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

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05575037

Collaborator

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Nasal Polyps Asthma, Aspirin-Induced Aspirin-Exacerbated Respiratory Disease Aspirin-Sensitive Asthma With Nasal Polyps	Drug: Dupilumab Drug: Placebo	Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

33 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Nov 1, 2022

Anticipated Primary Completion Date :

Nov 1, 2026

Anticipated Study Completion Date :

Nov 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dupilumab Subjects will be randomized to receive dupilumab (300mg every-other-week for 8 weeks).	Drug: Dupilumab 8-week, double-blind, placebo-controlled parallel-design trial of dupilumab (an anti-IL-4a) in patients with AERD. Other Names: Dupilumab Prefilled Syringe [Dupixent]
Placebo Comparator: Placebo Subjects will be randomized to receive placebo (every-other-week for 8 weeks).	Drug: Placebo 8-week, double-blind, placebo-controlled parallel-design trial of dupilumab (an anti-IL-4a) in patients with AERD. Other Names: Placebo Injection

Arm

Intervention/Treatment

Active Comparator: Dupilumab

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

Drug: Dupilumab

8-week, double-blind, placebo-controlled parallel-design trial of dupilumab (an anti-IL-4a) in patients with AERD.

Other Names:

Dupilumab Prefilled Syringe [Dupixent]

Placebo Comparator: Placebo

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

Drug: Placebo

8-week, double-blind, placebo-controlled parallel-design trial of dupilumab (an anti-IL-4a) in patients with AERD.

Other Names:

Placebo Injection

Outcome Measures

Primary Outcome Measures

Nasal fluid levels of LTE4 [At Week 8 (Visit 3)]
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 [At Week 8 (Visit 3)]
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) [At Week 8 (Visit 3)]
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) [At Week 8 (Visit 3)]
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) [At Week 8 (Visit 3)]
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) [At Week 8 (Visit 3)]
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) [At Week 8 (Visit 3)]
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) [At Week 8 (Visit 3)]
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 [At Week 8 (Visit 3)]
Safety will be measured by the number of treatment-related AEs and SAEs leading to study drug (dupilumab) discontinuation.

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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