Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multicentre, Randomised, Double-Blind, Double Dummy, Parallel Group, 104-week Study to Compare the Effect of the Salmeterol/Fluticasone Propionate Combination Product (SERETIDE*) 50/500mcg Delivered Twice Daily Via the DISKUS*/ACCUHALER* Inhaler With Tiotropium Bromide 18 mcg Delivered Once Daily Via the HandiHaler Inhalation Device on the Rate of Health Care Utilisation Exacerbations in Subjects With Severe Chronic Obstructive Pulmonary Disease (COPD)
Brief Summary: This is a comparator study to assess the relative efficacy of the combination product fluticasone propionate/salmeterol 50/500 and tiotropium bromide on the rate of exacerbations of chronic obstructive pulmonary disease (COPD) over a two year study interval.


Options:
A: Inclusion Criteria:

* Prior to participation in the study all patients must sign and date an informed consent consistent with ICH-GCP guidelines.
* Male or female patients 40 years of age or older.
* Patients with a diagnosis of COPD according to BTS criteria..A stable disease state with airway obstruction of FEV1 between 30- 65% of predicted normal value and FEV1 /FVC\<70% pre bronchodilators.
* Predicted normal values will be calculated according to ECCS:
* For height measured in metres

  * Males: FEV1 predicted (L) = 4.30 X (Ht in mts) - 0.029 X (Age in yrs) - 2.49
  * Females:FEV1 predicted (L) = 3.95 X (Ht in mts) - 0.025 X (Age in yrs) - 2.60
* For height measured in inches

  * Males: FEV1 predicted (L) = 4.30 X (Ht in inches/39.37) - 0.029 X (Age in yrs) - 2.49
  * Females:FEV1 predicted (L) = 3.95 X (Ht in inches/39.37) - 0.025 X (Age in yrs) - 2.60
* Maintained on a stable respiratory medication for 4 weeks prior to visit 1 (no changes in respiratory medication oral dosage).
* Currently taking salbutamol or terbutaline MDI or DPI.
* Patient must be able to inhale medication through the HandiHaler?
* Patients must be able to perform technically acceptable pulmonary function tests in accordance with ATS criteria and must be able to maintain records (Patient Daily Record) during the study period as required in the protocol.
* Patients must be current or ex-smokers with a smoking history of more than 10 pack years.
* Pack Years = Number of cigarettes/day 20 (Patients who have never smoked cigarettes must be excluded.)

NOTE: An exacerbation of COPD requiring treatment occurring within the four week period prior to screening visit 1 will mean that screening should be postponed for at least four weeks. Therefore, the patient should have duration of at least 4 weeks free of exacerbations.

Exclusion Criteria:

* Patients with significant diseases, other than COPD will be excluded. A significant disease is defined as a disease which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study.
* Patients who have taken inhaled anticholinergics in the previous 12 months. Patients that have been treated with inhaled anticholinergics (via nebuliser or metered dose inhaler) due to an exacerbation for a time period no longer than 7 days may be included.
* Patients with an upper respiratory tract infection or exacerbation of COPD requiring treatment in the four weeks prior to the screening visit (visit 1) or during the two-week run-in period.

Patients with a recent history (i.e., six months or less) of myocardial infarction.

* Any unstable or life threatening cardiac arrhythmia requiring intervention or a change in drug therapy within the last year.
* Patients with known active tuberculosis.
* Patients who have a history of thoracotomy with pulmonary resection or have planned lung transplantation or lung volume reduction surgery.
* Patients with a history of asthma, cystic fibrosis, bronchiectasis, interstitial lung disease or pulmonary thromboembolic disease.
* Patients who are being treated with antihistamines (H1 receptor antagonists) for asthma or excluded allergic conditions.
* Patients with a history of cancer in the last five years; Basal cell tumours or patients whose length of time in remission is greater than five years can be included.
* Patient with known hypersensitivity to atropine, and other anticholinergic drugs or lactose or any previous adverse reaction to anticholinergic drugs that resulted in withdrawal of the anticholinergic compound.
* Patients using oral corticosteroid medication at unstable doses (i.e. Patients have been on a stable dose for less than 6 weeks prior to randomisation) or at doses in excess of the equivalent of 10mg o
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:

* Established clinical history of moderate to severe COPD.
* Post bronchodilator FEV1 of \< 50% of predicted normal.
* FEV1 / FVC ratio \<70%.
* Reversibility to 400mcg albuterol of less or equal to 10 predicted at Visit 1.
* Free from exacerbation in the 6 weeks prior to screening.
* Current or former smoker with a smoking history of = 10 pack-years and has a history of COPD exacerbations.

