Dupilumab Effects Against Aeroallergen Challenge

Study Overview
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Brief Summary
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The trial involves two interventions: (i) exposure to HDM in the ACC and (ii) administration of dupilumab/placebo for dupilumab.

Detailed Description
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(i)Intervention #1: HDM exposures in the ACC This trial utilizes exposures to House dust mites (HDM) in the Aeroallergen Challenge Chamber (ACC) as a two-pronged tool for (i) precision phenotyping of HDM+PARC+AA+ persons to identify those with the adaptive and maladaptive phenotypes and (ii) assessment of symptoms intermittently throughout the clinical trial to monitor effects of dupilumab/placebo on symptom severity . (ii) Participants classifying to the adaptive and maladaptive phenotypes are then randomized to 18-weeks dupilumab vs. placebo, with ACC HDM visits during this phase.

Official Title
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Mechanistic Trial of Dupilumab in Adults With House Dust Mite-associated Asthma Using an Aeroallergen Challenge Chamber

Conditions
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Asthma, Allergic

Intervention / Treatment
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* Drug: Dupilumab
* Other: House Dust Mites (HDM)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Will demonstrate understanding of the study and will provide a signed and dated informed consent. Will be male or female, 18 to 65 years of age at the time of the screening visit. Will be vaccinated with at least one primary COVID-19 vaccination and at least one booster and/or will provide proof of infection with COVID-19 in the last 6 months. Will have symptoms consistent with perennial nasal allergy for a minimum of 2 years prior to the screening visit. Will have a positive standard skin prick test (SPT) to D. pteronyssinus within the past 12 months. A positive SPT is defined as a wheal diameter of at least 5 mm larger than the negative control (normal saline). Will have asthma with a documented reversibility of FEV1 of ≥10% within the past 12 months and an Asthma Control Questionnaire-7 (ACQ-7) Score of ≥1.0 at selection visit. Will have a negative SARS-CoV-2 rapid antigen nasopharyngeal swab test before each HDM exposure visit. Note: Participation of individuals who pass eligibility criteria but are disqualified due to a positive SARS-CoV2 test and/or COVID-19 questionnaire will be deferred for the following study year. Will not display COVID-19 symptoms, based on a questionnaire before each HDM exposure visit. A woman of childbearing potential, must have a negative urine pregnancy test at Visit 1 and prior to each exposure in the ACC. All women of childbearing potential must agree to a medically acceptable form of birth control throughout the study duration and for at least 2 months prior to Visit 1. Acceptable methods of birth control for this study include: oral, patch, or intra-vaginal contraceptives Norplant System® Depo-Provera® Intrauterine device (IUD) double barrier method abstinence surgical sterility (hysterectomy or tubal ligation) Women who are at least 1-year post-menopausal qualify as non-childbearing for this study. Will have never smoked or will be an ex-smoker (<20 packs years and no cigarette or smokeless tobacco use in the past year). Exclusion Criteria: Have a chronic lung disease other than asthma. Have atopic dermatitis Have any ocular disease that is not associated with allergic rhinoconjunctivitis Are on home oxygen requirement. Have a history of rebound nasal congestion (brought on by extended use of topical decongestants), chronic rhinosinusitis with or without nasal polyps, nasal septal perforation, or severe nasal tract malformations noted on physical exam. Have Forced Expiratory volume/Forced vital capacity (FEV1/ FVC) of <70% predicted as determined by baseline pre-bronchodilator spirometry. Are unwilling/unable to withhold intranasal steroids or asthma medications before specified visits. Are unwilling/unable to abstain from protocol-defined prohibited medications for the protocol-specified times before and during screening/selection and ACC HDM exposure visits. Have received any oral or other form of systemic glucocorticosteroids within 1 month prior to the screening visit. Have received Janus kinase-1 (JAK-1) inhibitors within 3 months prior to the screening visit. Have known hypersensitivity to dupilumab or any of its excipients. Have an ongoing helminth infection. Have received a live vaccine within 30 days of screening or are planned to receive one during study participation. Are pregnant or nursing. Have a history of keratoconjunctivitis sicca. Have indoor pet exposure causing upper or lower symptoms. Have received allergen immunotherapy of any form within 12 months of screening visit. Have received biologics for any indication within 12 months of screening visit. Have participated in a trial with an investigational drug in the past 6 months. Have past or current medical problems or findings from