Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 12 Month Open-label Randomized Parallel Group Study to Investigate the Influence of Salmeterol Xinafoate/Fluticasone Propionate Either in Fixed Combination or Separately Via Diskus Inhalers on the Course of the Disease and Frequency of Exacerbations in Subjects With Severe and Very Severe COPD.
Brief Summary: This is a 12 month randomized, open-label, parallel-group study to obtain data on the frequency and variability of exacerbations in severe and very severe Chronic Obstructive Pulmonary Disease (COPD) patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage III and IV) receiving salmeterol xinafoate and fluticasone propionate either in fixed combination (SFC) or from separate inhalers (Sal/FP) with standard therapy. 200 subjects will be enrolled in approximately 30 study centres in Germany. Data on health care utilisation will be collected to compare direct costs associated with COPD in these two groups.

Baseline data will be collected for all subjects at Visit 1 and eligible subjects will be randomized to receive either SFC 50/500 µg bid (twice daily) as fixed combination or Sal 50 µg bid (twice daily) and FP 500 µg bid (twice daily) concurrently over 52 weeks. Subjects will return for study visits every two to three months until week 52. Additional telephone calls will be made between scheduled visits every 4 weeks. Assessments will include monitoring of frequency of exacerbations, health care utilisation (including emergency visits and hospitalizations) and rescue medication, lung function, drug compliance, health-related quality of life (SGRQ = St George's Respiratory Questionnaire) and safety.


Options:
A: Inclusion Criteria:

Patients with stable COPD according to the current GOLD guidelines (GOLD 2013). Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack /day x 10 yrs, or ½ pack/day x 20 yrs)..

Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥40% and \<80% of the predicted normal, and a post-bronchodilator FEV1/FVC \<0.70

Exclusion Criteria:

Patients with conditions 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, anticholinergics, long and short acting beta2 agonists, sympathomimetic amines, lactose or any of the other excipients Patients who have a clinically significant ECG abnormality at Visit 1, who in the judgment of the investigator would be at potential risk if enrolled into the study.

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., 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 baseline and screening visits, with a resting ventricular rate \< 100/min.

Patients with Type I or uncontrolled Type II diabetes and patients with a history of blood glucose levels consistently outside the normal range Patients with narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention.

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 non-melanoma skin carcinoma may be considered for the study.

Patients with a body mass index (BMI) of more than 40 kg/m2. Women who are pregnant or breast feeding Patients requiring long term oxygen therapy on a daily basis for chronic hypoxemia.

Patients who have had a COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization in the 6 weeks prior to screening.

Patients who have had a respiratory tract infection within 4 weeks prior to screening.

Patients with any history of asthma. Patients with concomitant pulmonary disease Patients with clinically significant bronchiectasis. Other protocol-defined inclusion/exclusion criteria may apply
B: Inclusion Criteria:

* Diagnosis of COPD
* 10 pack-year or greater history of cigarette smoking
* Post-bronchodilator FEV1/FVC of \<0.7
* Predicted FEV1 of 70% of normal or less
* Modified Medical Research Council (mMRC) dyspnea score of 2 or greater

Exclusion Criteria:

* Women who are pregnant, lactating, or planning to become pregnant
* Respiratory disorders other than COPD, including a current diagnosis of asthma
* Clinically significant non-respiratory diseases or abnormalities that are not adequate controlled
* Significant allergy or hypersensitivity to anticholinergics, beta-agonist, or the excipients of magnesium stereate or lactose used in the inhaler delivery device
* Hospitalization for COPD or pneumonia within 12 weeks prior to screening
* Lung volume reduction surgery within 12 weeks prior to screening
* Abnormal and clinically significant ECG findings at screening
* Clinically significant laboratory findings at screening
* Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong cytochrome P450 3A4 inhibitors, high dose inhaled steroids (\>1000mcg fluticasone propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short- and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or nedocromil sodium, or investigational medicines for defined time periods prior to the screening visit
* Use of long-term oxygen therapy (12 hours or greater per day)
* Regular use of nebulized treatment with short-acting bronchodilators
* Participation in the acute phase of a pulmonary rehabilitation program
* A know or suspected history of alcohol or drug abuse
* Affiliation with the investigational site
* Previous use of GSK573719 or GW642444 alone or in combination, including the combination of fluticasone furoate and GW64244
C: Inclusion criteria:

* Subject must have a diagnosis of COPD based on the American Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria.
* Male or female subjects, aged \>=40 years. Females must be of Non Child Bearing Potential. The definition of Non Child Bearing Potential is as following: Females, regardless of their age, with functioning ovaries and who have a current documented tubal ligation or hysterectomy, or females who are post-menopausal.
* Have diagnosed COPD stage III or IV according to GOLD criteria: a baseline post-bronchodilator Forced Expiratory Volume, measured at 1 second (FEV1) \<50% of predicted normal and a baseline post- bronchodilator FEV1/Inspiratory Vital Capacity (IVC) ratio \<70%.
* Have experienced at least 2 moderate or severe COPD exacerbations leading to medical consultation (requiring oral corticosteroids or increasing dosage of oral corticosteroids and/or antibiotics or hospitalization) within the 12 months preceding Visit 1.
* Have stable COPD medication within 4 weeks prior to Visit 1 (no new medication added and no dosage changes in medication).
* Current or ex-smokers with a smoking history of at least 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).
* Are currently managed at home (outpatients), are ambulatory and able to travel to the clinic. Subjects can be treated with all relevant COPD medication. This includes vaccines, inhaled short-acting beta-2-agonists as needed, short-acting or long-acting anticholinergics (tiotropium), systemic beta-2-agonists, theophylline, mucolytics, antioxidants, beta-1-agonists (for cardiovascular indication), non-invasive ventilation, long term oxygen therapy and can have Cor Pulmonale.
* A signed and dated written informed consent is obtained prior to participation.
* Able to comply with the requirements of the protocol and be available for study visits over 52 weeks.

Exclusion criteria:

* Known other respiratory disorders or signs for other respiratory disorders (e.g. asthma, lung cancer, sarcoidosis, tuberculosis, lung fibrosis, cystic fibrosis, bronchoectasis).
* Known history of significant inflammatory disease, other than COPD (e.g. rheumatoid arthritis and systemic lupus erythematosus).
* Known to be severely alpha-1-antitrypsin deficient (PI SZ or ZZ)
* Having undergone lung surgery (e.g. lung resection including lung volume reduction surgery, lung transplant) or subjects scheduled for surgery.
* Concurrent medication from Visit 1 and for the duration of the study with any of the prohibited medications: monoamine oxidase inhibitors and tricyclic antidepressants, and ritonavir (a highly potent cytochrome P450 3A4 inhibitor).
* Subjects receiving chronic or prophylactic antibiotic therapy.
* Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study or impact on subject safety.
* Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse.
* History of depression.
* History or presence of clinically significant drug sensitivity or clinically significant allergic reaction to corticosteroids or salmeterol.
* Moderate or severe COPD exacerbation (requiring corticosteroids or increased dosage of corticosteroids and/or antibiotics or hospitalization) within the 4 weeks prior to Visit 1
* Lower respiratory tract infection within the 4 weeks prior to Visit 1 .
* Pregnant or lactating female and female of childbearing potential.
* Subject is a participating investigator, sub-investigator, study coordinator, or other employee of a participating investigator, or is an immediate family member of the before mentioned. Subject is an employee of GlaxoSmithKline (GSK).
* Subject participated in an investigational drug study within 30 days prior to Visit 1
D: Inclusion criteria:

1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions.
2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:

   Patients must have relatively stable airway obstruction with, at visit 1:

   a post-bronchodilator 30% \<= FEV1 \<80% of predicted normal (ECSC) and a post-bronchodilator FEV1/FVC \<70% at Visit 1
3. Male or female patients, between 40 and 75 years (inclusive) of age on day of signing informed consent.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years Patients who have never smoked cigarettes must be excluded.
5. Patients must be able to perform technically acceptable pulmonary function tests (spirometry), must be able to complete multiple symptom-limited cycle ergometry tests (and for a subset also shuttle walk tests), as required in the protocol.
6. Patients must be able to inhale medication in a competent manner from the RESPIMAT inhaler and from a metered dose inhaler (MDI).

Exclusion criteria:

1. Patients with a significant disease other than COPD
2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT \> x2 ULN, SGPT \> x2 ULN, bilirubin \> x2 ULN or creatinine \> x2 ULN will be excluded regardless of clinical condition
3. Patients with a history of asthma
4. A diagnosis of thyrotoxicosis
5. A diagnosis of paroxysmal tachycardia (\>100 beats per minute)
6. A history of myocardial infarction within 1 year of screening visit (Visit 1)
7. Unstable or life-threatening cardiac arrhythmia
8. Hospitalized for heart failure within the past year
9. Known active tuberculosis
10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years
11. A history of life-threatening pulmonary obstruction and patients with chronic respiratory failure
12. A history of cystic fibrosis
13. Clinically evident bronchiectasis
14. A history of significant alcohol or drug abuse
15. Any contraindications for exercise testing
16. Patients who have undergone thoracotomy with pulmonary resection
17. Patients being treated with any oral ß-adrenergics
18. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day
19. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits
20. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program
21. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea or morbid obesity
22. Patients with an endurance time \>=25 minutes during the training (Visit 2) or baseline (Visit 3) constant work rate cycle ergometry
23. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1)
24. Patients with known hypersensitivity to ß-adrenergic drugs, anticholinergic drugs, BAC, EDTA or any other component of the RESPIMAT inhalation solution delivery system
25. Pregnant or nursing women
26. Women of childbearing potential not using a highly effective method of birth control.

    Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years
27. Patients who have previously been randomized in this study or are currently participating in another study
28. Patients who are unable to comply with pulmonary medication restrictions prior to randomization

    At sites performing the shuttle walk tests, patients with the following criteria will be excluded from the shuttle walk tests:
29. Patients who complete level 12 at the incremental shuttle walk test at visit 1a.
30. Patients with an endurance time \>=15 minutes during the training (Visit 2a) or baseline (visit 3a) endurance shuttle walk test.

Answer: C