Exclusion criteria:

* Current asthma, eczema, atopic dermatitis and/or allergic rhinitis.
* Has a known respiratory disorder other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis).
* Has narrow-angle glaucoma, prostatic hyperplasia or obstruction of the neck of the bladder that in the opinion of the investigator should prevent the subject from entering the study.
* Has undergone lung transplantation and/or lung volume reduction.
* Female who is a nursing mother.
* Requires regular (daily) long-term oxygen therapy (LTOT).
* Is receiving beta-blockers (except eye drops).
* Has a serious, uncontrolled disease likely to interfere with the study.
* Has received any other investigational drugs within the 4 weeks prior to Visit 1.
* Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse.
* Has a known or suspected hypersensitivity to beta2-agonists, inhaled corticosteroids, anticholinergic agents or any components of the formulations (e.g. lactose or milk protein).
D: Main Inclusion criteria: 1.Diagnosis of chronic obstructive pulmonary disease. 2.Patient is male or female, age \<=than 40 years. 3. Patient has a smoking history of \<=10 pack-year.4.Patient is able to be trained in the proper use of HandiHaler 5.Patient is able to be trained to perform technically satisfactory spirometry and must be able to maintain records during the study period as required by the protocol. 6.Patient must be willing and able to sign informed consent prior to participation in the study i.e. prior to washout of their usual pulmonary medications.

Main exclusion criteria 1.History of asthma, allergic rhinitis or atopy. 2. A lower respiratory tract infection or any COPD exacerbation in the past 4 weeks prior to Visit 1 or during the two week Screening Period 3.History of life threatening bronchial obstruction, cystic fibrosis or bronchiectasis 4. Oral corticosteroid medication if initiated or modified within the last 6 weeks prior to Visit 1 or if daily dose \> 10 mg prednisone or 20 mg or more every other day (or equivalent). 5.Patients who have started or stopped an exercise rehabilitation program within 4 weeks of visit 6.Patients who regularly use daytime oxygen therapy for more than one hour per day and who, in the investigator's opinion, will be unable to abstain from the use of oxygen therapy during testing. 7. Patients who have undergone thoracotomy with pulmonary resection or lobectomy (lung volume reduction surgery). 8.Tuberculosis with indication for treatment. 9. Recent history (i.e. 6 months or less) of myocardial infarction.10. Patients with known moderate or severe renal insufficiency.11. Patients with symptomatic prostatic hypertrophy or bladder neck obstruction. 12.Patients with known narrow-angle glaucoma.13.History of unstable arrhythmia with a life threatening event or change of therapy during the past year.14. History of cancer, other than treated basal cell carcinoma, within the last 5 years 15.Intolerance to anticholinergic containing products, and/or to lactose or any other components of the inhalation capsule delivery system.16.Patients who are being treated with beta-blockers including eye drops.17.Patients who are being treated with antihistamines (H1 receptor antagonists), for asthma or excluded allergic conditions (See Exclusion Criteria No.2).18.Patients who are being treated with monoamine oxidase inhibitors or tricyclic antidepressants.19. Patients who are being treated with oral beta-adrenergics.20. Patients who have taken cromolyn sodium or nedocromil sodium within 1 month of Visit 1.21.Patients who have taken antileukotrienes or leukotriene receptor antagonists within 1 month of Visit 1. 22.Concomitant or recent (within the last month or 6 half lives, whichever is greater) use of investigational drugs prior to the screening visit (Visit 1). 23. Significant alcohol or drug abuse within the past 12 months. 24. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception.24. Previous participation in this study (i.e. randomized).26. Patients who have taken commercially available Spiriva. 27.History of any clinically significant disease, defined as a disease which in the opinion of the investigator may the patient at risk because of participation in the study OR a disease which may influence the results of the study OR the patient's ability to participate in the study.

Answer: C