Phenotyping Disease Severity in Asthma

  • STATUS
    Recruiting
  • End date
    Sep 9, 2024
  • participants needed
    60
  • sponsor
    University of Calgary
Updated on 9 June 2022

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.

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.

Details
Condition Asthma
Treatment Bronchoscopy
Clinical Study IdentifierNCT05078021
SponsorUniversity of Calgary
Last Modified on9 June 2022

Eligibility

Yes No Not Sure

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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note