Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients - SANOB Study
Condition: Chronic Obstructive Pulmonary Disease (COPD)
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 4

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)
    

Intervention name(s): Formoterol Fumarate; Salmeterol
Intervention type(s): Drug; Drug
Intervention description(s): Formoterol Fumarate, one inhalation of 12 mcg via MDI (Metered Dose Inhaler) Modulite will be taken in double blind randomized way immediately after T0 evaluation.; Salmeterol 50 mcg via MDI (Metered Dose Inhaler), one inhalation only, immediately after T0 evaluation
Other intervention name(s): Foradil spray, Novartis Farma S.p.A.; Serevent, GlaxoSmithKline S.p.A.
Intervention MeSH terms: Formoterol Fumarate; Salmeterol Xinafoate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
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