physical examination or laboratory testing that are not listed above, that, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or may impact the quality or interpretation of the data obtained from the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a prospective, double-blind, randomized placebo-controlled mechanistic clinical trial to test the effects of an 18-week course of dupilumab on HDM allergen challenge-induced nasal mucosa and peripheral blood traits and symptoms in persons with HDM-associated perennial allergic rhinoconjunctivitis (PARC) with allergic asthma (HDM+PARC+AA+) participants. For each yearly cohort, participants of each phenotype will be randomly selected, resulting in two groups classified as the (i) adaptive, and (ii) maladaptive phenotypes. Using the R package SeqAlloc, a covariate-adjusted randomization will be employed to randomize each of these two groups into two subgroups; the subgroups within each group (phenotype) will be balanced by age and gender. Thus, this will result in the generation of four groups: (i) adaptive-A (ii) adaptive-B (iii) maladaptive-A (iv) maladaptive-B
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Adaptive Phenotypes randomized to study drug<br>This group will be comprised of the Adaptive-A and Adaptive-B subgroup and will consist of the adaptive phenotype participants identified during the initial HDM ACC challenge, administered the study drug. | Drug: Dupilumab<br>* Dupixent is an interleukin-4 receptor alpha antagonist<br>* Other names: Dupixent;Other: House Dust Mites (HDM)<br>* House Dust Mites used to challenge subjects using an aeroallergen challenge chamber<br>|
| Experimental: Maladaptive Phenotypes randomized to study drug<br>This group will be comprised of the Maladaptive-A and Maladaptive-B subgroup and will consist of the maladaptive phenotype participants identified during the initial HDM ACC challenge administered the study drug. | Drug: Dupilumab<br>* Dupixent is an interleukin-4 receptor alpha antagonist<br>* Other names: Dupixent;Other: House Dust Mites (HDM)<br>* House Dust Mites used to challenge subjects using an aeroallergen challenge chamber<br>|
| Placebo Comparator: Adaptive Phenotype randomized to placebo<br>This group will be comprised of the Adaptive-A and Adaptive-B subgroup and will consist of the adaptive phenotype participants identified during the initial HDM ACC challenge, administered the placebo. | Other: House Dust Mites (HDM)<br>* House Dust Mites used to challenge subjects using an aeroallergen challenge chamber<br>Other: Placebo<br>* Inert placebo administered to placebo arms of study.<br>* Other names: Placebo for Dupixent;|
| Placebo Comparator: Maladaptive Phenotype randomized to placebo<br>This group will be comprised of the Maladaptive-A and Maladaptive-B subgroup and will consist of the maladaptive phenotype participants identified during the initial HDM ACC challenge administered the placebo. | Other: House Dust Mites (HDM)<br>* House Dust Mites used to challenge subjects using an aeroallergen challenge chamber<br>Other: Placebo<br>* Inert placebo administered to placebo arms of study.<br>* Other names: Placebo for Dupixent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall change in ACC HDM exposure-induced nasal airway gene expression profile | The overall (longitudinal) change in the ACC HDM exposure-induced nasal airway gene expression profiles observed during the first HDM exposure (visit 3; pre-randomization) and during the three on-treatment HDM exposures (visits 7, 11, and 15) | Baseline to 33 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall change in ACC HDM during first HDM exposure-induced peripheral blood gene expression | The overall (longitudinal) change in the ACC HDM exposure-induced peripheral blood gene expression profiles observed during the first HDM exposure (Visit 3; pre-randomization) and during the three on-treatment HDM exposures (visits 7, 11, and 15). | Baseline to 33 weeks | 
| Average symptom scores (Instantaneous Summated Symptom Score-Average: iSSS-AV) | The change in the average symptom scores (iSSS-AV - average of the 10 instantaneous symptom score recordings obtained at 30-minute intervals, from t=30 min to t=300 min, throughout the 5-hour HDM exposure) assessed during the first HDM exposure (Visit 3; pre-randomization) and across the three on-treatment HDM exposures (visits 7, 11, and 15). Summated Symptom Score (SSS) scoring system Symptom Score range TNSS (Total Nasal Symptom score) 0-12 Rhinorrhea(1) 0-3 Congestion(1) 0-3 Sneezing(1) 0-3 Nasal itching(1) 0-3 TOSS (Total Ocular Symptom Score) 0-9 Ocular redness(2) 0-3 Tearing(2) 0-3 Ocular itching(2) 0-3 TASS (Total Asthma Symptom Score) 0-9 Cough(3) 0-3 Wheeze(3) 0-3 Dyspnea(3) 0-3 Summated symptom score (SSS) = TNSS + TOSS + TASS 0-30 (1),(2),(3)Scored on a Likert-scale of 0=absent, 1=mild, 2=moderate, 3=severe Component of (1)TNSS, (2)TOSS, (3)TASS | Baseline to 33 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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House Dust Mite Allergy, Asthma, Aeroallergen chamber, Dupilumab