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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Nasal Polyps, Asthma, Aspirin-Induced, Aspirin-Exacerbated Respiratory Disease, Aspirin-Sensitive Asthma With Nasal Polyps

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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, compared between the dupilumab group and the placebo group. | At Week 8 (Visit 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 study drug (dupilumab) discontinuation. | At Week 8 (Visit 3) | 
| 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. | 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, compared between the dupilumab group and the placebo group. | 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, compared between the dupilumab group and the placebo group. | At Week 8 (Visit 3) | 
| 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. | 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, compared between the dupilumab group and the placebo group. | At Week 8 (Visit 3) | 
| 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. | At Week 8 (Visit 3) |