Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double-blind, Double-dummy, Active-controlled Study Evaluating the Efficacy, Safety and Tolerability of Twice-daily Aclidinium Bromide/Formoterol Fumarate Compared With Twice-daily Salmeterol/Fluticasone Propionate for 24 Weeks Treatment in Symptomatic Patients With Chronic Obstructive Pulmonary Disease (COPD)
Brief Summary: The purpose of the study is to compare the efficacy, safety and tolerability of aclidinium bromide/formoterol fumarate and salmeterol/fluticasone propionate in patients with chronic obstructive pulmonary disease (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:

* 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
C: Inclusion Criteria

* Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to acceptable contraceptive methods used consistently and correctly for the duration of the study.
* Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS),
* Current or former smokers with a history of at least 10 pack-years of cigarette smoking.
* Forced expiratory volume in 1 second (FEV1)/Forced vital capacity (FVC) ratio must be \<0.70 and FEV1 must be \<65% predicted normal value calculated using NHANES III reference equations (or reference norms applicable to other regions).
* Subjects with history of exacerbations.

Please refer to the study protocol for the complete inclusion criteria list.

Exclusion Criteria

* Significant diseases or conditions other than COPD, which, in the opinion of the Investigator, may put the subject at risk because of participation in the study or may influence either the results of the study or the subject's ability to participate in the study.
* Women who are pregnant or lactating, or are planning to become pregnant during the course of the study, or women of childbearing potential who are not using an acceptable method of contraception.
* Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma.
* Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening)
* Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening)
* Immune suppression or severe neurological disorders affecting control of the upper airway or other risk factors that in the opinion of the Investigator would put the subject at substantial risk of pneumonia.
* Subjects with a diagnosis of narrow angle glaucoma, who, in the opinion of the Investigator, have not been adequately treated.
* Subjects who have a history of hypersensitivity to β2-agonists, budesonide or any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or any other component of the IMPs.

Please refer to the study protocol for the complete inclusion criteria list.
D: Inclusion Criteria:

* Type of subject: Outpatient
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Age: Subjects 40 years of age or older at Visit 1.
* Gender: Male or female subjects. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Or if of child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods mentioned in the protocol used consistently and correctly:
* Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: COPD is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
* Smoking history: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years \[number of pack years = (number of cigarettes per day/20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack year history.
* Severity of disease: A pre and post-salbutamol FEV1/FVC ratio of \<0.70 and a post-salbutamol FEV1 of \>=30% and \<=70% of predicted normal values calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations at Visit 1.
* Dyspnea: A score of \>=2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* Asthma: A current diagnosis of asthma.
* Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject, who, in the opinion of the investigator, has any other significant respiratory condition in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Inactive tuberculosis in more than one lobe is exclusionary. Allergic rhinitis is not exclusionary.
* Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for \<5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
* Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic.
* Hospitalization: Hospitalization for pneumonia within 12 weeks prior to Visit 1.
* History of COPD Exacerbation: A documented history of at least one COPD exacerbation in the 12 months prior to Visit 1 that required either oral corticosteroids, antibiotics, and/or hospitalization. Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence.
* Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
* 12-Lead electrocardiogram (ECG): An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility.
* Medication Prior to Spirometry: Unable to withhold salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
* Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids - 12 weeks, Systemic, oral or parenteral corticosteroids - 6 weeks, Antibiotics (for lower respiratory tract infection) - 6 weeks, Cytochrome P450 3A4 strong inhibitors - 6 weeks, Herbal medications potentially containing oral or systemic steroids - 6 weeks, Inhaled corticosteroids (ICS) - 30 days, Long-acting beta2-agonist (LABA)/ICS combination products - 30 days, Phosphodiesterase 4 (PDE4) inhibitors (e.g., roflumilast) - 14 days, Inhaled long-acting anticholinergics - 7 days, Olodaterol and Indacaterol - 10days, Theophyllines - 48 hours, Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) - 48 hours, Oral beta2-agonists Long-acting-48 hours/Short-acting - 12 hours, Inhaled long acting beta2-agonists (LABA, e.g., salmeterol, formoterol, indacaterol) - 48 hours, Inhaled sodium cromoglycate or nedocromil sodium - 24 hours, Inhaled short acting beta2-agonists - 4 hours, Inhaled short-acting anticholinergics - 4 hours, Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products - 4 hours, Any other investigational medication - 30 days or within 5 drug half-lives (whichever is longer).
* Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., \<=12 hours per day) is not ex-clusionary.
* Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., salbutamol) via nebulized therapy.
* Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
* Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
* Affiliation with Investigator Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
* Inability to read: A subject will not be eligible for the study if in the opinion of the investigator the subject cannot read.

Answer: B