Phenotyping Disease Severity in Asthma

NCT05078021 | Unknown

• 1 other identifier: 20-2123
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Asthma

Outcome Measures

Primary Outcomes (2)

• Molecular gene expression profile

  From endobronchial biopsies and cells recovered in bronchial washings

  Sept 2021-Sept 2024

• To test whether intrinsic differences exist between the responses to ICS

  From cultured epithelial cells

  Sept 2021-Sept 2024

Study Arms (4)

Normal control

Healthy, non-asthmatic control subjects

Diagnostic Test: Bronchoscopy

Mild asthma

Requiring low dose inhaled corticosteroid (ICS) plus as needed short acting beta-agonist (SABA) or as needed ICS-Formoterol.

Diagnostic Test: Bronchoscopy

Moderate asthma

Low dose ICS-Long acting beta-agonist (LABA) maintenance + ICS-LABA reliever or SABA reliever

Diagnostic Test: Bronchoscopy

Severe asthma

Medium to high dose ICS-LABA maintenance + as needed SABA or ICS-formoterol

Diagnostic Test: Bronchoscopy

Interventions

Bronchoscopy DIAGNOSTIC_TEST

Bronchoscopy will be performed in all groups with endobronchial biopsies, brushings and bronchial washing performed.

Mild asthma; Moderate asthma; Normal control; Severe asthma

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Age Groups: Adult (18-64)
• 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.

You may qualify if:

• 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%

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N 4Z6, Canada

RECRUITING

Related Publications (20)

• Lougheed MD, Leniere C, Ducharme FM, Licskai C, Dell SD, Rowe BH, FitzGerald M, Leigh R, Watson W, Boulet LP; Canadian Thoracic Society Asthma Clinical Assemby. Canadian Thoracic Society 2012 guideline update: Diagnosis and management of asthma in preschoolers, children and adults: executive summary. Can Respir J. 2012 Nov-Dec;19(6):e81-8. doi: 10.1155/2012/214129.

  PMID: 23248807 BACKGROUND

• Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2019. Available from: www.ginasthma.org

  BACKGROUND

• Hossny E, Caraballo L, Casale T, El-Gamal Y, Rosenwasser L. Severe asthma and quality of life. World Allergy Organ J. 2017 Aug 21;10(1):28. doi: 10.1186/s40413-017-0159-y. eCollection 2017.

  PMID: 28855973 BACKGROUND

• FitzGerald J.M., Lemiere C, Lougheed M.D., Ducharme F, Dell S. Recognition and management of severe asthma: A Canadian Thoracic Society position statement. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2017; 1 (4), 199-221. https://doi.org/10.1080/24745332.2017.1395250

  BACKGROUND

• Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: from benchside to clinical practice. Can Respir J. 2010 Jul-Aug;17(4):e85-93. doi: 10.1155/2010/318029.

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• Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma: what really matters. Cell Tissue Res. 2017 Mar;367(3):551-569. doi: 10.1007/s00441-016-2566-8. Epub 2017 Feb 11.

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• Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med. 2012 May 4;18(5):684-92. doi: 10.1038/nm.2737.

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• Klassen C, Karabinskaya A, Dejager L, Vettorazzi S, Van Moorleghem J, Luhder F, Meijsing SH, Tuckermann JP, Bohnenberger H, Libert C, Reichardt HM. Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma. J Immunol. 2017 Jul 1;199(1):48-61. doi: 10.4049/jimmunol.1601691. Epub 2017 May 17.

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• Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012 May 4;18(5):716-25. doi: 10.1038/nm.2678.

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• Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009 Sep 1;180(5):388-95. doi: 10.1164/rccm.200903-0392OC. Epub 2009 May 29.

  PMID: 19483109 BACKGROUND

• Singh P, Sharma A, Jha R, Arora S, Ahmad R, Rahmani AH, Almatroodi SA, Dohare R, Syed MA. Transcriptomic analysis delineates potential signature genes and miRNAs associated with the pathogenesis of asthma. Sci Rep. 2020 Aug 7;10(1):13354. doi: 10.1038/s41598-020-70368-5.

  PMID: 32770056 BACKGROUND

• Wang M, Bu X, Luan G, Lin L, Wang Y, Jin J, Zhang L, Wang C. Distinct type 2-high inflammation associated molecular signatures of chronic rhinosinusitis with nasal polyps with comorbid asthma. Clin Transl Allergy. 2020 Jul 3;10:26. doi: 10.1186/s13601-020-00332-z. eCollection 2020.

  PMID: 32637070 BACKGROUND

• Leigh R, Mostafa MM, King EM, Rider CF, Shah S, Dumonceaux C, Traves SL, McWhae A, Kolisnik T, Kooi C, Slater DM, Kelly MM, Bieda M, Miller-Larsson A, Newton R. An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti- and proinflammatory effector genes. Pharmacol Res Perspect. 2016 Jul 12;4(4):e00243. doi: 10.1002/prp2.243. eCollection 2016 Aug.

  PMID: 28116096 BACKGROUND

• Donnelly LE, Barnes PJ. Expression of heme oxygenase in human airway epithelial cells. Am J Respir Cell Mol Biol. 2001 Mar;24(3):295-303. doi: 10.1165/ajrcmb.24.3.4001.

  PMID: 11245628 BACKGROUND

• Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV. Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma. J Allergy Clin Immunol. 2010 May;125(5):1046-1053.e8. doi: 10.1016/j.jaci.2010.03.003.

  PMID: 20451039 BACKGROUND

• Kunicka JE, Talle MA, Denhardt GH, Brown M, Prince LA, Goldstein G. Immunosuppression by glucocorticoids: inhibition of production of multiple lymphokines by in vivo administration of dexamethasone. Cell Immunol. 1993 Jun;149(1):39-49. doi: 10.1006/cimm.1993.1134.

  PMID: 8513511 BACKGROUND

• Newton R, Shah S, Altonsy MO, Gerber AN. Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance. J Biol Chem. 2017 Apr 28;292(17):7163-7172. doi: 10.1074/jbc.R117.777318. Epub 2017 Mar 10.

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• Newton R. Molecular mechanisms of glucocorticoid action: what is important? Thorax. 2000 Jul;55(7):603-13. doi: 10.1136/thorax.55.7.603. No abstract available.

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• Newton R, Leigh R, Giembycz MA. Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases. Pharmacol Ther. 2010 Feb;125(2):286-327. doi: 10.1016/j.pharmthera.2009.11.003. Epub 2009 Nov 22.

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• King EM, Chivers JE, Rider CF, Minnich A, Giembycz MA, Newton R. Glucocorticoid repression of inflammatory gene expression shows differential responsiveness by transactivation- and transrepression-dependent mechanisms. PLoS One. 2013;8(1):e53936. doi: 10.1371/journal.pone.0053936. Epub 2013 Jan 14.

  PMID: 23349769 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Bronchoscopic samples including endobronchial brushings, endobronchial biopsies as well as bronchial washings.

MeSH Terms

Conditions

Asthma

Interventions

Bronchoscopy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Diagnostic Techniques, Respiratory System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Minimally Invasive Surgical Procedures; Surgical Procedures, Operative; Pulmonary Surgical Procedures; Thoracic Surgical Procedures

Central Study Contacts

Brianne S Philipenko, MD

CONTACT

3063806777; brianne.philipenko@gmail.com

Richard Leigh

CONTACT

403-943-8666

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2021
• First Posted: October 14, 2021
• Study Start: April 21, 2022
• Primary Completion: September 1, 2024
• Study Completion: September 1, 2024
• Last Updated: November 30, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)