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

NCT05036733 | Completed Phase 4 Results FDA Drug

• 1 other identifier: HUM00196809
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Asthma

Keywords

Inhaled corticosteroids; Dupilumab

Outcome Measures

Primary Outcomes (18)

• 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 Outcomes (8)

• Forced Expiratory Volume ( FEV1) / Forced Vital Capacity (FVC) Ratio

  Baseline, 1 month, 4 months

• Forced Expiratory Volume (FEV1)

  Baseline, 1 month, 4 months

• Change in Fractional Exhaled Nitric Oxide (FeNO)

  Baseline, 1 month, 4 months

• Asthma Control Test (ACT)

  Baseline, 1 month, 4 months

• Mini Asthma Quality of Life Questionnaire Score (mAQLQ)

  Baseline, 1 month, 4 months

Study Arms (1)

Dupilumab

EXPERIMENTAL

Drug: Dupilumab

Interventions

Dupilumab DRUG

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.

Also known as: Dupixent

Dupilumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Michigan: lead
• Regeneron Pharmaceuticals: collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Asthma

Interventions

dupilumab

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: Yvonne J Huang MD
• Organization: University of Michigan

yvjhuang@med.umich.edu

734-936-5047

Study Officials

• Yvonne Huang, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Internal Medicine and Microbiology/Immunology

Study Record Dates

• First Submitted: August 30, 2021
• First Posted: September 8, 2021
• Study Start: February 22, 2022
• Primary Completion: June 29, 2023
• Study Completion: June 29, 2023
• Last Updated: October 23, 2024
• Results First Posted: October 23, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)