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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Nasal Polyps; Aspirin-Sensitive Asthma With Nasal Polyps; Asthma, Aspirin-Induced; Aspirin-Exacerbated Respiratory Disease
• Intervention / Treatment: Drug: Dupilumab

Detailed Description

The protocol involves an 8-week trial of dupilumab in patients with AERD. Participants will have 4 total doses of dupilumab 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).

• Study Type: Interventional
• Enrollment (Estimated): 33
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tanya M Laidlaw, MD; Phone Number: 617-525-1034; Email: tlaidlaw@bwh.harvard.edu
• Study Contact Backup: Name: Tessa Ryan; Phone Number: 617-525-3824; Email: tryan6@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Laura Bailey, BA; Phone Number: 857-307-1166; Email: lbailey0@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. 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.
2. Visible nasal polyps bilaterally on otoscope physical exam at the time of screening.
3. Evidence of sense of smell impairment, with a University of Pennsylvania Smell Identification Test (UPSIT) score of <34.
4. Stable asthma (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 3 months).
5. Consistent (daily) use of an intranasal steroid for at least 4 weeks prior to Screening.
6. No current smoking (not more than one instance of smoking in the last 3 months).
7. 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.

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 Screening.
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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dupilumab; Subjects will receive dupilumab (300mg every-other-week for 8 weeks).	Drug: Dupilumab; 8-week trial of dupilumab (an anti-IL-4a) in patients with AERD.; Other Names: Dupilumab Prefilled Syringe [Dupixent]

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At Week 8 (Visit 3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At Week 8 (Visit 3)
Sense of smell - University of Pennsylvania Smell Identification Test (UPSIT)	Patients' sense of smell will be assessed at week 8 using the UPSIT.	At Week 8 (Visit 3)
Rhinoscopic Total Polyp Score (TPS)	The extent of patients' nasal polyps will be assessed at week 8 using a TPS.	At Week 8 (Visit 3)
Peak Nasal Inspiratory Flow (PNIF)	Patients' nasal congestion will be assessed at week 8 by a PNIF.	At Week 8 (Visit 3)
Quality of life - 22-Item Sino-Nasal Outcome Test (SNOT-22)	Quality of life will be assessed at week 8 with a SNOT-22.	At Week 8 (Visit 3)
Lung function - Forced Expiratory Volume 1 (FEV1)	Patients' lung function will be assessed at week 8 with an FEV1.	At Week 8 (Visit 3)
Asthma control - Asthma Control Questionnaire-6 (ACQ-6)	Asthma control will be measured at week 8 with an ACQ-6.	At Week 8 (Visit 3)
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 dupilumab discontinuation.	At Week 8 (Visit 3)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in sense of smell - University of Pennsylvania Smell Identification Test (UPSIT)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in UPSIT.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in Rhinoscopic Total Polyp Score (TPS)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in TPS.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in Peak Nasal Inspiratory Flow (PNIF)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in PNIF.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in 22-Item Sino-Nasal Outcome Test (SNOT-22)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in SNOT-22.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in lung function - Forced Expiratory Volume 1 (FEV1)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in FEV1.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in Asthma control - Asthma Control Questionnaire-6 (ACQ-6)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in ACQ-6.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in Nasal fluid levels of eicosanoids	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid eicosanoid levels.	weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in Nasal fluid levels of albumin	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid albumin levels.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in urinary levels of eicosanoids	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in urinary eicosanoid levels.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in serum tryptase	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in serum tryptase levels.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in IgE levels	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid and plasma levels of IgE.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)
Change in eosinophilic cationic protein (ECP)	Change from Visit 1 to Visit 2 and from Visit 1 to Visit 3 in nasal fluid levels of ECP.	2 weeks (between Visit 1 and Visit 2) and 8 weeks (between Visit 1 and Visit 3)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Tanya M Laidlaw, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: October 7, 2022
• First Submitted That Met QC Criteria: October 7, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Otorhinolaryngologic Diseases; Pathological Conditions, Anatomical; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Drug-Related Side Effects and Adverse Reactions; Drug Hypersensitivity; Asthma; Nasal Polyps; Polyps; Respiration Disorders; Respiratory Tract Diseases; Asthma, Aspirin-Induced; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: 2022P002407; U19AI095219 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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