screening. Use of systemic (enteral or injected) glucocorticoids within 4 weeks prior to randomization/Visit 1 History of any sinonasal surgery within 4 months prior to Screening Current use of zileuton Current use of high-dose aspirin therapy (no more than 325 mg aspirin per day will be allowed) Pregnant, nursing, or planning to become pregnant Note: Other inclusion and exclusion criteria apply.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tanya M Laidlaw, MD
Phone
617-525-1034
Email
tlaidlaw@bwh.harvard.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Tessa Ryan
Phone
857-307-1166
Email
tryan6@bwh.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tanya M Laidlaw, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tessa Ryan
Phone
857-307-1166
Email
tryan6@bwh.harvard.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Mechanisms of Benefit of IL4RA Inhibition in Aspirin-Exacerbated Respiratory Disease

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