Studying the Airway Microenvironment in Patients Undergoing Surgical and Bronchoscopic Interventions for COPD

Chronic Obstructive Pulmonary Disease Clinical Trial

— COPD-ENVIRON  

Official title:

Studying the Airway Microenvironment in Patients Undergoing Surgical and Bronchoscopic Interventions for COPD

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03010592
• Other study ID #: 217587
• Status: Recruiting
• Start date: February 6, 2017
• Est. completion date: January 1, 2023

Study information

• Verified date: September 2021
• Source: Royal Brompton & Harefield NHS Foundation Trust
• Contact: Justin L Garner, MBBS MRCP
• Phone: 02073518029
• Email: J.Garner[@]rbht.nhs.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Studying the airway microenvironment in patients undergoing surgical and bronchoscopic interventions for COPD

Description:

Chronic obstructive pulmonary disease (COPD) is an umbrella term encompassing two entities causing progressive and ultimately disabling breathlessness. Emphysema is a process destructive of the airspaces distal to the terminal bronchioles, with loss of gas exchange tissue, of elastic recoil and of circumferential tethering of the small airways leading to their collapse on forced expiration. Chronic bronchitis is a disorder of the bronchi causing excess production and impaired mobilisation of mucus. Increased parasympathetic tone and progressive remodelling of airways impairs response to bronchodilators. Static and dynamic hyperinflation ensue - a persistently expanded chest and flattened diaphragms despite increasing use of accessory respiratory muscles - resulting in a disadvantaged respiratory pump.

Patients with severe emphysema and hyperinflation benefit from lung volume reduction techniques designed to reduce gas trapping and to improve airflow, chest wall and lung mechanics. The best evidence exists for lung volume reduction surgery (LVRS), which however is not without risk and there is increasing interest in the development of bronchoscopic lung volume reduction (BLVR) techniques including emplacement of endobronchial valves and coils and targeted lung denervation (TLD), which have all been shown to improve lung function, exercise capacity, and quality of life.

Endobronchial cryotherapy is a novel investigational treatment in patients with chronic bronchitis. Porcine models have shown ablation of abnormal metaplastic goblet cells and regeneration of healthy ciliated epithelium and submucosa within 48 hours with complete healing by 60 days following treatment. A pilot study evaluated 11 patients undergoing a lobectomy or pneumonectomy for presumed lung cancer. Metered sprays, one to each of two separate locations, were administered 2 weeks prior to surgery, at least 2cm distal to the proposed resection margin (first segmental and lobular bronchi). No adverse events were reported. Histology of the 8 submitted specimens demonstrated localised cryothermic effect extending to but not beyond the submucosa, and minimal inflammation.

Chronic airway infiltration by neutrophils, macrophages, and Th-1 predominant lymphocytes driven by increased expression of inflammatory proteins, cytokines and chemokines, is intensified during exacerbations. It is generally accepted that acute exacerbations accelerate the decline in lung function in COPD. Recent studies have suggested a role for microvesicles (MVs) in the pathogenesis of COPD, driving exacerbations. MVs are fragments of cell membrane ranging from 0.1 to 1µm in diameter shed by almost all eukaryotic cells. They are recognised to be key mediators of intercellular communication, transporting a variety of molecular cargo including proteins and nucleic acids to distant cells, and have been implicated in various inflammatory diseases including COPD. The majority of studies have looked at circulating endothelial-derived MVs, which are elevated in patients with COPD, are significantly higher during an exacerbation, and are predictive of rapid forced expiratory volume in 1 second (FEV1) decline. However, there is a paucity of data on epithelial-derived MVs within the lung. We know from acute lung injury models that alveolar macrophage-derived microvesicles, which carry biologically active tumour necrosis factor, are rapidly released during the early phase and may play a role in initiating the disease process.

Bronchoalveolar lavage and brushings are established techniques to obtain material for respectively, measurement of inflammatory proteins and microvesicles, and for cytology and messenger ribonucleic acid (mRNA) analysis. A novel technique sampling the mucosal lining fluid using a synthetic absorptive matrix ('bronchosorption') has been shown to have greater sensitivity to standard bronchoalveolar lavage (BAL), eliminating the disadvantage of dilution.

A combination of all three techniques to directly harvest lower airway samples at multiples sites of pulmonary inflammation would allow comparison of proteomic, transcriptomic, and histology data from the endobronchial environment before and after intervention. This would be the first study evaluating the lung microenvironment in this context, which may identify predictive biomarkers of response to intervention and future exacerbation risk.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: January 1, 2023
• Est. primary completion date: January 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Scheduled for lung volume reduction treatment or endobronchial cryotherapy for the management of severe COPD.

