Effects of Interleukin (IL)- 4R-alpha Inhibition on Respiratory Microbiome and Immunologic Correlates in Severe Asthma

Study Overview
=================
Brief Summary
-----------------
The overall goal of this study is to understand biological responses related to dupilumab treatment among severe asthma patients. Not all asthma is the same, and characteristics of asthma vary from person to person. The study will investigate whether the study drug can help to improve the health of participants lungs, boost immune response, as well as improve quality of life.

Official Title
-----------------
Effects of IL-4R-alpha Inhibition (Dupixent) Inhibition On The Respiratory Microbiome And Immunologic Correlates In Patients With Severe Asthma

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Dupilumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Physician-diagnosed/managed severe asthma patients that are clinically eligible for dupilumab Current treatment with a medium-to-high-dose inhaled glucocorticoid (fluticasone propionate at a total daily dose of greater or equal (≥) 440 μg or equipotent equivalent) plus up to at least one additional controller (e.g., a long-acting β2-agonist or leukotriene receptor antagonist) Eosinophilic asthma phenotype (blood eosinophil level >300) or asthma requiring daily oral corticosteroids Asthma that is uncontrolled, as defined by a score on the Asthma Control Test of 19 or lower, or a worsening of asthma in the past year that led to an asthma hospitalization, Emergency Department visit, or 3 days of oral corticosteroids Severity of asthma that, in the opinion of the subject's asthma care specialist, requires dupilumab for control For women of childbearing age: agree to use birth control or remain abstinent during the duration of the study. Exclusion Criteria: Patients with diagnosis of other chronic lung diseases (e.g. Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, Churg-Strauss syndrome, Allergic bronchopulmonary aspergillosis, etc.) Current smoker or reported smoking within 1 month of the screening visit (tobacco or any inhaled recreational product) Greater than 10 total pack-year of cigarette smoking history Treatment with oral corticosteroids for an asthma exacerbation 1 month prior to screening or during the screening period Use of any biologic therapy for asthma within the past 3 months Respiratory or Gastrointestinal illness within 1 month prior to screening or during the screening period Treatment with antibiotics for acute infections within six weeks prior to screening or during the screening period. Pregnancy at enrollment or during the study Known hypersensitivity to dupilumab or its excipients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br> | Drug: Dupilumab<br>* Participants will receive 8 doses of Dupilumab. The initial loading dose (visit 1) of 600 milligrams (two 300 milligram injections) will be given subcutaneously (SQ). Then the participants will receive 300 milligrams SQ every other week (q 2 weeks) either at a study visit or self-administered at home between visits. Additionally, participants will complete questionnaires, have specimens collected, as well as perform breathing procedures at various timepoints.<br>* Other names: Dupixent;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in alpha-diversity of respiratory microbiota | This will be profiled from induced sputum. | Baseline (before dupilumab), 1 month | 
| Changes in alpha-diversity of respiratory microbiota | This will be profiled from induced sputum. | Baseline (before dupilumab), 4 month | 
| Changes in alpha-diversity of respiratory microbiota | This will be profiled from induced sputum. | 1 month, 4 months | 
| Change in beta-diversity of respiratory microbiota | This will be profiled from induced sputum. | Baseline (before dupilumab), 1 month | 
| Change in beta-diversity of respiratory microbiota | This will be profiled from induced sputum. | Baseline (before dupilumab), 4 month | 
| Change in beta-diversity of respiratory microbiota | This will be profiled from induced sputum. | 1 month, 4 months | 
| Change in relative abundances of microbiota members | This will be profiled from induced sputum. | Baseline (before dupilumab), 1 month | 
| Change in relative abundances of microbiota members | This will be profiled from induced sputum. | Baseline (before dupilumab), 4 month | 
| Change in relative abundances of microbiota members | This will be profiled from induced sputum. | 1 month, 4 months | 
| Change in respiratory bacterial burden | This will be profiled from induced sputum. | Baseline (before dupilumab), 1 month | 
| Change in respiratory bacterial burden | This will be profiled from induced sputum. | Baseline (before dupilumab), 4 month | 
| Change in respiratory bacterial burden | This will be profiled from induced sputum. | 1 month, 4 months | 
| Changes in alpha-diversity of stool microbiota | This will be based on stool samples. | Baseline (before dupilumab), 1 month | 
| Changes in alpha-diversity of stool microbiota | This will be based on stool samples. | Baseline (before dupilumab), 4 month | 
| Changes in alpha-diversity of stool microbiota | This will be based on stool samples. | 1 month, 4 months | 
| Change in beta-diversity of stool microbiota | This will be based on stool samples. | Baseline (before dupilumab), 1 month | 
| Change in beta-diversity of stool microbiota | This will be based on stool samples. | Baseline (before dupilumab), 4 month | 
| Change in beta-diversity of stool microbiota | This will be based on stool samples. | 1 month, 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced expiratory volume ( FEV1) / forced vital capacity (FVC) ratio | This will be based on Spirometry | up to 4 months | 
| Forced expiratory volume (FEV1) | This will be based on Spirometry | up to 4 months | 
| Change in Fractional exhaled nitric oxide (FeNO) |  | Baseline, 4 months | 
| Asthma Control Test (ACT) | This is a self-administered 5 item questionnaire. The ACT score is the sum of the values for all 5 items. The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma; the minimal clinically important difference in score is 3. | up to 4 months | 
| Mini Asthma Quality of Life Questionnaire Score (mAQLQ) | This is a patient self-administered questionnaire with 15 questions covering 4 domains: Symptoms (5 questions), Activity Limitations (4 questions), Emotional Function (3 questions), and Environmental Stimuli (3 questions). Scores range from 0-6 (lower is worse). The mini AQLQ score is calculated as the average of domain items. The minimum clinically important difference is 0.5. Overall score (average of 15 questions): add up responses to all questions, and divide by 15. | up to 4 months | 
| Sino-nasal outcome test (SNOT-22) | This is a 22 item questionnaire. Each item is rated as follows: 0=no problem, 1=very mild problem, 2=mild or slight problem, 3=moderate problem, 4=severe problem, 5=problem as bad as it can be. The score ranges between 0 and 110. A higher score means worse outcome. | up to 4 months | 
| Change in prescribed maintenance corticosteroid use (inhaled or oral), between baseline and 4 months. |  | Baseline, 4 months | 
| Number of asthma exacerbations requiring at least 3 days of oral corticosteroids |  | up to 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Inhaled corticosteroids, Dupilumab