2-arm Parallel Group Study of Fixed Combination of CHF 5993 vs Ultibro® in COPD Patients (TRIBUTE)

Inclusion :

1. Male and female ≥ 40 years
2. Severe or very severe COPD diagnosed for at least 12 months
3. Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years
4. Post-bronchodilator FEV1 < 50% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio < 0.7
5. Documented history of at least one exacerbation in the 12 months

6. Patient under double therapy for at least 2 months prior to screening. Double therapy will be defined by treatment with any of the following:

   Orally inhaled corticosteroid (ICS) and (long-acting beta2-agonist) LABA ICS and long-acting muscarinic antagonist (LAMA) Orally LABA and LAMA Monotherapy with LAMA for at least 2 months prior to screening

7. Symptomatic patient at screening with a CAT score ≥ 10.
8. Cooperative attitude and ability to use correctly the inhalers, the spacer AeroChamber Plus (only to patients who are using a spacer), the electronic devices with COPD questionnaire.

Exclusion :

1. Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS are willing to use one or more of the reliable methods of contraception
2. Patient with a current clinical diagnosis of asthma with a physician-judged need for inhaled or oral corticosteroid therapy

3. Patient requiring use of the following medications:

   Course of systemic steroids > 3 days for COPD exacerbation in the 4 weeks prior to screening Course of antibiotics for COPD exacerbation > 7 days in the 4 weeks prior to screening Phosphodiesterase-4 inhibitor in the 4 weeks prior to screening Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening

4. COPD exacerbation requiring prescription of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period
5. Patient treated with non-cardioselective β-blockers in the month preceding the screening or during the run-in period.
6. Patient 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 needed
7. Patient requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia
8. Known respiratory disorders other than COPD which may impact the efficacy of the study drug
9. Patient who have clinically significant cardiovascular condition
10. Patient with atrial fibrillation (AF): Paroxysmal atrial fibrillation, Persistent, Long standing or Permanent
11. Abnormal and clinically significant 12-lead ECG that results in active medical problem which may impact the safety of the patient
12. Patient whose ECG shows QTcF >450 ms for males or QTcF >470 ms for females at screening visit are not eligible (not applicable for patient with pacemaker)
13. Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction would prevent use of anticholinergic agents
14. History of hypersensitivity to M3 Antagonists, β2-agonist, corticosteroids 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
15. Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study drug
16. Patients with hypokalaemia (serum potassium <3.5 mEq/L or 3.5 mmol/L) or uncontrolled hyperkalaemia
17. Unstable concurrent disease which may impact the results of the study
18. 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
19. History of alcohol abuse or substance/drug abuse within 12 months prior to screening visit
20. Participation in another clinical trial if investigational drug was received less than 8 weeks prior to screening visit