Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicentre, Randomised, Double-blind, Parallel Group, Placebo-controlled Study to Investigate the Long-term Effects of Salmeterol/Fluticasone Propionate (Seretide tm) 50/500mcg BD, Salmeterol 50mcg BD and Fluticasone Propionate 500mcg BD, All Delivered Via the Diskus tm/Accuhaler tm Inhaler, on Mortality and Morbidity of Subjects With Chronic Obstructive Pulmonary Disease (COPD) Over 3 Years of Treatment
Brief Summary: The purpose of this study is to see if fluticasone 500mcg/salmeterol 50mcg can improve the survival of subjects with COPD and also assess the long term safety profile of this drug.


Options:
A: Inclusion criteria:

* Patients with COPD and FEV1 \<60% of predicted normal and baseline (pre-bronchodilator) FEV1/FVC ratio \<70%.
* Current or ex-smokers with a smoking history of at least 10 pack-years.

Exclusion criteria:

* Diagnosis of other respiratory disorders (including asthma).
* Requirement for long term oxygen therapy.
B: Inclusion Criteria:

* Moderate to severe COPD based on prebronchodilator FEV1/forced vital capacity (FVC) ratio of \<=70%.
* At Screening, postbronchodilator FEV1 must be \<=60% predicted normal \& \>=25% predicted normal.
* COPD symptoms for \>=24 months.
* Ex- or current smoker with smoking history \>=10 pack years.
* Only albuterol/salbutamol for relief for at least 2 weeks prior to randomization.
* Withdraw from parenteral \& oral steroids, anticholinergics, \& antibiotics at least 4 weeks prior to Screening.
* No harm in changing current COPD therapy, willing to discontinue his/her anticholinergics, inhaled corticosteroids (ICS) or ICS/long-acting beta agonists (LABA) at Screening, \& transferred to albuterol/salbutamol for relief for 2 weeks prior to randomization.
* Lab tests conducted at Screening must be acceptable to investigator. Electrocardiogram (ECG) performed at Screening Visit or within 30 days prior to Screening must be acceptable to investigator. Chest x-ray performed at Screening or within 12 months prior to Screening must be acceptable to investigator.
* Women who have

been surgically sterilized or are at least 1 year postmenopausal are not

considered to be of childbearing potential. A female subject of childbearing

potential must have a negative serum pregnancy test at Screening in order to

be considered eligible for enrollment. Female of childbearing potential must use birth control. Includes: hormonal contraceptives, intra-uterine device (IUD), condom in combination with spermicide, monogamous relationship with male partner who had vasectomy. Started birth control at least 3 months prior to Screening (exception condom), \& agree to continue. Female who is not currently sexually active must agree/consent to use a method should she become sexually active. Women surgically sterilized or are at least 1 year postmenopausal are not considered to be of childbearing potential. Female must have negative serum pregnancy test at Screening.

Exclusion Criteria:

* Evidence (upon visual inspection) of oropharyngeal candidiasis at Baseline with or without treatment. If there is evidence at Screening, may be treated as appropriate \& visit can be scheduled upon resolution. If there is evidence at Baseline Visit, may be treated as appropriate \& visit can be rescheduled upon resolution.
* History of renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmological, respiratory, gastrointestinal, cerebrovascular, or other which could interfere with study or require treatment which might interfere with study. Examples include (but are not limited to) hypertension being treated with beta-blockers, active hepatitis, coronary artery disease, arrhythmia, significant QTc prolongation (ie QTcF or QTcB \[Fridericia or Bazett corrections, respectively \>500 milliseconds (msecs)\]), stroke, severe rheumatoid arthritis, chronic open-angle glaucoma or posterior subcapsular cataracts, acquired immune deficiency syndrome (AIDS), or conditions that may interfere with respiratory function such as asthma, bronchiectasis, cystic fibrosis. Others which are well-controlled \& stable (eg hypertension not requiring beta-blockers) will not prohibit participation if deemed appropriate per investigator.
* Allergy/sensitivity to glucocorticosteroids, beta-2 agonists, study drug/excipients.
* Female who is breast-feeding, pregnant, or intends to become pregnant.
* Illicit drug user.
* Human immunodeficiency virus (HIV) positive (testing not conducted).
* Unable to correctly use oral MDI.
* Taking any restricted medications prior to Screening without meeting washout.
* Cannot adhere to permitted concomitant \& prohibited medications.
* May not participate in this same study at another investigational site. Cannot participate in different investigational study at any site, during same time of study.
* Not be randomized into study more than once.
* No person directly associated with administration of study may participate.
* Previously participated in MF/F trial.
* Increase in absolute volume of \>=400 milliliters (mL) at Screening or prior to Baseline within 30 minutes after administration of 4 inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg), or nebulized 2.5 mg albuterol/salbutamol.
* Asthma.
* Blood eosinophil count greater than 0.57 x 10\^3/microliter (uL).
* Lobectomy, pneumonectomy or lung volume reduction surgery.
* Lung cancer.
* Requires long-term administration of oxygen (\>15 hours per day).
* A subject who experiences an exacerbation of COPD requiring medical

