Acute Effect of Aclidinium on Hyperinflation and Ventilation Inhomogeneity in Severe COPD Patients
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 4

Summary: 
      -  Chronic Obstructive Pulmonary Disease (COPD) is characterized by lung hyperinflation and
           flow limitation. These physiopathological modifications are secondary to loss of elastic
           recoil and bronchial obstruction due to emphysema.

        -  The cornerstone of COPD treatment is represented by inhaled beta-2 agonists and
           anticholinergics. The molecules of the latter classes can be characterized by short
           lasting action (few hours), long acting action (12 hours) or ultra long acting duration
           of action (24 hours).

        -  For years the only anticholinergic (or antimuscarinic) drug other than those used by
           aerosol, was Tiotropium Bromide. Recently two new antimuscarinic agents have been
           launched on the market: glycopyrronium bromide (once daily) and aclidinium (twice
           daily).

        -  The Single Breath Nitrogen Test is capable of identifying the pulmonary closing volume.
           The part of the curve that reflects lung ventilation inhomogeneity is the slope of phase
           III

        -  For COPD patients, the most important characteristic for an inhalatory drug is a prompt
           action in order to give a quick relief from respiratory symptoms, in particular
           dyspnoea.

        -  The objective of this study is to study the acute action of glycopyrronium and
           aclidinium in terms of reduction of hyperinflation, pulmonary specific resistances, lung
           volume distribution and dyspnoea at rest in severe COPD patients.

        -  To our knowledge no study has explored these aspects before.
    

Detailed description: 
      Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by progressive and
      evolutionary physiopathological changes that are responsible for the developing of
      respiratory symptoms, disability, poor quality of life and morbidity. These changes are
      secondary to parenchymal disruption and chronic bronchiolar inflammation in major part due to
      cigarette smoke.

      Lung architectural derangement and loss of elastic recoil secondary to emphysema together
      with decreased internal bronchiolar lumen due to mucosal chronic inflammation are responsible
      for bronchial obstruction, flow limitation and lung hyperinflation. All these features bring
      to exertional dyspnoea, chronic cough and sputum and so decreased activeness in daily life
      activities.

      The Single Breath Nitrogen Washout Test (SBN2) is one of the test that more adequately can
      catch the modifications of small airways and their premature collapse called closing volume
      (CV). Together with CV the test reflects pulmonary ventilation inhomogeneity through the
      slope of the so called phase III (a plateau line of nitrogen concentration that is steeper
      the bigger the ventilation inhomogeneity). In literature the effects of COPD inhalatory
      treatments on this modifications and on hyperinflation were until today poorly analysed.
      Recently some new anticholinergic molecules were developed, in particular Aclidinium Bromide
      and Glycopyrronium Bromide, and there is no trace of such evaluation in medical literature
      with those new inhalatory drugs.

      The study of the acute effects of these drugs on lung mechanics are mandatory because the
      quicker the effects, the faster the patient's dyspnoea relief.

      The study will comprise a first enrollment visit and then the suitable subjects will undergo
      a pharmacological washout of 72 hours from any inhalatory drug except from Salbutamol.

      Then the patients will be randomised to be given Glycopyrronium Bromide 44 mcg (and matched
      Aclidinium Bromide 322 mcg placebo) or Aclidinium Bromide 322 mcg (and matched Glycopyrronium
      Bromide 44 mcg placebo) (Day 1) with a double dummy scheme.

      At day 1 the pre-dose (baseline) evaluation consists of:

        -  body plethysmography (with residual volume and specific resistances evaluation),

        -  arterial blood gas analysis (partial pressure of oxygen and carbon dioxide evaluation),

        -  SBN2

        -  Visual Analogic Scale for Dyspnoea (VAS scale) evaluation

        -  Diffusion Lung Capacity for Carbon Monoxide with Single Breath method (DLCO). These
           tests will be repeated after 5, 15, 30, 60 and 180 minutes after study drug inhalation.
           DLCO and arterial blood gas analysis will be performed only at baseline and after 180
           minutes after study drug inhalation.

      After day 1 all the patients will undergo another period of inhalatory therapy washout of 72
      hours (only rescue Salbutamol spray permitted).

      After the second pharmacological washout the patients will undergo the crossing over. The
      ones who were given Aclidinium Bromide will assume Glycopyrronium Bromide and vice versa (Day
      2) always in double dummy conditions.

      At Day 2 all the patients will undergo the same evaluation as in day 1. At day 1 and day 2
      the study drugs with the two different devices (active drug + placebo) will be given to the
      patients by medical personnel not involved in the performing of any of the tests of day 1 and
      2, in order to maintain the double blind conditions.
    

Intervention name(s): Aclidinium Bromide; Glycopyrronium Bromide
Intervention type(s): Drug; Drug
Intervention description(s): Aclidinium Bromide 322 mcg inhalation powder via Genuair inhaler (Eklira) Product by Almirall, S.A. Ronda General Mitre, 151. ES-08022 Barcelona, Spain; Glycopyrronium Bromide 44 mcg dry powder (capsules) inhaled via Breezehaler inhaler, Seebri - product by Novartis Europharm Limited - Wimblehurst Road, Horsham, West Sussex, RH12 5AB; United Kingdom
Other intervention name(s): Eklira Genuair (UK); Tudorza Pressair (US); Bretaris Genuair (EU); Seebri Breezhaler
Intervention MeSH terms: Glycopyrrolate; Bromides
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: COPD; Hyperinflation; Aclidinium; Glycopyrronium; Volume distribution; Anticholinergic; Pharmacokinetics; Single Breath Nitrogen Test; Phase III