Phenotyping Disease Severity in Asthma

November 29, 2023 updated by: University of Calgary

Phenotyping Disease Severity in Asthma: Molecular Investigations of Corticosteroid

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Observational

Enrollment (Estimated)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Richard Leigh
  • Phone Number: 403-943-8666

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N 4Z6
        • Recruiting
        • University of Calgary
        • Contact:
          • Curtis Dumonceaux
          • Phone Number: 403-220-2123

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 56 years (Adult)

Accepts Healthy Volunteers

N/A

Sampling Method

Non-Probability Sample

Study Population

For the asthma cohort, the asthma diagnosis will be defined by objective evidence of ≥12% post-bronchodilator reversibility or PC20 methacholine <16mg/ml within the past 36 months. Asthma severity will be defined by the requirement of low, medium, or high dose of ICS to achieve symptom control, with the correlating ICS doses being the daily equivalent of budesonide 200-400mcg, 400-800mcg, or >800mcg respectively Control subjects will be those without a diagnosis of asthma.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Molecular gene expression profile
Time Frame: Sept 2021-Sept 2024
From endobronchial biopsies and cells recovered in bronchial washings
Sept 2021-Sept 2024
To test whether intrinsic differences exist between the responses to ICS
Time Frame: Sept 2021-Sept 2024
From cultured epithelial cells
Sept 2021-Sept 2024

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Calgary

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 21, 2022

Primary Completion (Estimated)

September 1, 2024

Study Completion (Estimated)

September 1, 2024

Study Registration Dates

First Submitted

September 22, 2021

First Submitted That Met QC Criteria

October 13, 2021

First Posted (Actual)

October 14, 2021

Study Record Updates

Last Update Posted (Actual)

November 30, 2023

Last Update Submitted That Met QC Criteria

November 29, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20-2123

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

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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