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Chronic Obstructive Pulmonary Disease (COPD)Phase 4SANOBNCT01853787

Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients - SANOB Study

A Phase 4 study testing Formoterol Fumarate and Salmeterol in people with Chronic Obstructive Pulmonary Disease (COPD), run by University of Milan at 2 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 45 to 90 years
What is being tested?
Formoterol Fumarate and Salmeterol
Could I receive a placebo?
No, everyone receives an active treatment
How many people
49 participants
Where
2 sitesItaly
Study dates
Jul 2014to Jun 2015
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 45 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 13Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

Italy2 sites
  • Clinica di Malattie dell'Apparato Respiratorio, Dipartimento di Scienze Mediche, Università di Ferrara

    Ferrara, Ferrara, 44121

  • : Pneumologia Riabilitativa-Fondazione Maugeri-Istituto Scientifico di Milano- IRCCS

    Milan, Milano, 20138

Other trials in Italy

About this 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

  • 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.
Read the 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)

Being tested
Formoterol Fumarate, Salmeterol
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
Medical subject headings
Pulmonary Disease, Chronic Obstructive

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Formoterol FumarateDrug

    Also called Foradil spray, Novartis Farma S.p.A.

    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.

  • SalmeterolDrug

    Also called Serevent, GlaxoSmithKline S.p.A.

    Salmeterol 50 mcg via MDI (Metered Dose Inhaler), one inhalation only, immediately after T0 evaluation

Study groups in NCT01853787
Study groupRoleWhat they receive
Formoterol FumarateExperimentalAt study day n°1 the patients will be randomized to take either Salmeterol or Formoterol in a double blind way.
Receives: Drug: Formoterol Fumarate; Drug: Salmeterol
SalmeterolActive comparatorThe second study arm represents the crossing over arm. Every patient, at study day number 2 will take a different medication (Salmeterol 50 mcg or Formoterol 12 mcg) from that taken at the study day n° 1.
Receives: Drug: Formoterol Fumarate; Drug: Salmeterol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in exhaled Nitric Oxide concentration after Long acting Beta 2 Agonist assumption

    The evaluation of exhaled Nitric Oxide concentration will be performed following the schedule below:

    • at baseline (T0), after 72 hours of inhalatory therapy washout
    • 30 minutes (T1) after the assumption of a inhaled bronchodilator (Salmeterol 50 mcg or Formoterol 12 mcg)
    • 60 minutes after T0 (T2)
    • 180 minutes after T0 (T3) every patient will repeat the same four steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day.

    The measurements of Exhaled NO will be performed by Medi-Soft Exp'air FeNo concentration sampling device, Sorinnes (Dinant) Belgium. At every step, will be performed 3 measurements at different flows (50 ml/sec, 100 ml/sec, 150 ml/sec and 350 ml/sec), for a total of 12 valid measurements for each step.

    Alveolar NO and Bronchial Wall NO concentrations will be taken in consideration.

    Measured: - At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption

Secondary outcomes (5)
  1. Change in static plethysmographic volumes, assessment of desufflation and resistances after Long acting Beta 2 Agonist assumption and

    The evaluation of pulmonary desufflation and pulmonary specific resistances (sRAW) will be performed with a plethysmographic maneuver for each of the following steps:

    • at baseline (T0), after 72 hours of inhalatory therapy washout
    • 30 minutes (T1) after the assumption of a inhaled bronchodilator (Salmeterol 50 mcg or Formoterol 12 mcg)
    • 60 minutes after T0 (T2)
    • 180 minutes after T0 (T3) every patient will repeat the same four steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day.

    The considered pulmonary volumes will be the Residual Volume and the Functional Residual Capacity, while Specific Resistances of AirWays (sRAW)will be evaluated using a Jaeger (Germany) plethysmographic cabin. At every step, 3 measurements will be performed, following the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines on pulmonary Function testing.

    Measured: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption

  2. Diffusion Lung Capacity for Carbon Monoxide (DLCO) and Alveolar Volume (VA) variation from baseline

    The evaluation of DLCO and VA will be assessed performing the Single Breath method for each of the following steps:

    • at baseline (T0), after 72 hours of inhalatory therapy washout
    • 30 minutes (T1) after the assumption of a inhaled bronchodilator (Salmeterol 50 mcg or Formoterol 12 mcg)
    • 60 minutes after T0 (T2)
    • 180 minutes after T0 (T3) Every patient will repeat the same four steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day.

    DLCO and VA will be obtained using a Jaeger (Germany) pneumotachograph with an integrated gas analyzer, by means of a fixed gas mixture made as follows : 10% Helium, 6% Carbon Monoxide, 84% Nitrogen At every step 3 consecutive measurements will be performed, following the ATS/ERS guidelines on pulmonary Function testing.

    Measured: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption

  3. Modification of arterial gases concentration after bronchodilator therapy in acute conditions

    An arterial blood sampling will be taken for each of the following steps:

    • at baseline (T0), after 72 hours of inhalatory therapy washout
    • 180 minutes after T0 (T3) Every patient will repeat the same two steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day.

    Partial arterial pressure of Oxygen and Partial arterial pressure of Carbon Dioxide will be obtained using a arterial gas analyzer GEM Premier 3000

    Measured: At baseline, after 180 minutes of LABA assumption

  4. Closing Capacity variability from baseline at the Single Breath Nitrogen Washout test

    The evaluation of the appearance of the CLosing Capacity (CC) will be assessed performing the Single Breath Nitrogen Washout test (SBN2 test) for each of the following steps:

    • at baseline (T0), after 72 hours of inhalatory therapy washout
    • 30 minutes (T1) after the assumption of a inhaled bronchodilator (Salmeterol 50 mcg or Formoterol 12 mcg)
    • 60 minutes after T0 (T2)
    • 180 minutes after T0 (T3) Every patient will repeat the same four steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day.

    The CC will be obtained using Vmax, Jaeger (Germany) pneumotachograph with an integrated gas analyzer. The parameters considered will be the phase III (alveolar phase) and the phase IV (Closing Capacity appearance) at the SBN2 test.

    At every step 3 consecutive measurements will be performed, following the ATS/ERS guidelines on pulmonary function testing.

    Measured: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption

  5. Change from baseline in dyspnoea, evaluated with VAS (Visual Analogue Scale).

    The evaluation of grade of dyspnea will assessed through the VAS scale for each of the following steps:

    • at baseline (T0), after 72 hours of inhalatory therapy washout
    • 30 minutes (T1) after the assumption of a inhaled bronchodilator (Salmeterol 50 mcg or Formoterol 12 mcg)
    • 60 minutes after T0 (T2)
    • 180 minutes after T0 (T3) Every patient will repeat the same four steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day.

    Measured: At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 May 2013 (estimated)
  2. Study startJul 2014
  3. Primary completionJun 2015
  4. Study completionJun 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
49 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01853787
Sponsor's protocol ID
898CEC
Acronym
SANOB
Status last verified
Jul 2015
First submitted
5 May 2013
Last updated
10 Jul 2015
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 29775687

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Formoterol Fumarate and Salmeterol in people with Chronic Obstructive Pulmonary Disease (COPD), run by University of Milan at 2 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in exhaled Nitric Oxide concentration after Long acting Beta 2 Agonist assumption (time frame: - At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01853787, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2015.

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