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Mechanisms of Dupilumab in AERD

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ClinicalTrials.gov Identifier: NCT05031455
Recruitment Status : Not yet recruiting
First Posted : September 2, 2021
Last Update Posted : September 2, 2021
Sponsor:
Collaborators:
University of California, San Diego
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Andrew White, Scripps Clinic

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Aspirin-exacerbated Respiratory Disease Biological: Dupilumab Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Subjects will receive dupilumab (study drug) or placebo in 1:1 randomized double blinded manner.
Primary Purpose: Treatment
Official Title: Mechanisms of Dupilumab in AERD - Effects on Aspirin Hypersensitivity Response, With a Focus on Innate Type 2 Inflammatory Responses
Estimated Study Start Date : January 1, 2022
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : February 28, 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Dupilumab

Arm Intervention/treatment
Experimental: Dupilumab
Time 0 - 600mg subcutaneous Week 1 - 300mg subcutaneous Week 3 - 300mg subcutaneous Week 5 - 300mg subcutaneous
Biological: Dupilumab

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.

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.

Other Name: Dupixent

Placebo Comparator: Placebo
Time 0 - 600mg subcutaneous Week 1 - 300mg subcutaneous Week 3 - 300mg subcutaneous Week 5 - 300mg subcutaneous
Drug: Placebo
8 of 16 subjects will randomly receive placebo. All subjects will undergo an aspirin challenge/desensitization procedure. 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 placebo loading dose.




Primary Outcome Measures :
  1. Rate of positive challenges to aspirin challenge [ Time Frame: Aspirin challenge = 6 weeks after starting dupilumab/placebo. Aspirin challenge day = up to 8 hours ]

    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.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

-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
  • ongoing treatment with an asthma biologic or dupilumab
  • previous use of an asthma biologic of dupilumab in the past 3 months
  • need for systemic corticosteroids to stabilize asthma prior to challenge
  • time from sinus surgery <1 month.
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Responsible Party: Andrew White, Director, Aspirin Exacerbated Respiratory Disease Clinic, Scripps Clinic
ClinicalTrials.gov Identifier: NCT05031455    
Other Study ID Numbers: SHUCSD06242020
First Posted: September 2, 2021    Key Record Dates
Last Update Posted: September 2, 2021
Last Verified: August 2021

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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
Additional relevant MeSH terms:
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Respiration Disorders
Respiratory Tract Diseases