Phenotyping Disease Severity in Asthma

Sponsor

University of Calgary (Other)

Overall Status

Recruiting

CT.gov ID

NCT05078021

Collaborator

(none)

Enrollment

Location

28.4

Anticipated Duration (Months)

2.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize and compare the molecular gene expression profile in endobronchial biopsies and cells recovered in bronchial washings from study subjects who have asthma of varying disease severity and who are on maintenance inhaled corticosteroid (ICS) treatment, with that for healthy control subjects. These studies will produce transcriptomic profiles of gene expression associated with asthma disease severity. The investigators will also culture epithelial cells from study participant endobronchial brushings, including those with asthma of varying disease severity and healthy control subjects, to examine differences in the response to corticosteroids (CS) in vitro. These studies will test whether intrinsic differences exist between the responses to ICS in each group.

60 participants will be recruited with 15 of each mild, moderate and severe asthma as defined by the Global Initiative for Asthma (GINA) guidelines, as well as 15 healthy controls. Participants will undergo an initial visit to obtain informed consent, bloodwork and to assess asthma control using the Asthma Control Questionnaire (ACQ); if >1.5, ICS dose will be increased, as per GINA strategy, for a 2 week 'stabilization' phase. Repeat ACQ, spirometry and sputum induction will be performed at visit 2. Bronchoscopy will be performed at visit 3, 2-4 weeks after visit 2. Mucosal biopsies, bronchial brushings and bronchial washings will be performed and processed as per our prior methods. Mucosal biopsies will be homogenized and processed for RNA, or fixed for later sectioning and histological examination. Biopsy RNA will be assessed for quality and subjected to RNA-sequencing of all human genes (mRNA-seq). Bronchial washing cells will be collected for differential cell counting and mRNA-seq analysis. Bronchial epithelial cells (BECs) from the brushings will be cultured. BECs treated with CS and inflammatory cytokines will allow comparative assessment of BEC responses.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Diagnostic Test: Bronchoscopy

Detailed Description

Background:

While inhaled corticosteroids (ICS), either as monotherapy or in combination with long-acting β2 agonists (LABA), provide effective control in mild to moderate asthma, they are less effective in severe asthma. Following a guideline-based stepwise approach of treatment escalation often results in extended periods during which both the underlying airway inflammation and the asthma symptoms remain uncontrolled in these patients with severe asthma. This can lead to permanent damage, often termed airway remodeling, which results in fixed airflow obstruction that is no longer amenable to pharmacological therapy. The ability to identify molecular phenotypes associated with severe asthma should enable a more direct transition to appropriate therapies.

The respiratory epithelium drives airway inflammation and represents a primary target for ICS, which act through the glucocorticoid receptor (GR) to inhibit inflammatory gene expression. In an effort to predict therapeutic responses, considerable work has gone into investigating the clinical and molecular phenotyping of asthmatic individuals. This has produced a focus on gene-expression profiles (in blood) of asthmatics that associates with Th2 inflammatory phenotypes. However, there remains a paucity of studies investigating transcriptomic differences in the airways of mild and severe asthmatics.

The investigators now submit that characterization of inflammatory gene expression that escapes repression by CS or, alternatively, induces further inflammation, even in the setting of increasing ICS exposure, is crucial to understanding the mechanisms underpinning severe asthma.

Hypothesis:

Rather than being merely an amplified version of mild asthma, the investigators hypothesize that severe asthma shows a distinct inflammatory gene expression profile, with specific genes escaping repression, or being enhanced in expression by CS. Such effects, as apparent in cell-based models, could contribute to a molecular phenotype that is inherently resistant to the anti-inflammatory effects of ICS.

Study Design

Study Type:

Observational

Anticipated Enrollment :

60 participants

Observational Model:

Case-Control

Time Perspective:

Cross-Sectional

Official Title:

Phenotyping Disease Severity in Asthma: Molecular Investigations of Corticosteroid

Actual Study Start Date :

Apr 21, 2022

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Sep 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Normal control Healthy, non-asthmatic control subjects	Diagnostic Test: Bronchoscopy Bronchoscopy will be performed in all groups with endobronchial biopsies, brushings and bronchial washing performed.
Mild asthma Requiring low dose inhaled corticosteroid (ICS) plus as needed short acting beta-agonist (SABA) or as needed ICS-Formoterol.	Diagnostic Test: Bronchoscopy Bronchoscopy will be performed in all groups with endobronchial biopsies, brushings and bronchial washing performed.
Moderate asthma Low dose ICS-Long acting beta-agonist (LABA) maintenance + ICS-LABA reliever or SABA reliever	Diagnostic Test: Bronchoscopy Bronchoscopy will be performed in all groups with endobronchial biopsies, brushings and bronchial washing performed.
Severe asthma Medium to high dose ICS-LABA maintenance + as needed SABA or ICS-formoterol	Diagnostic Test: Bronchoscopy Bronchoscopy will be performed in all groups with endobronchial biopsies, brushings and bronchial washing performed.

Outcome Measures

Primary Outcome Measures

Molecular gene expression profile [Sept 2021-Sept 2024]
From endobronchial biopsies and cells recovered in bronchial washings
To test whether intrinsic differences exist between the responses to ICS [Sept 2021-Sept 2024]
From cultured epithelial cells

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Inclusion Criteria:

Age 18-60
Confirmed diagnosis of asthma by CTS criteria
No contraindication to bronchoscopy
No treatment with azithromycin
No oral corticosteroid in the 4 weeks prior
No participation in another drug study in the 4 weeks prior
On stable doses of asthma inhaled therapies for 12 weeks prior to bronchoscopy
FEV1 >80%

Exclusion Criteria:

Current smokers (within past year)
Subjects with ≥10 pack-year lifetime smoking history
History of asthma exacerbation (requiring oral prednisone) in the 4 weeks prior to study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6

Sponsors and Collaborators

University of Calgary

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

University of Calgary

ClinicalTrials.gov Identifier:

NCT05078021

Other Study ID Numbers:

20-2123

First Posted:

Oct 14, 2021

Last Update Posted:

May 19, 2022

Last Verified:

Sep 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Asthma

Study Results

No Results Posted as of May 19, 2022