Mechanisms of Dupilumab in AERD

Study Overview
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Brief Summary
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Aspirin-Exacerbated Respiratory Disease (AERD), although uncommon in the general population, is an important phenotype of severe asthma and nasal polyposis where it occurs in 15% of severe asthmatics, and up to 30% of those with nasal polyposis. An important therapy for AERD is aspirin therapy after desensitization (ADAT). This is an inexpensive and proven therapy to improve the burden of sinus disease in AERD. Aspirin desensitization is the mechanism by which tolerance is induced in AERD patients. This is a 1-2 day outpatient procedure whereby increasing doses of aspirin are administered and the patients invariably experience some degree of hypersensitivity reactions. It is important to understand the effect of medications on the aspirin desensitization. It is known that the leukotriene modifier medications decrease the severity of the reactions in AERD. Other treatments such as antihistamines and the biologic agent omalizumab might have an effect on either blocking or blunting reactivity in AERD during desensitization. Dupilumab is a new respiratory biologic approved for atopic dermatitis, eosinophilic asthma and nasal polyposis. As such, it is well situated to be used for many AERD patients whose disease cannot be well controlled. The effect of dupilumab on the aspirin desensitization process and reaction is unknown and is the topic of this investigation. The primary objective is to determine the effect of dupilumab on reactions during aspirin challenge/desensitization.

Official Title
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Mechanisms of Dupilumab in AERD - Effects on Aspirin Hypersensitivity Response, With a Focus on Innate Type 2 Inflammatory Responses

Conditions
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Aspirin-exacerbated Respiratory Disease

Intervention / Treatment
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* Drug: Aspirin Challenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects >18 years old with Aspirin-Exacerbated Respiratory Disease This is diagnosed via either a positive oral aspirin or intranasal ketorolac challenge OR a history of at least two stereotypical hypersensitivity reactions to aspirin leading to nasal-ocular symptom and/or asthmatic symptoms. Current treatment with dupilumab at standard asthma/nasal polyposis dosing of 300mg subcutaneously every 2 weeks for a minimum of 12 weeks. All subjects will be required to have a known history of nasal polyposis either via imaging, endoscopy, or nasal examination Exclusion Criteria: History of gastrointestinal reactions (severe abdominal pain with or without vomiting) during NSAID triggered events Unstable asthma or history of severe reactions during previous desensitization attempts inability to take montelukast pretreatment history of gastrointestinal bleeding or bleeding disorder pregnancy previous use of any other respiratory biologic in the past 3 months (omalizumab, tezepelumab, mepolizumab, reslizumab, benralizumab) need for systemic corticosteroids to stabilize asthma prior to challenge time from sinus surgery <1 month.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aspirin Challenge<br>All subjects will undergo a standardized aspirin challenge | Drug: Aspirin Challenge<br>* Dupilumab is a fully human monoclonal antibody that blocks the receptor component for IL-4 and IL-13, which are key drivers of type 2 inflammation. All subjects will be prescribed this at standard 300mg subcutaneous dosing every 2 weeks. The intervention will be the response to aspirin challenge. 8 of 16 subjects will randomly receive dupilumab. All subjects will undergo an aspirin challenge/desensitization procedure. To achieve adequate steady state levels of dupilumab, the dosing regimen will be a 600mg loading dose of dupilumab followed by 300mg subcutaneous at 1 week, 3 weeks and 5 weeks. Aspirin challenge/desensitization will take place at week 6 after dupilumab loading dose.<br>* Other names: Dupixent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of positive challenges to aspirin challenge | Aspirin challenge reactions will be defined as either 1) >15% drop in FEV1 or 2) >25% drop in peak nasal inspiratory flow (PNIF) or 3) >5 point change in composite symptom score. Spirometry is a standardized measure of airflow obstruction used to define lower airway reaction to aspirin in AERD. Nasal inspiratory flow rates are measured using an inverted peak flow meter and have been correlated with nasal obstruction occurring during nasal reactions to aspirin in AERD. Symptom Score - symptoms are a typical part of an aspirin reaction with increase in congestion, itching, cough, and chest tightness. | Aspirin challenge = 6 weeks after starting dupilumab/placebo. Aspirin challenge day = up to 8 hours |