Clinical trial NCT01853787: Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients - SANOB Study
Official title: Acute Bronchodilation and Bronchial Inflammation: Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients. Stretching of Airways and Nitric Oxide in Bronchodilation, SANOB Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: COPD
bronchial inflammation
NO concentration
small airways
LABA
Small Airways Stretching
Stretch and strain of small airways in COPD
Acute LABA effect on NO production
Pulmonary desufflation
Lead sponsor: University of Milan
Sponsor class: OTHER
Collaborators: name: Fondazione Salvatore Maugeri
name: Università degli Studi di Ferrara
First posted: 2013-05-15
Enrollment: 49
Sex: ALL
Minimum age (years): 45
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: * Among many other causes, Bronchial obstruction in Chronic Obstructive Pulmonary Disease (COPD) is also caused by inflammation of peripheral airways walls.
* Neutrophils and other inflammatory mediators like Interleukin-6 (IL6), Interleukin-8 (IL8), Interleukin-1 alpha (IL-1 alpha),Interleukin-1beta (IL-1 beta), Tumor Necrosis Factor alfa (TNF-alfa), Reactive Oxygen Species (ROS), Leukotriene B4 (LTB4), Nitric Oxyde (NO) are implicated in the inflammation.
* NO is produced in response to physical and chemical stress on bronchial epithelium and plays a critical role in small airways remodelling
* Exhaled NO concentration is usually used to monitor bronchial inflammation
* The relationship between stretch and strain of small airways and bronchial inflammation is not well understood.
* The investigators hypothesis is that cyclic opening and closure of peripheral obstructed airways through the consequent stretching and strain acting on them can provoke an inflammatory response which can be monitored by exhaled NO.
* The pharmacological effects of bronchodilators may play a role on bronchial inflammation by reducing the stretching stress on bronchiolar walls thus reducing the production of NO in exhalate
* Data about these physiopathological aspects is missing in literature.

Detailed description: Bronchial inflammation in COPD represents one of the main causes of not fully reversible obstruction and airflow limitation. The main inflammatory cells involved are represented by the neutrophils, while some inflammatory mediators like Interleukin-6 (IL6), Interleukin-8 (IL8), Interleukin-1 alpha (IL1alpha), Interleukin-1 beta (IL1beta), Tumor Necrosis Factor alfa (TNFalfa), Reactive Oxygen Species (ROS), Leukotriene B4 (LTB4) and Nitric Oxide (NO) provoke the disruption of the elastic alveolar bonds that support the small airways, thus invalidating their physical and mechanical characteristics. During tidal volume respiration, in such patients, the chronically obstructed small airways are subjected, the investigators suppose, to one of the following effects:

* a total closure of the smaller bronchioli causing atelectasis
* a cyclic opening and closure of the airways thus provoking friction and strain stress and an inflammatory response of mechanical origin.

The Fraction of Exhaled Nitric Oxyde (FeNO) concentration is largely used in clinical practice as a marker to monitor the lung inflammatory status. Formoterol and Salmeterol are two of the most used Long Acting Beta 2 Agonists (LABA) for inhaled therapy of COPD, representing the basis of the bronchodilator therapy in this disease.

The purpose of the study is to evaluate the possible mechanical origin of the bronchial inflammation and then the capacity of inhaled LABA in acute conditions to modify the trend of production of NO by reducing stretching and strain forces. Thus the possible decline of exhaled NO concentration will be used as an index of the small airways inflammatory state occurring after inhaled therapy.

To do this the investigators will measure the exhaled NO concentration in COPD patients with moderate to severe obstruction, that is a Forced Expiratory Volume less than 70% of predicted value (FEV1\<70%pred). The evaluation will be done in four different moments:

1. at baseline, after 72 hours of pharmacological washout conditions
2. at 30 minutes after the assumption of inhaled therapy (Salmeterol 50 mcg or Formoterol 12 mcg in double blind conditions)
3. at 60 minutes after step 2
4. at 180 minutes after step 2 Together with NO concentration, also the Respiratory Frequency and Tidal Volume will be registered during each evaluation.

