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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05036733

Enrollment

Registered

2021-09-08

Start date

2022-02-22

Completion date

2023-06-29

Last updated

2024-10-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Keywords

Inhaled corticosteroids, Dupilumab

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.

Interventions

DRUGDupilumab

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Changes in Alpha-diversity of Respiratory Microbiota	Baseline (before dupilumab), 1 month	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.
Change in Beta-diversity of Respiratory Microbiota	Baseline (before dupilumab), 1 month	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.
Change in Relative Abundances of Microbiota Members	Baseline (before dupilumab), 1 month	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.
Change in Respiratory Bacterial Burden	Baseline (before dupilumab), 1 month	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.
Changes in Alpha-diversity of Stool Microbiota	Baseline (before dupilumab), 1 month	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.
Change in Beta-diversity of Stool Microbiota	Baseline (before dupilumab), 1 month	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..

Secondary

Measure	Time frame	Description
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.
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.
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.
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Dupilumab 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.	15
Total	15

Arm

Count

Dupilumab

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.

Total

Baseline characteristics

Characteristic	Dupilumab
Age, Continuous	59 years STANDARD_DEVIATION 18
alpha-diversity of respiratory (sputum) microbiota: Shannon index	3.08 Shannon's index STANDARD_DEVIATION 0.36
alpha-diversity of stool microbiota: Shannon index	3.20 score on a scale STANDARD_DEVIATION 0.31
Asthma Control Test (ACT) score	15 score on a scale STANDARD_DEVIATION 5
Blood eosinophils	200 cells/microliter STANDARD_DEVIATION 200
Body-mass index	30.1 (kg/m^2) STANDARD_DEVIATION 12.7
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
FEV1:FVC	0.75 ratio STANDARD_DEVIATION 0.12
Fractional exhaled nitric oxide (FeNO)	32 parts per billion STANDARD_DEVIATION 33
mini-Asthma Quality of Life Questionnaire (mAQLQ) score	4.2 score on a scale STANDARD_DEVIATION 1.2
Oral Corticosteroid Use	1 Participants
Race/Ethnicity, Customized Race other than White	1 Participants
Race/Ethnicity, Customized White	14 Participants
Region of Enrollment United States	15 Participants
Relative abundances of respiratory (sputum) microbiota members Bifidobacterium dentium	0.55 percentages STANDARD_DEVIATION 0.8
Relative abundances of respiratory (sputum) microbiota members Bifidobacterium longum	0.81 percentages STANDARD_DEVIATION 1.5
Relative abundances of respiratory (sputum) microbiota members Parvimonas micra	3.5 percentages STANDARD_DEVIATION 4.5
Relative abundances of respiratory (sputum) microbiota members Rothia mucilaginosa	7.2 percentages STANDARD_DEVIATION 5.6
Relative abundances of respiratory (sputum) microbiota members Streptococcus anginosus	3.5 percentages STANDARD_DEVIATION 8.7
Relative abundances of respiratory (sputum) microbiota members Streptococcus gordonii	2.9 percentages STANDARD_DEVIATION 3.7
Relative abundances of respiratory (sputum) microbiota members Streptococcus parasanguinis	10.8 percentages STANDARD_DEVIATION 8.4
Relative abundances of respiratory (sputum) microbiota members Streptococcus salivarius	17.8 percentages STANDARD_DEVIATION 14.5
Relative abundances of respiratory (sputum) microbiota members Streptococcus sanguinis	2.2 percentages STANDARD_DEVIATION 1.2
Relative abundances of respiratory (sputum) microbiota members Tropheryma whipplei	2.23 percentages STANDARD_DEVIATION 2.4
Respiratory bacterial burden (#bacterial cells, sputum)	4,622,000,000 bacterial cells
Sex: Female, Male Female	7 Participants
Sex: Female, Male Male	8 Participants
Sino-nasal outcome test (SNOT-22) score	44 score on a scale STANDARD_DEVIATION 16

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 15
other Total, other adverse events	0 / 0
serious Total, serious adverse events	2 / 15

Outcome results

Primary

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.

Time frame: Baseline (before dupilumab), 1 month