Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, 52 Week, Randomized, Double-blind, 3-arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination FF/UMEC/VI With the Fixed Dose Dual Combinations of FF/VI and UMEC/VI, All Administered Once-daily in the Morning Via a Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease
Brief Summary: The study evaluates the efficacy of fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) to reduce the annual rate of moderate and severe exacerbations compared with dual therapy of FF/VI or UMEC/VI in subjects with COPD. Published studies which assessed the use of an 'open' triple therapy (use of Inhaled Corticosteroid \[ICS\]/ Long-acting Muscarinic Receptor Antagonists \[LAMA\])/ Long Acting Beta-Agonist \[LABA\] delivered via multiple inhalers) in moderate-severe COPD patients, reported improvements in lung function, Health Related Quality of Life (HRQoL), hospitalization rates and rescue medication use, compared to dual therapy (ICS/LABA) or LAMA alone. These studies have also shown similar safety profile with dual or monotherapy doses for periods of up to one year. Given the clinical experience with FF, UMEC and VI, and that the associated risks with these compounds are anticipated from their known pharmacology, the potential benefit of a new therapy option in patients with moderate to severe COPD supports the further development of the closed triple combination (delivered via one inhaler). In the current study subjects meeting all inclusion/exclusion criteria will complete 2-week run-in period; 52 week treatment period and a 1-week safety follow-up period. Eligible subjects will be randomized to one of the following double-blind treatment groups FF/UMEC/VI 100 micrograms (mcg)/62.5 mcg/25 mcg once daily (QD), FF/VI 100 mcg/25 mcg QD, or UMEC/VI 62.5 mcg/25 mcg QD


Options:
A: Inclusion Criteria:

1. The patient has signed an Informed Consent Form in accordance with GCP and local legislative requirements prior to participation in the trial, i.e., prior to pre-trial washout of any restricted medications.
2. The patient has a clinical diagnosis of chronic obstructive pulmonary disease (COPD).
3. The patient has relatively stable, moderate to severe airway obstruction.
4. The patient has a pre-bronchodilator forced expiratory volume in the first second (FEV1) less than or equal to 65% of predicted normal determined at Visit 1 using the following predicted equations (R94-1408):

   1. Males Forced expiratory volume in the first second (FEV1) predicted \[Litres (L)\] = 4.30 x Height \[metres\] minus 0.029 x Age \[years\] minus 2.49
   2. Females Forced expiratory volume in the first second (FEV1) predicted \[Litres (L)\] = 3.95 x Height \[metres\] minus 0.025 x Age \[years\] minus 2.60 and a Thoracic Gas Volume (Functional residual volume) ((TGV)(FRC)) bigger than 120% predicted normal at visit 1 (or historical data not older than 6 month)
   3. Males Thoracic Gas Volume (Functional residual volume) ((TGV(FRC)) pred. \[Litres (L)\] = 2.34 x Height \[metres\] + 0.009 x Age \[years\] minus 1.09
   4. Females Thoracic Gas Volume (Functional residual volume) ((TGV(FRC)) pred. \[Litres (L)\] = 2.24 x Height \[metres\] + 0.001 x Age \[years\] minus 1.00
5. The patient is at least 40 years and less than or equal to 75 years old.
6. The patient has a cigarette smoking history of at least 10 pack-years. A pack-year is defined as the equivalent of smoking one pack of cigarettes per day for a year.
7. The patient is able to perform all specified procedures and able to maintain all necessary records during the study period as required in the protocol.
8. The patient is able to inhale the trial medication from the HandiHaler device.
9. The patient is able to inhale the trial medication from the Diskus/Accuhaler device.

Exclusion Criteria:

1. a significant disease other than chronic obstructive pulmonary disease (COPD). (review contraindications for exercise testing),
2. a recent history of myocardial infarction within one year.
3. a recent history of heart failure, pulmonary oedema, or patients with cardiac arrhythmia or any contraindication to exercise described in the CTProtocol within the last 3.
4. daytime supplemental oxygen.
5. a diagnosis of known active tuberculosis.
6. a history of cancer within the last 5 years.
7. a history of life-threatening pulmonary obstruction, or a history of cystic fibrosis or bronchiectasis.
8. thoracotomy with pulmonary resection.
9. an upper respiratory tract infection or an exacerbation of chronic obstructive pulmonary disease (COPD)
10. a known hypersensitivity to anticholinergic drug, ß-adrenergic or corticosteroids, lactose or any other component of the inhalation capsule delivery system.
11. a known symptomatic prostatic hypertrophy or bladder neck obstruction.
12. a known moderate or severe renal insufficiency.
13. a known narrow-angle glaucoma.
14. a known untreated hypokalemia.
15. a known untreated thyrotoxicosis.
16. a history of asthma, allergic rhinitis or atopy, or a total blood eosinophil count larger than 600/mm3.
17. treatment with cromolyn sodium or nedocromil sodium
18. treatment with antihistamines or antileukotrienes.
19. treatment with tiotropium for 1 month before Visit 1.
20. treatment with oral corticosteroid medication.
21. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception
22. a history of or active alcohol or drug abuse.
23. an investigational drug within 1 month or 10 half lives
24. a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea.
25. participation in a rehabilitation program for chronic obstructive pulmonary disease (COPD).
26. treatment with monoamine oxidase inhibitors inhibitors or tricyclic antidepressants.
27. participation in another study.
28. more than eight puffs of salbutamol/day during the run-in period
B: Inclusion Criteria:

1. Age from 30 to 40 years or older.
2. Patient with 30%≥ FEV1\<80% predicted and FEV1/FVC \<70% predicted.

Exclusion Criteria:

1. Patients with FEV1\< 30% predicted or FEV1\< 50% predicted plus chronic respiratory failure.
2. Patients with recent chest infection or had been hospitalised for an exacerbation or respiratory infection in the 6 weeks before screening.
3. Patients with history of asthma.
4. Patient with clinically significant condition ex; unstable ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes.
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:

* Informed Consent: A signed and dated written informed consent prior to study participation
* Type of subject: Outpatient
* 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). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, \> 45 years, in the absence of hormone replacement therapy OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to safety follow-up contact): Abstinence; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Estrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS); Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records. Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
* COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society
* Smoking History: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years at screening (visit 1) \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Note: Pipe and/or cigar use cannot be used to calculate pack-year history
* Severity of COPD symptoms: A score of \>=10 on the COPD Assessment Test (CAT) at screening
* Severity of COPD Disease: A post-albuterol/salbutamol FEV1/ Forced Vital Capacity (FVC) ratio of \<0.70 at Screening
* Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening. Note: Subjects receiving only Pro re nata (PRN) COPD medications are not eligible
* History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 \<50% predicted normal and a documented history of \>= 1 moderate or severe COPD exacerbation in the previous 12 months OR a post-bronchodilator 50% \<=FEV1 \< 80% predicted normal and a documented history of \>= 2 moderate exacerbations or a documented history of \>=1 severe COPD exacerbation (hospitalized) in the previous 12 months. Note: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations. Note: A documented history of a COPD exacerbation (e.g., medical record verification) is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation). 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 (color). Subject verbal reports are not acceptable
* Liver function tests: alanine aminotransferase (ALT) \<2x upper limit of normal (ULN); alkaline phosphatase \<=1.5xULN; bilirubin \<=1.5xULN (isolated bilirubin \>1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study
* Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD)
* Alpha1-antitrypsin deficiency: Subjects with Alpha1-antitrypsin deficiency as the underlying cause of COPD
* Other respiratory disorders: Subjects with active tuberculosis, lung cancer, significant 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
* Risk Factors for Pneumonia: immune suppression (e.g. human immunodeficiency virus \[HIV\], Lupus) or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis). Patients at potentially high risk (e.g. very low BMI, severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator
* Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). In addition, any subject that experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in period will be excluded
* Other Respiratory tract infections that have not resolved at least 7 days prior to screening
* Abnormal Chest x-ray(CXR): Chest x-ray (posteroanterior and lateral) reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest x-ray at Screening Visit 1 (or historical radiograph or computerised tomography (CT) scan obtained within 3 months prior to screening) that will be over-read by a central vendor. Note: Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation within 3 months of screening must provide a post pneumonia/exacerbation chest x-ray to be over-read by the central vendor or have a chest x-ray conducted at screening. For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz \[BfS\])
* Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. 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
* Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria
* Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV Heart failure
* Abnormal and clinically significant 12-Lead Electrocardiogram (ECG) finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Principal Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation (AF) with rapid ventricular rate \>120 beats per minute); sustained or nonsustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate (QTcF) \>=500 milliseconds (msec) in patients with QRS \<120 msec and QTcF \>=530 msec in patients with QRS \>=120 msec
* Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, 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 Investigator contraindicates study participation
* Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the subject has been considered cured by treatment
* Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy \>3 Liter/minute (L/min) (Oxygen use =\<3L/min flow is not exclusionary)
* Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit
* Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening or subjects who plan to enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded
* Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
* 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
* Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or study site, or immediate family members of the aforementioned that is involved with this study
* Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials
* Medication prior to screening: Use of the following medications within the following time intervals prior to Screening (Visit 1) or during the study: Long term antibiotic therapy Subjects receiving antibiotics for long term therapy are not eligible for the study (Antibiotics are allowed for the short term treatment of an exacerbation or for short term treatment of other acute infections during the study); Systemic, Oral, parenteral corticosteroids 30 days (Except during the study oral/systemic corticosteroids may be used to treat COPD exacerbations/pneumonia) Intra-articular injections are allowed; Any other investigational drug (30 days or 5 half lives whichever is longer)

Answer: D