intervention within 4 weeks prior to randomization, beta-blocking agents, or

treatment with additional excluded medication (other than short-acting beta agonists (SABA)/short-acting

anticholinergic to be used as rescue medication).

* alpha-1-antitrypsin deficiency.
* Cataract extractions on both eyes.
* A history and/or presence of intraocular pressure in either eye \>=22 millimeters of mercury (mm Hg), glaucoma, and/or posterior subcapsular cataracts. A subject who has undergone incisional or intraocular surgery in which the natural lens is still present in the eye. A subject with a history of penetrating trauma to both eyes. A subject with one or more of the following Lens Opacities Classification System (LOCS) III grades at screening:

nuclear opalescence (NO): \>=3.0,

nuclear color (NC): \>=3.0,

cortical cataract (C): \>=2.0,

posterior subcapsular (P): \>=0.5.
C: Inclusion Criteria:

* Type of subject: outpatient
* Informed consent: Subjects must give their signed and dated written informed consent to participate.
* Gender: Male or female subjects A female is eligible to enter and participate in the study if she is of:
* Non-child bearing potential OR
* Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods defined in the protocol
* Age: ≥40 years of age at Screening (Visit 1)
* COPD diagnosis: Subjects with a clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[Celli, 2004\]
* Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1).
* Severity of Disease: Subjects with a Screening (Visit 1) measured post-albuterol/salbutamol:
* FEV1/FVC ratio of ≤0.70 and
* FEV1 ≤70% of predicted normal values
* Dyspnea: Achieved a score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Screening (Visit 1).

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* Asthma: Subjects with a current diagnosis of asthma
* α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying cause of COPD
* Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases
* Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1)
* Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD.
* Hospitalization: Subjects who are hospitalized due to poorly controlled COPD within 12 weeks of Visit 1.
* Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of the following in the 6 weeks prior to Visit 1: Acute worsening of COPD that is managed by subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician.
* Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1.
* Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular (i.e., pacemaker), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled.
* Peptic Ulcer disease: Subjects with clinically significant peptic ulcer disease that is uncontrolled.
* Hypertension: Subjects with clinically significant hypertension that is uncontrolled.
* Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis.
* Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medication or components of the inhalation powder
* Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
* Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol and/or their ipratropium 4 hours prior to spirometry testing at each study visit
* Additional medication: Use of certain medications such as bronchodilators and corticosteroids for the protocol-specified times prior to Visit 1 (the Investigator will discuss the specific medications)
* Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e., ≤12 hours per day) is not exclusionary.
* Sleep apnea: Subjects with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) device.
* Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening (Visit 1) or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study.
* Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
* Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
* Prior use of study medication/other investigational drugs
* Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.
D: Inclusion Criteria:

