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

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Dupilumab

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dupilumab

Drug: Dupilumab; 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.; Other Names: Dupixent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Alpha-diversity of Respiratory Microbiota	α-diversity was calculated using the Shannon Diversity Index at the species level from induced sputum samples obtained at Baseline and after 1 month 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.	Baseline (before dupilumab), 1 month
Changes in Alpha-diversity of Respiratory Microbiota	α-diversity was calculated using the Shannon Diversity Index at the species level from induced sputum samples obtained at baseline 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.	Baseline (before dupilumab), 4 month
Changes in Alpha-diversity of Respiratory Microbiota	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.	1 month, 4 months
Change in Beta-diversity of Respiratory Microbiota	Beta-diversity was calculated using the Bray-Curtis Distance at the species level from induced sputum samples obtained at baseline and after 1 month 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, which is unitless, indicates a greater difference in diversity between the time points.	Baseline (before dupilumab), 1 month
Change in Beta-diversity of Respiratory Microbiota	Beta-diversity was calculated using the Bray-Curtis Distance at the species level from induced sputum samples obtained at baseline 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.	Baseline (before dupilumab), 4 month
Change in Beta-diversity of Respiratory Microbiota	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.	1 month, 4 months
Change in Relative Abundances of Microbiota Members	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 at baseline and after 1 month on dupilumab. The change in relative abundance of each species across all available samples was calculated by taking the difference between time points.	Baseline (before dupilumab), 1 month
Change in Relative Abundances of Microbiota Members	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 at baseline 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.	Baseline (before dupilumab), 4 month
Change in Relative Abundances of Microbiota Members	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.	1 month, 4 months
Change in Respiratory Bacterial Burden	Bacterial burden was estimated by scaling species relative abundances to a known cell count of Imtechella halotolerans (Zymo) that was spiked into an induced sputum sample before extraction for sequencing. Bacterial burden was calculated at baseline and after 1 month on dupilumab. The change in bacterial burden was calculated by aggregating all burden values per participant and taking the difference between time points.	Baseline (before dupilumab), 1 month
Change in Respiratory Bacterial Burden	Bacterial burden was estimated by scaling all species relative abundances to a known cell count of Imtechella halotolerans that was spiked into sputum samples before extraction for sequencing. Bacterial burden was calculated at baseline 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.	Baseline (before dupilumab), 4 month
Change in Respiratory Bacterial Burden	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.	1 month, 4 months
Changes in Alpha-diversity of Stool Microbiota	α-diversity was calculated using the Shannon diversity index at the species level from stool samples obtained at baseline and after 1 month 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.	Baseline (before dupilumab), 1 month
Changes in Alpha-diversity of Stool Microbiota	α-diversity was calculated using the Shannon diversity Index at the species level from stool samples obtained at baseline 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.	Baseline (before dupilumab), 4 month
Changes in Alpha-diversity of Stool Microbiota	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.	1 month, 4 months
Change in Beta-diversity of Stool Microbiota	Beta-diversity was calculated using the Bray-Curtis Distance at the species level from stool samples. Samples were obtained baseline and after 1 month on dupilumab and the Bray-Curtis Distance calculated. 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..	Baseline (before dupilumab), 1 month
Change in Beta-diversity of Stool Microbiota	Beta-diversity was calculated using the Bray-Curtis Distance at the species level from stool samples obtained at baseline 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.	Baseline (before dupilumab), 4 month
Change in Beta-diversity of Stool Microbiota	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.	1 month, 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume ( FEV1) / Forced Vital Capacity (FVC) Ratio	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.	Baseline, 1 month, 4 months
Forced Expiratory Volume (FEV1)	FEV1 measure reported as a percentage of predicted FEV1.	Baseline, 1 month, 4 months
Change in Fractional Exhaled Nitric Oxide (FeNO)	Fractional exhaled nitric oxide is a clinical biomarker for type 2 airway inflammation. FeNO >25 is considered indicative of type 2 airway inflammation.	Baseline, 1 month, 4 months
Asthma Control Test (ACT)	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.	Baseline, 1 month, 4 months
Mini Asthma Quality of Life Questionnaire Score (mAQLQ)	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.	Baseline, 1 month, 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.	Baseline, 1 month, 4 months
Change in Prescribed Maintenance Corticosteroid Use (Inhaled or Oral), Between Baseline and 4 Months.	Count of participants whose maintenance corticosteroid prescription changed between baseline and 4 months.	Baseline, 4 months
Number of Asthma Exacerbations Requiring at Least 3 Days of Oral Corticosteroids	Number of asthma exacerbations requiring at least 3 days of oral corticosteroids across the entire study population over the course of the study.	up to 4 months

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Regeneron Pharmaceuticals
• Investigators: Principal Investigator: Yvonne Huang, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2022
• Primary Completion (Actual): June 29, 2023
• Study Completion (Actual): June 29, 2023

Study Registration Dates

• First Submitted: August 30, 2021
• First Submitted That Met QC Criteria: August 30, 2021
• First Posted (Actual): September 8, 2021

Study Record Updates

• Last Update Posted (Actual): October 23, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Dupilumab; Inhaled corticosteroids
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Asthma
• Other Study ID Numbers: HUM00196809

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: No