Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 52-week Treatment, Multi-center, Randomized, Double-blind, Double Dummy, Parallel-group, Active Controlled Study to Compare the Effect of QVA149 (Indacaterol Maleate / Glycopyrronium Bromide) With Salmeterol/Fluticasone on the Rate of Exacerbations in Subjects With Moderate to Very Severe COPD. (FLAME).
Brief Summary: This study will assess the efficacy, safety and tolerability of QVA149 in patients with moderate to very severe COPD.


Options:
A: Inclusion Criteria:

* Male and female adults aged ≥ 40 years
* Patients with moderate COPD according to the GOLD criteria 2013
* Current or ex-smokers who have a smoking history of at least 10 pack years
* Patients with airflow limitation indicated by a postbronchodilator FEV1 ≥50% and \<80% of the predicted normal value and a post-bronchodilator FEV1/FVC \<0.7 at Visit 2. Post- bronchodilator refers to within 10-15 min of inhalation of 400 μg (4x100 μg) of salbutamol
* Patients who, at Visit 1, have been for at least 3 months on a stable dose of one of the following COPD baseline treatments: \*Any SABA monotherapy (such as, but not limited to, salbutamol) \*Any SAMA monotherapy (such as, but not limited to, ipratropium) \*Any SABA and SAMA in free or FDC (such as, but not limited to, salbutamol/ipratropium) \*Any LABA monotherapy (such as, but not limited to, formoterol, salmeterol, indacaterol) \*Any LAMA monotherapy (such as, but not limited to, tiotropium, aclidinium) except glycopyrronium bromide (NVA237) \*Any LABA and ICS in free (ICS such as, but not limited to, beclomethasone, fluticasone) or FDC (such as, but not limited to, salmeterol/fluticasone, formoterol/budesonide).
* Patients with an mMRC score ≥1 at Visit 1.

Exclusion Criteria:

* Patients with conditions contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or to drugs of similar chemical classes or any component thereof: Anti-cholinergic agents, Long- and short-acting 2-adrenergic agonists, Sympathomimetic amines, Lactose or any of the other excipients of the trial medication.
* Patients with narrow-angle glaucoma or urinary retention, severe renal impairment (history of estimated glomerular filtration rate below 30 ml/min/1.73 m2 within 12 months prior to visit 1), including those with end-stage renal disease requiring dialysis.
* Patients with active/ clinical history of asthma.If the Investigator finds clear and compelling evidence that a patient was misdiagnosed with asthma in the past, then the burden of proof is on the Investigator to properly document this previous misdiagnosis. This documentation must include the rationale for this change in diagnosis including reference to the differential diagnosis that supports this decision.
* Patients with a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
* Patients who have a post-bronchodilator FEV1 decrease more than 10% compared to pre-bronchodilator FEV1 result at Visit 2 (see Appendix 5 for details).
* A documented history of \>1 COPD exacerbation requiring treatment with systemic corticosteroids or antibiotics and/or hospitalization in the previous 12 months.
* Patients who have NOT had a COPD exacerbation in the previous 12 months and develop a COPD exacerbation between screening (Visit 1) and (Visit 2) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation. (Patients suffering an exacerbation between Visit 1 and Visit 2 can only be re-screened in case it is the first one in the previous 12 months. In case this COPD exacerbation has led to an alteration of the patient COPD treatment, before this patient can be re-screened 3 months of stable COPD treatment will be required as described in Inclusion Criterion 6).
* Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to): \*Unstable ischemic heart disease, left ventricular failure (NYHA Class III \& IV), history of myocardial infarction,arrhythmia (excluding chronic stable atrial fibrillation). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study.\*Uncontrolled hypo-or hyperthyroidism, hypokalaemia or hyperadrenergic state. \*Any condition which might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study
* History of resting QTc (Fridericia preferred, but Bazett acceptable) \>450 msec (male) or \>460 msec (female) within five years before Visit 1.
* Patients who are treated with glycopyrronium bromide (NVA237) at visit 1 are not allowed to be included into the trialPatients on non-selective beta-blockers. Those patients may enter the study after non-selective beta-blocker withdrawal during a 7-day wash-out period.
* Patients receiving any other prohibited COPD-related medications specified in Table 5-2 Prohibited COPD related medications must undergo the required wash-out period prior to Visit 2.
* Patients who are, in the opinion of the investigator known to be unreliable or non-compliant.
* Patients with a body mass index (BMI) of more than 40 kg/m2.
* Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer.
* 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 hCG laboratory test.
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
B: Inclusion Criteria:

