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

Phase 4

Completed

Conditions: Asthma

Interventions: Drug: Dupilumab

Registration Number: NCT05036733

Lead Sponsor: University of Michigan

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dupilumab	Dupilumab	-

Primary Outcome Measures

Name	Time	Method
Changes in Alpha-diversity of Respiratory Microbiota	1 month, 4 months	α-diversity was calculated using the Shannon Diversity Index at the species level from induced sputum samples obtained after 1 month and after 4 months on dupilumab. The change in diversity was calculated by aggregating all participants' calculated diversity and then finding the difference between time points. A higher Shannon Diversity Index value indicates higher diversity. A value of zero indicates the presence of only one kind of species of bacteria.
Change in Beta-diversity of Respiratory Microbiota	1 month, 4 months	Beta-diversity was calculated using the Bray-Curtis Distance at the species level from induced sputum samples obtained after 1 month and after 4 months on dupilumab. The change in diversity was calculated by aggregating all participants' distance between time points. Bray-Curtis dissimilarity ranges from 0 to 1. A higher Bray-Curtis Distance indicates a greater difference in diversity between time points.
Change in Relative Abundances of Microbiota Members	1 month, 4 months	Relative abundance was calculated by finding the proportion of a classified species out of all bacterial classifications in an induced sputum sample. Relative abundance was calculated after 1 month and after 4 months on dupilumab. The change in relative abundance of each species across all available samples was calculated by taking the difference between time points.
Change in Respiratory Bacterial Burden	1 month, 4 months	Bacterial Burden was estimated by scaling the species relative abundance to a known cell count of I. Halotolerans that was spiked into an induced sputum sample before extraction for sequencing. Bacterial burden was calculated at after 1 month and after 4 months on dupilumab. The change in bacterial burden was calculated by aggregating all burden values per participant and taking the difference between time points.
Changes in Alpha-diversity of Stool Microbiota	1 month, 4 months	α-diversity was calculated using the Shannon Diversity Index at the species level from stool samples. Shannon's Diversity Index values were obtained after 1 month and after 4 months on dupilumab. The change in diversity was calculated by aggregating all participants' calculated diversity and then finding the difference between time points. A higher Shannon Diversity Index value indicates higher diversity. A value of zero indicates the presence of only one kind of species of bacteria.
Change in Beta-diversity of Stool Microbiota	1 month, 4 months	Beta-diversity was calculated using the Bray-Curtis Distance at the species level from stool samples obtained after 1 month and after 4 months on dupilumab. The change in diversity was calculated by aggregating all participants' distance between time points. Bray-Curtis dissimilarity ranges from 0 to 1. A higher Bray-Curtis Distance indicates a greater difference in diversity between time points.

Secondary Outcome Measures

Name	Time	Method
Forced Expiratory Volume ( FEV1) / Forced Vital Capacity (FVC) Ratio	Baseline, 1 month, 4 months	Ratio of the volume of air exhaled in 1 sec (FEV1) divided by the total volume exhaled (FVC). FEV1/FVC \< 0.70 (or less than lower limit of age-predicted normal) is clinically diagnostic of obstructive lung disease.
Forced Expiratory Volume (FEV1)	Baseline, 1 month, 4 months	FEV1 measure reported as a percentage of predicted FEV1.
Change in Fractional Exhaled Nitric Oxide (FeNO)	Baseline, 1 month, 4 months	Fractional exhaled nitric oxide is a clinical biomarker for type 2 airway inflammation. FeNO \>25 is considered indicative of type 2 airway inflammation.
Asthma Control Test (ACT)	Baseline, 1 month, 4 months	The Asthma Control Test is a clinically validated questionnaire that assesses level of asthma control based on a 4-week recall of symptoms and daily functioning captured in 5 items. Each item is scored on a 5-point scale, and the total score is the sum of the values for all 5 items (range 5-25). A score of 5 represents worst-controlled asthma and 25 represents best-controlled asthma. An ACT score \>19 indicates well-controlled asthma; the minimal clinically important difference in score is 3.
Mini Asthma Quality of Life Questionnaire Score (mAQLQ)	Baseline, 1 month, 4 months	The mini-Asthma Quality of Life Questionnaire (mAQLQ) consists of 15 questions covering 4 domains: symptoms (5 questions), activity limitations (4 questions), emotional function (3 questions), and environmental stimuli (3 questions). The recall time for the mAQLQ is 2 weeks and each item is scored on a 7-point scale. Total scores per participant are the average of the 15 items and range from 1-7, with higher scores indicative of better quality of life. The minimum clinically important difference is 0.5.
Sino-nasal Outcome Test (SNOT-22)	Baseline, 1 month, 4 months	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.
Change in Prescribed Maintenance Corticosteroid Use (Inhaled or Oral), Between Baseline and 4 Months.	Baseline, 4 months	Count of participants whose maintenance corticosteroid prescription changed between baseline and 4 months.
Number of Asthma Exacerbations Requiring at Least 3 Days of Oral Corticosteroids	up to 4 months	Number of asthma exacerbations requiring at least 3 days of oral corticosteroids across the entire study population over the course of the study.