All the subjects will be inpatients accessing a respiratory rehabilitation unit or outpatients of the ambulatory service. After every NO measure, a functional respiratory assessment will be made (spirometry, plethysmography, Carbon Monoxide (CO) diffusion lung test, Single Breath N2 washout test), together with an arterial blood gas analysis.

At every step a dyspnoea assessment will be made by Visual Analogic Scale, while Modified Medical Research Council (mMRC) scale will be assessed at the beginning of the test.

Every patient will repeat the four step assessment after 72 hours, while a double blind pharmacological crossover will be performed, thus creating a controlled study in witch every patients, at the end of the study, will take Salmeterol and Formoterol in a randomized way.

For the study duration all the patients will perform a pharmacological washout (living the short acting inhaled Beta 2 agonists as rescue medication)

Eligibility criteria: Inclusion criteria:

* Signature of informed consent
* COPD patients with age raging from 50 to 85 years old
* Patients with at least a history of COPD of one year
* COPD patients clinically stable in the last three months
* COPD subjects with FEV1 (Forced Expiratory Volume in 1st second)\<70% of predicted value
* FEV1/FVC (Forced Expiratory Volume in 1st second/Forced Vital Capacity) \<88% (males) or \<89% (females) of LLN (Low Levels of Normality)
* COPD former or active smokers with at least a smoking history of 20 pack year

Exclusion Criteria:

* Acute Bronchial Exacerbation at recruitment
* Fertile women with age between 18 and 50 years old or with active period
* Pregnancy
* Subjects enrolled in other clinical trials or that have taken part in one of them in the month preceding the enrollment.
* FEV1/FVC more than 70% of predicted value in basal conditions
* FEV1 more than 70% of predicted value in basal conditions
* Known deficit of alpha 1 antitrypsin
* Subjects that underwent a Lung Volume Reduction Surgery (LVRS)
* Subjects with known positivity to Human Immunodeficiency Virus (HIV)
* Misuse of alcool or drugs
* Lack of compliance in performing respiratory tests
* Subjects not capable to follow the study prescriptions because of psychic disorders or language problems.
* Long Term Oxygen Therapy with flows \> 6 litres per minute (l/min) at rest

Primary outcomes:
measure: Change in exhaled Nitric Oxide concentration after Long acting Beta 2 Agonist assumption
timeFrame: - At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption
Secondary outcomes:
measure: Change in static plethysmographic volumes, assessment of desufflation and resistances after Long acting Beta 2 Agonist assumption and
timeFrame: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption
measure: Diffusion Lung Capacity for Carbon Monoxide (DLCO) and Alveolar Volume (VA) variation from baseline
timeFrame: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption
measure: Modification of arterial gases concentration after bronchodilator therapy in acute conditions
timeFrame: At baseline, after 180 minutes of LABA assumption
measure: Closing Capacity variability from baseline at the Single Breath Nitrogen Washout test
timeFrame: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption
measure: Change from baseline in dyspnoea, evaluated with VAS (Visual Analogue Scale).
timeFrame: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption
Other outcomes:
Locations:
city: Ferrara
country: Italy
facility: Clinica di Malattie dell'Apparato Respiratorio, Dipartimento di Scienze Mediche, Università di Ferrara
city: Milano
country: Italy
facility: : Pneumologia Riabilitativa-Fondazione Maugeri-Istituto Scientifico di Milano- IRCCS
Study officials:
affiliation: Università degli Studi di Milano-Pneumologia Riabilitativa-Fondazione Salvatore Maugeri-MILANO
name: Pierachille santus, Md, PhD
role: STUDY_DIRECTOR
References:
citation: Santus P, Radovanovic D, Mascetti S, Pauletti A, Valenti V, Mantero M, Papi A, Contoli M. Effects of bronchodilation on biomarkers of peripheral airway inflammation in COPD. Pharmacol Res. 2018 Jul;133:160-169. doi: 10.1016/j.phrs.2018.05.010. Epub 2018 May 23.