Small Airways Involvement in Smoker Asthmatic Patients: a Pilot Study

Study Overview
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Brief Summary
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Asthma is an inflammatory disease affecting the whole respiratory system, from central to peripheral airways. Anti-inflammatory treatment with inhaled corticosteroids (ICS), with or without long-acting β2-adrenoceptor agonists (LABA), is the cornerstone of asthma management [GINA Guideline - available at www.ginasthma.com]. Nevertheless, a considerable subset of asthmatic patients neither benefits from ICS nor gain optimal asthma control even with ICS/LABA combinations. The involvement of the distal lung, i.e. the peripheral membranous bronchioles < 2 mm in diameter (so-called small airways), in the pathogenesis of asthma has been extensively investigated and its significance debated. However, whether specifically targeting distal lung abnormalities can lead to further clinical benefit is still an open question. In this context, interest has been raised by hydrofluoroalkane (HFA) pressurised metered-dose inhalers, which can deliver compounds with a mass median aerodynamic diameter that is significantly smaller than other available devices, leading to increase peripheral airways drug deposition. Up to 30% of asthmatic patients smoke, mirroring the rate found in the general population. Several data document that smoking habit negatively affect corticosteroid efficacy in asthma. In particular, asthmatic patients who smoke experience faster lung function decline, increased frequency of exacerbations and reduced asthma control despite being regularly treated. Several molecular mechanisms have been proposed to address the issue of reduced corticosteroids responsiveness in smoker patients. However it has been never investigated whether reduced corticosteroid responsiveness in asthmatic patients who smoke can be related to more severe small airways involvement leading to impaired distribution or impaired peripheral deposition of inhaled corticosteroids. If this is the case, asthmatic patients who smoke might benefit from a pharmacological approach able to target and to reach small airways.

Official Title
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Small Airways Involvement in Smoker Asthmatic Patients: a Pilot Study

Conditions
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Asthma

Intervention / Treatment
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* Drug: Extrafine treatment (Clenilexx(R) or Foster(R))


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients aged 18-50 years old, at stage 2-3 according to GINA international guidelines patients must be free from an exacerbation from at least 2 months patients must be on inhaled treatment (ICS alone or combination ICS/LABA) other than extrafine formulations from at least 3 months. according to smoking habit, patients will be divided in two groups: nonsmokers: patients who never smoked smokers: patients with a smoking habit ranging from 10 to 20 pack/years. Exclusion Criteria: to avoid possible overlapping with chronic obstructive pulmonary disease, patients will not be included in the study if any of the following exclusion criteria are present: aged > 50 years heavy-smoker patients (pack/years > 20) patients with a not fully reversible airflow obstruction (i.e. post-bronchodilator FEV1/FVC < 70%) patients with an impaired diffusion capacity (DLCO < 80%v predicted).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Asthmatic nonsmokers<br>Asthmatic patients aged 18-50 years old, at stage 2-3 according to GINA international guidelines, on inhaled treatment (ICS alone or combination ICS/LABA) other than extrafine formulations, will be enrolled. This group includes patients who never smoked. Following the initial evaluation (cross-sectional - primary outcome) patients will be switched to an extrafine equipotent dose of the same compound (BDP-HFA if the patient was on ICS) or combination (BDP-HFA/F if the patient was on ICS/LABA combination). After 3-months patients will be reassessed for lung function and asthma control | Drug: Extrafine treatment (Clenilexx(R) or Foster(R))<br>* Following the initial evaluation (cross-sectional) patients will be switched to an extrafine equipotent dose of the same compound (extrafine beclomethasone dipropionate - Clenilexx(R) - if the patient was on ICS) or combination (extrafine beclomethasone dipropionate/formoterol - Foster(R) - if the patient was on ICS/LABA combination). After 3-months patients will be reassessed for lung function and asthma control<br>|
| Active Comparator: Asthmatic smokers<br>Asthmatic patients aged 18-50 years old, at stage 2-3 according to GINA international guidelines, on inhaled treatment (ICS alone or combination ICS/LABA) other than extrafine formulations, will be enrolled. This group includes patients who smoked with a smoking habit ranging from 10 to 20 pack/years. Following the initial evaluation (cross-sectional - primary outcome) patients will be switched to an extrafine equipotent dose of the same compound (BDP-HFA if the patient was on ICS) or combination (BDP-HFA/F if the patient was on ICS/LABA combination). After 3-months patients will be reassessed for lung function and asthma control | Drug: Extrafine treatment (Clenilexx(R) or Foster(R))<br>* Following the initial evaluation (cross-sectional) patients will be switched to an extrafine equipotent dose of the same compound (extrafine beclomethasone dipropionate - Clenilexx(R) - if the patient was on ICS) or combination (extrafine beclomethasone dipropionate/formoterol - Foster(R) - if the patient was on ICS/LABA combination). After 3-months patients will be reassessed for lung function and asthma control<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| slope of phase III (dN2) by nitrogen single breath test | The primary outcome will measure and compare at baseline slope of phase III (dN2) by nitrogen single breath test (NSBT) between asthmatic who smoke and asthmatic who do not smoke matched for age, gender and % predicted FEV1 | At baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Closing volume and closing capacity by nitrogen single breath test (NSBT) | To evaluate and compare at baseline other nitrogen single breath test measures including closing volume and closing capacity in asthmatic who smoke and asthmatic who do not smoke matched for age, gender and % predicted FEV1. | At baseline | 
| Respiratory Resistance by oscillometry technique | To evaluate differences in mean resistive component of respiratory impedence (Rrs) and resistance at different frequency (Rr0, Rr5, Rr20) by forced oscillometry technique (FOT) at baseline between asthmatics who smoke compared to asthmatics who do not smoke matched for age, gender and % predicted FEV1. | At baseline | 
| Lung volumes | To evaluate differences in forced vital capacity (FVC), slow vital capacity/forced vital capacity ratio (SVC/FVC), residual volume (RV) and total lung capacity (TLC) at baseline between asthmatics who smoke compared to asthmatics who do not smoke matched for age, gender and % predicted FEV1. | At baseline | 
| Asthma control | To evaluate differences in parameters related to asthma control (Asthma Control Test scores, use of rescue medications) at baseline between asthmatics who smoke compared to asthmatics who do not smoke matched for age, gender and % predicted FEV1. | At baseline | 
| Correlations between small airway functional parameters and asthma control scores | To evaluate at baseline correlations between parameters related to asthma control (questionnaire scores, symptoms and use of rescue medications) and functional measurements | At baseline | 
| Changes after extrafine intervention | To evaluate changes in functional parameters and parameters related to asthma control in asthmatic patients who smoke compared to asthmatic patients who do not smoke after a 3-months extrafine inhaled treatment. | Change at 3 months vs baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Cigarette smoke, Small airways, Lung function, Asthma control