Exclusion Criteria:

• Unwilling or unable to sign the informed consent form

• Patients with known Category 3 Organisms as per the Advisory Committee on Dangerous Pathogens (ACDP) for example, Tuberculosis or Human Immunodeficiency Virus.

Related Conditions & MeSH terms

• Bronchitis
• Bronchitis, Chronic
• Chronic Bronchitis
• Chronic Obstructive Pulmonary Disease
• Emphysema
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Locations

Country	Name	City	State
United Kingdom	Chelsea & Westminster Hospital	London	Chelsea
United Kingdom	Royal Brompton & Harefields Hospital	London	Fulham

Sponsors (1)

Lead Sponsor	Collaborator
Royal Brompton & Harefield NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (11)

Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008 Mar;8(3):183-92. doi: 10.1038/nri2254. Epub 2008 Feb 15. Review. — View Citation

Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002 Oct;57(10):847-52. Erratum in: Thorax. 2008 Aug;63(8):753. — View Citation

Eltom S, Dale N, Raemdonck KR, Stevenson CS, Snelgrove RJ, Sacitharan PK, Recchi C, Wavre-Shapton S, McAuley DF, O'Kane C, Belvisi MG, Birrell MA. Respiratory infections cause the release of extracellular vesicles: implications in exacerbation of asthma/C — View Citation

Gordon C, Gudi K, Krause A, Sackrowitz R, Harvey BG, Strulovici-Barel Y, Mezey JG, Crystal RG. Circulating endothelial microparticles as a measure of early lung destruction in cigarette smokers. Am J Respir Crit Care Med. 2011 Jul 15;184(2):224-32. doi: 1 — View Citation

Leaker BR, Nicholson GC, Ali FY, Daudi N, O'Connor BJ, Barnes PJ. Bronchoabsorption; a novel bronchoscopic technique to improve biomarker sampling of the airway. Respir Res. 2015 Sep 4;16:102. doi: 10.1186/s12931-015-0268-5. — View Citation

Nieri D, Neri T, Petrini S, Vagaggini B, Paggiaro P, Celi A. Cell-derived microparticles and the lung. Eur Respir Rev. 2016 Sep;25(141):266-77. doi: 10.1183/16000617.0009-2016. Review. — View Citation

Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013 Feb 18;200(4):373-83. doi: 10.1083/jcb.201211138. Review. — View Citation

Soni S, Wilson MR, O'Dea KP, Yoshida M, Katbeh U, Woods SJ, Takata M. Alveolar macrophage-derived microvesicles mediate acute lung injury. Thorax. 2016 Nov;71(11):1020-1029. doi: 10.1136/thoraxjnl-2015-208032. Epub 2016 Jun 10. — View Citation

Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, He M, Yamada M, Suzuki S, Yanai M, Kurosawa S, Yamaya M, Kubo H. Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility. Thorax. 20 — View Citation

Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, Tando Y, Yamada M, Yanai M, Yamaya M, Kurosawa S, Yamauchi M, Kubo H. Annual FEV1 changes and numbers of circulating endothelial microparticles in patients with COPD: a prospective study. BMJ Open. 2014 — View Citation

Thomashow MA, Shimbo D, Parikh MA, Hoffman EA, Vogel-Claussen J, Hueper K, Fu J, Liu CY, Bluemke DA, Ventetuolo CE, Doyle MF, Barr RG. Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Athero — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in airway cytokine levels at 3 months follow-up	Change in airway cytokine levels measured using a multiplex assay, 3 months following interventional treatment	Baseline versus 3 months follow-up
Secondary	Association between baseline cytokine levels and future exacerbation frequency at 3 months follow-up		Baseline versus 3 months follow-up
Secondary	Association between baseline cytokine levels and future decline in lung function at 3 months follow-up		Baseline versus 3 months follow-up
Secondary	Association between baseline microvesicle levels and future exacerbation frequency at 3 months follow-up		Baseline versus 3 months follow-up
Secondary	Association between baseline microvesicle levels and future decline in lung function at 3 months follow-up		Baseline versus 3 months follow-up
Secondary	Change from baseline in airway microvesicle levels at 3 months follow-up	Change in airway microvesicle levels measured using flow cytometry, 3 months following interventional treatment	Baseline versus 3 months follow-up