Please select the eligibility criteria that correspond to the clinical trial below.
Title: 52-week, Double Blind, Randomized, 2 Active Parallel Arms Study of Fixed Combination CHF 5993 Administered vs Ultibro® in COPD Patients
Brief Summary: The aim of the present study is to evaluate the superiority of the fixed triple therapy with BDP/FF/GB at a daily dose of 400/24/50 mcg respectively with that of Ultibro® Breezhaler® (DPI), fixed combination of indacaterol 85 mcg and of glycopyrronium 43 mcg in COPD patients.


Options:
A: Inclusion Criteria:

* Adult male or non-pregnant, non-lactating female aged ≥40.
* Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years
* Patients with a clinical diagnosis of COPD according to GOLD guidelines 2013, with a post-bronchodilator FEV1 \<80%, and FEV1/FVC \< 70% at Screening Visits
* Symptomatic patients with a COPD assessment test (CAT) ≥10 at Screening and Randomisation Visits
* Patient must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Screening Visits
* Patients eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained

Exclusion Criteria:

* History or current diagnosis of asthma
* Development of a respiratory tract infection or COPD exacerbation within 6 weeks (or 3 months if hospitalisation was required) before the Screening Visit or during the run-in period
* Clinically significant respiratory conditions
* Type I or uncontrolled Type II diabetes, uncontrolled hypo- or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension
* Patients who, in the investigator's opinion, may need to start a pulmonary rehabilitation programme during the study and/or patients who started/finished it within 3 months prior to Screening Visit
* Use of long-term oxygen therapy (≥15 hours/day)
* Patients treated on daily basis with triple therapy (LABA+LAMA+ICS) within 4 weeks prior to the Screening Visit
* Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers
* Clinically significant cardiovascular conditions
* Patient with clinically relevant abnormalities in the results of the clinical laboratory tests, ECG parameters or in the physical examination at the Screening Visit
* Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm)
* Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy
* Patient with known non-controlled history of infection with human immunodeficiency virus (HIV) and/or active hepatitis
* History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer
* Patient with any other serious or uncontrolled physical or mental dysfunction
* Patient with a history (within 2 years prior to Screening Visit) of drug and/or alcohol abuse that may prevent study compliance based on investigator judgment
* Patient unlikely to be cooperative or that can't comply with the study procedures
* Patient treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening Visit
* Patient who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required stabilization periods for prohibited medication
* Any other conditions that, in the investigator's opinion, might indicate the patient to be unsuitable for the study
B: 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
C: Inclusion Criteria:

* Patients with moderate to severe stable COPD (Stage II or Stage III) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline.

Current or ex-smokers who have a smoking history of at least 10 pack years. Patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥ 30% and \< 80% of the predicted normal, and post-bronchodilator FEV1/FVC \< 0.7.

Modified Medical Research Council (mMRC) grade of at least 2 at Visit 2.

Exclusion Criteria:

* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test.

Patents with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH), bladder-neck obstruction, moderate to severe renal impairment or urinary retention. BPH patients who are stable on treatment can be considered.

Patients with a history of long QT syndrome or whose QTc measured at run-in (Visit 2) (Fridericia method) is prolonged (\>450 ms for males and females) as confirmed by the central Electrocardiogram (ECG) assessor.

Patients with Type I or uncontrolled Type II diabetes. Patients who have not achieved spirometry result at Visit 2 in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria for acceptability and repeatability.

Patients with, a) any history of asthma or, b) onset of respiratory symptoms prior to age 40 years.

Patients with concomitant pulmonary disease (e.g. lung fibrosis, primary bronchiectasis, sarcoidosis, interstitial lung disorder, pulmonary hypertension).

Other protocol-defined inclusion/exclusion criteria may apply
D: Inclusion Criteria:

1. The patient has signed an Informed Consent Form in accordance with GCP and local legislative requirements prior to participation in the trial, i.e., prior to pre-trial washout of any restricted medications.
2. The patient has a clinical diagnosis of chronic obstructive pulmonary disease (COPD).
3. The patient has relatively stable, moderate to severe airway obstruction.
4. The patient has a pre-bronchodilator forced expiratory volume in the first second (FEV1) less than or equal to 65% of predicted normal determined at Visit 1 using the following predicted equations (R94-1408):

   1. Males Forced expiratory volume in the first second (FEV1) predicted \[Litres (L)\] = 4.30 x Height \[metres\] minus 0.029 x Age \[years\] minus 2.49
   2. Females Forced expiratory volume in the first second (FEV1) predicted \[Litres (L)\] = 3.95 x Height \[metres\] minus 0.025 x Age \[years\] minus 2.60 and a Thoracic Gas Volume (Functional residual volume) ((TGV)(FRC)) bigger than 120% predicted normal at visit 1 (or historical data not older than 6 month)
   3. Males Thoracic Gas Volume (Functional residual volume) ((TGV(FRC)) pred. \[Litres (L)\] = 2.34 x Height \[metres\] + 0.009 x Age \[years\] minus 1.09
   4. Females Thoracic Gas Volume (Functional residual volume) ((TGV(FRC)) pred. \[Litres (L)\] = 2.24 x Height \[metres\] + 0.001 x Age \[years\] minus 1.00
5. The patient is at least 40 years and less than or equal to 75 years old.
6. The patient has a cigarette smoking history of at least 10 pack-years. A pack-year is defined as the equivalent of smoking one pack of cigarettes per day for a year.
7. The patient is able to perform all specified procedures and able to maintain all necessary records during the study period as required in the protocol.
8. The patient is able to inhale the trial medication from the HandiHaler device.
9. The patient is able to inhale the trial medication from the Diskus/Accuhaler device.

Exclusion Criteria:

1. a significant disease other than chronic obstructive pulmonary disease (COPD). (review contraindications for exercise testing),
2. a recent history of myocardial infarction within one year.
3. a recent history of heart failure, pulmonary oedema, or patients with cardiac arrhythmia or any contraindication to exercise described in the CTProtocol within the last 3.
4. daytime supplemental oxygen.
5. a diagnosis of known active tuberculosis.
6. a history of cancer within the last 5 years.
7. a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or bronchiectasis.
8. thoracotomy with pulmonary resection.
9. an upper respiratory tract infection or an exacerbation of chronic obstructive pulmonary disease (COPD)
10. a known hypersensitivity to anticholinergic drug, ß-adrenergic or corticosteroids, lactose or any other component of the inhalation capsule delivery system.
11. a known symptomatic prostatic hypertrophy or bladder neck obstruction.
12. a known moderate or severe renal insufficiency.
13. a known narrow-angle glaucoma.
14. a known untreated hypokalemia.
15. a known untreated thyrotoxicosis.
16. a history of asthma, allergic rhinitis or atopy, or a total blood eosinophil count larger than 600/mm3.
17. treatment with cromolyn sodium or nedocromil sodium
18. treatment with antihistamines or antileukotrienes.
19. treatment with tiotropium for 1 month before Visit 1.
20. treatment with oral corticosteroid medication.
21. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception
22. a history of or active alcohol or drug abuse.
23. an investigational drug within 1 month or 10 half lives
24. a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea.
25. participation in a rehabilitation program for chronic obstructive pulmonary disease (COPD).
26. treatment with monoamine oxidase inhibitors inhibitors or tricyclic antidepressants.
27. participation in another study.
28. more than eight puffs of salbutamol/day during the run-in period

Answer: B