Clinical trial NCT03010592: Studying the Airway Microenvironment in Patients Undergoing Surgical and Bronchoscopic Interventions for COPD
Official title: Studying the Airway Microenvironment in Patients Undergoing Surgical and Bronchoscopic Interventions for COPD
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Chronic Obstructive Pulmonary Disease
Emphysema
Chronic Bronchitis
Keywords: Lung volume reduction treatment
Endobronchial cryotherapy
Microvesicles
Lead sponsor: Royal Brompton & Harefield NHS Foundation Trust
Sponsor class: OTHER
First posted: 2017-01-05
Enrollment: 80
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with severe COPD who are scheduled to undergo surgical or bronchoscopic lung intervention (n=80)

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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change from baseline in airway cytokine levels at 3 months follow-up
timeFrame: Baseline versus 3 months follow-up
Secondary outcomes:
measure: Association between baseline cytokine levels and future exacerbation frequency at 3 months follow-up
timeFrame: Baseline versus 3 months follow-up
measure: Association between baseline cytokine levels and future decline in lung function at 3 months follow-up
timeFrame: Baseline versus 3 months follow-up
measure: Association between baseline microvesicle levels and future exacerbation frequency at 3 months follow-up
timeFrame: Baseline versus 3 months follow-up
measure: Association between baseline microvesicle levels and future decline in lung function at 3 months follow-up
timeFrame: Baseline versus 3 months follow-up
measure: Change from baseline in airway microvesicle levels at 3 months follow-up
timeFrame: Baseline versus 3 months follow-up
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Chelsea & Westminster Hospital
state: Chelsea
city: London
country: United Kingdom
facility: Royal Brompton & Harefields Hospital
state: Fulham
Study officials:
affiliation: Royal Brompton & Harefields Hospital
name: Pallav L Shah, MBBS MD FRCP
role: PRINCIPAL_INVESTIGATOR
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