* Moderate to severe COPD based on prebronchodilator FEV1/forced vital capacity (FVC) ratio of \<=70%.
* At Screening \& Baseline, postbronchodilator FEV1 must be \>= 60% predicted normal \& \>=25% predicted normal.
* COPD symptoms for \>=24 months.
* \>=2 COPD exacerbations requiring course of oral corticosteroid \&/or antibiotics within 2-12 months before screening.
* Ex- or current smoker with smoking history \>=10 pack years.
* Only albuterol/salbutamol for relief for at least 2 weeks prior to randomization.
* Withdraw from parenteral \& oral steroids, anticholinergics, \& antibiotics 4 weeks prior to Screening.
* No harm in changing current COPD therapy, willing to discontinue his/her anticholinergics, inhaled corticosteroids (ICS) or ICS/long-acting beta agonists (LABA) at Screening, \& transferred to albuterol/salbutamol for relief for 2 weeks prior to Randomization.
* Lab tests conducted at Screening must be acceptable to investigator. Electrocardiogram (ECG) performed at Screening or within 30 days prior to Screening must be acceptable to investigator. Chest X-ray or computerized tomography (CT) scan is acceptable within 12 months prior to Screening must be acceptable to investigator.
* Female of childbearing potential must use birth control. Includes: hormonal contraceptives, intra-uterine device (IUD), condom in combination with spermicide, monogamous relationship with male partner who had vasectomy. Started birth control at least 3 months prior to Screening (exception condom), \& must agree to continue. Female who is not currently sexually active must agree/consent to using a method should she become sexually active. Women who have been surgically sterilized or are at least 1 year postmenopausal are not considered to be of childbearing potential. Female must have negative serum pregnancy test at Screening.

Exclusion Criteria:

* Evidence (upon visual inspection) of oropharyngeal candidiasis at Baseline with or without treatment. If there is evidence at Screening, may be treated as appropriate \& visit can be scheduled upon resolution. If there is evidence at Baseline, may be treated as appropriate \& visit can be rescheduled upon resolution.
* History of renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmological, respiratory, gastrointestinal, cerebrovascular, or other which could interfere with study or require treatment which might interfere with study. Examples include (but are not limited to) hypertension treated with beta-blockers), active hepatitis, coronary artery disease, arrhythmia, significant QTc prolongation (ie QTcF or QTcB \[Fridericia or Bazett corrections, respectively \>500 milliseconds (msecs)\]) stroke, severe rheumatoid arthritis, chronic open-angle glaucoma or posterior subcapsular cataracts, acquired immune deficiency syndrome (AIDS), or conditions that may interfere with respiratory function such as asthma, bronchiectasis, cystic fibrosis. Others which are well-controlled \& stable (eg hypertension not requiring beta-blockers) will not prohibit participation if appropriate to investigator.
* Allergy/sensitivity to glucocorticosteroids, beta-2 agonists, study drug/excipients.
* Female who is breast-feeding, pregnant, or intends to become pregnant.
* Illicit drug user.
* Human immunodeficiency virus (HIV) positive (testing not conducted).
* Unable to correctly use oral MDI.
* Taking any restricted medications prior to Screening without meeting washout.
* Cannot adhere to permitted concomitant \& prohibited medications.
* May not participate in this same study at another investigational site. Cannot participate in different investigational study at any site, during same time.
* Not be randomized into study more than once.
* No person directly associated with administration of study may participate.
* Previously participated in MF/F trial.
* Increase in absolute volume of \>=400 milliliters (mL) at Screening or prior to Baseline within 30 minutes after administration of 4 inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg), or nebulized 2.5 mg albuterol/salbutamol.
* Asthma.
* Lobectomy, pneumonectomy or lung volume reduction surgery.
* Lung cancer.
* Requires long-term administration of oxygen (\>15 hours/day).
* Alpha-1-antitrypsin deficiency.
* A history and/or presence of intraocular pressure in either eye \>=22 millimeters of mercury (mm Hg), glaucoma, and/or posterior subcapsular cataracts. A subject who has undergone incisional or intraocular surgery in which the natural lens is still present in the eye. A subject with a history of penetrating trauma to both eyes. A subject with one or more of the following Lens Opacities Classification System (LOCS) III grades at screening:

  * nuclear opalescence (NO): \>=3.0,
  * nuclear color (NC): \>=3.0,
  * cortical cataract (C): \>=2.0,
  * posterior subcapsular (P): \>=0.5.

Answer: A