The Effect of Twice Daily vs. Once Daily Bronchodilation on Hyperinflation in COPD Patients During 24 Hours.

Exclusion Criteria

• •1. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential)
• •2. Patients requiring use of the following medications:
• •1. A course of systemic steroids longer than 3 days for COPD exacerbation in the 4 weeks prior to screening.
• •2. A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to screening. NB; maintenance treatment of macrolides is allowed, without any changes in the regimen in the 4 weeks prior to the study.
• •3. PDE4 (phosphodiesterase-4) inhibitors in the 4 weeks prior to screening.
• •4. Xanthines in the 4 weeks prior to screening.
• •5. Use of antibiotics for a lower respiratory tract infection (e.g pneumonia) in the 4 weeks prior to screening.
• •3. COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period.
• •4. Patients treated with non-cardio selective β-blockers in the month preceding the screening visit or during the run-in period. Those patients may enter the study after non-selective β-blockers withdrawal and/or cardio selective β-blockers intake for at least 10 days before the first study day.
• •5. Patients treated with long-acting antihistamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as PRN (Pro Re Nata).
• •6. Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia.
• •7. Known respiratory disorders other than COPD which may impact the efficacy of the study drug according the investigator's judgment. This can include but is not limited to alpha-1 antitrypsin deficiency, active tuberculosis, a history of asthma, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease.
• •8. Previous lung surgery or endoscopic lung volume reduction interventions.
• •9. Patients who have clinically significant cardiovascular condition such as, but not limited to, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, acute ischemic heart disease in the last year prior to study screening, history of sustained cardiac arrhythmias or sustained and non-sustained cardiac arrhythmias diagnosed in the last 6 months (sustained means lasting more than 30 seconds and or ending only with external action, and or leads to hemodynamic collapse; non-sustained means \> 3 beats \< 30 seconds, and or ending spontaneously, and or asymptomatic), impulse conduction high degree blocks, patients with Implantable Cardioverter Defribrillator (ICD).
• •10. Patients with atrial fibrillation (AF):
• •1. Paroxysmal Atrial Fibrillation
• •2. Persistent: AF episode either lasts longer than 7 days or requires termination by cardioversion, either with drugs or by direct current cardioversion (DCC) within 6 months from screening.
• •3. Long standing persistent as defined by continuous atrial fibrillation diagnosed for less than 6 months with or without a rhythm control strategy.
• •4. Permanent: for at least 6 months with a resting ventricular rate ≥ 100/min controlled with a rate control strategy (i.e., selective β-blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy).
• •12. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic agents.
• •13. History of hypersensitivity to anticholinergics, β2-agonist or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator's judgement.
• •14. Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study drug according to investigator's judgement.
• •15. Patients with hypokalaemia (serum potassium levels \<3.5 mEq/L (or 3.5 mmol/L)) or uncontrolled hyperkalaemia according to investigator's judgment.
• •16. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); uncontrolled neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other which may impact the efficacy or the safety of the study drug according to investigator's judgment.
• •17. Patients with any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next six months (after V1) or with malignancy for which they are currently undergoing radiation therapy or chemotherapy.
• •18. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit.
• •19. Participation in another clinical trial where investigation drug was received less than 8 weeks prior to screening visit.