* Written informed consent must be obtained before any assessment is performed.
* Male and female ≥ 40 years
* Current or ex-smokers who have a smoking history of at least 10 pack years (Ten pack years are defined as 20 cigarettes per day for 10 years or 10 cigarettes per day for 20 years). An ex-smoker is defined as a patient who has not smoked for ≥ 6 months at visit 1
* Confirmed diagnosis of COPD and post-bronchodilator FEV1 ≥ 30% and \< 80% of the predicted normal value and post-bronchodilator FEV1/FVC \< 0.70 at visit 1
* Treated with salmeterol/fluticasone 50/500 µg b.i.d. for at least 3 months prior to visit 1
* Documented CAT score of ≥ 10 at Visit 1 and 2

Exclusion Criteria:

* Treatment with any LAMA in the 2 weeks prior to visit 1
* Presence of any contraindication, warning, precaution, hypersensitivity in the approved prescribing information for salmeterol/fluticasone
* Prior or current diagnosis of asthma
* More than one COPD exacerbation requiring treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the year prior to Visit 1
* Patients who developed a COPD exacerbation of any severity within the 6 weeks before the screening (Visit 1) or between screening (Visit 1) and start of treatment (Visit 2) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation
* Respiratory tract infection within 4 weeks prior to Visit 1
* Respiratory tract infection between Visit 1 and 2. Patients can be re-screened 4 weeks after resolution of the infection
* Requiring oxygen therapy prescribed for \>12 hours per day
* Onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years
C: Inclusion Criteria:

* Written informed consent must be obtained before any assessment is performed
* Male or female adults aged ≥40 years
* Patients with stable Chronic Obstructive Pulmonary Disease ( COPD) according to the current GOLD strategy (GOLD 2011)
* Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years)
* Patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥25 and \< 60% of the predicted normal value, and post-bronchodilator FEV1/FVC (Forced Vital Capacity) \< 0.70 at day -28. (Post refers to 1 hour after sequential inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol)
* A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics
* Patients taking stable COPD medication (at least 60 days) prior to day 28
* Patients with an mMRC grade of at least 2 at day 28

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 hCG (human Chorionic Gonadotropin) laboratory test
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
* Patients with Type I or uncontrolled Type II diabetes
* Patients with a history of long QT syndrome or whose QTc measured at day 28 (Fridericia method) is prolonged (\>450 ms for males and females) and confirmed by a central assessor. These patients should not be re-screened
* Patients who have a clinically significant ECG abnormality prior to randomization. (These patients should not be re-screened)
* Patients who have a clinically significant laboratory abnormality at screening
* Patients who have clinically significant renal, cardiovascular (such as but not limited to unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial infarction), arrhythmia (see below for patients with atrial fibrillation), neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities which could interfere with the assessment of the efficacy and safety of the study treatment
* Patients with paroxysmal (e.g. intermittent) atrial fibrillation are excluded
* Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at both pre-randomization visits, with a resting ventricular rate \< 100/min. At screening the atrial fibrillation must be confirmed by central reading
* Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof: anticholinergic agents, long and short acting beta-2 agonists, sympathomimetic amines, lactose or any of the other excipients of trial medication
* Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin
* Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. Benign Prostatic Hyperplasia (BPH) patients who are stable on treatment can be considered
* Patients who have not achieved an acceptable spirometry results at screening in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability (one retest may be performed for patients that don't meet the acceptability criteria)
* Patients who have had a COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to screening
* Patients who develop a COPD exacerbation of any severity (mild/moderate/severe) between screening and treatment will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation
* Patients who have had a respiratory tract infection within 4 weeks prior to screening
* Patients who develop a respiratory tract infection between screening and prior to treatment will not be eligible, but will be permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection
* Patients requiring long term oxygen therapy prescribed for \>12 hours per day
* Patients with any history of asthma
* Patients with an onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years
* Patients with a blood eosinophil count \> 600/mm3 at screening
* Patients with allergic rhinitis who use a H1 antagonist or intra-nasal corticosteroids intermittently (treatment with a stable dose or regimen is permitted)
* Patients with concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension)
* Patients with clinically significant bronchiectasis
* Patients with a diagnosis of α-1 anti-trypsin deficiency
* Patients with active pulmonary tuberculosis, unless confirmed by imaging to be no longer active
* Patients with pulmonary lobectomy or lung volume reduction surgery or lung transplantation
* Patients participating in or planning to participate in the active phase of a supervised pulmonary rehabilitation program during the study. (Maintenance program is permitted.)
* Patients receiving any medications in the classes listed in the protocol
* Patients receiving any COPD related medications in the classes specified in the protocol must undergo the required washout period prior to screening and follow the adjustment to treatment program
* Use of other investigational drugs/devices (approved or unapproved) at the time of enrollment, or within 30 days or 5 half-lives of screening, whichever is longer
* Patients unable to use an electronic patient diary and EXACT pro diary
* Patients unable to use a dry powder inhaler device, Metered Dose Inhaler (MDI) or a pressurized MDI (rescue medication) or comply with the study regimen.
D: 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

Answer: C