Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-blind, Active-controlled, Parallel Group, Stratified, Multi-center, 12-Week Study Comparing the Safety and Efficacy of Fluticasone and Formoterol Combination (FlutiForm™ 250/10ug Twice Daily) in a Single Inhaler (SkyePharma HFA pMDI) With the Administration of Fluticasone (250ug Twice Daily) Alone in SkyePharma HFA pMDI and Flovent® HFA pMDI in Adolescent and Adult Patients With Moderate to Severe Asthma
Brief Summary: The medications being used in this study are individually approved by the Food and Drug Administration (FDA). The medication under investigation is a combination of two medications in one inhaler. The purpose of this study is to determine how well your asthma is controlled when taking one of the three treatment.


Options:
A: Inclusion Criteria

* Subjects must give their signed and dated written informed consent to participate prior to commencing any study related activities.
* Subjects must be outpatients \>=12 years of age at Visit 1 who have had a diagnosis of asthma, as defined by the National Institutes of Health, for at least 12 weeks prior to Visit 1 (Note: Countries with local restrictions prohibiting enrollment of adolescents will enroll subjects \>=18 years of age only).
* Subjects may be male or an eligible female. An eligible female is defined as having non-childbearing potential or having childbearing potential and a negative urine pregnancy test at Screening and agrees to use an acceptable method of birth control consistently and correctly.
* Subjects must have a FEV1 of \>=80% of the predicted normal value.
* Subjects are eligible if they have received mid dose ICS plus LABA (equivalent to FP/salmeterol 250/50 twice daily or an equivalent combination via separate inhalers) for at least the 12 weeks immediately preceding Visit 1.
* All subjects must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at Visit 1 for use, as needed, for the duration of the study. Subjects must be able to withhold albuterol/salbutamol for at least 6 hours prior to study visits.
* If in the opinion of the investigator the subject's asthma is well controlled. Exclusion Criteria
* History of Life-Threatening Asthma, defined for this protocol as an asthma episode that required intubation and/or associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 5 years.
* Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1 and led to a change in asthma management or in the opinion of the Investigator, expected to affect the subject's asthma status or the subject's ability to participate in the study.
* Any asthma exacerbation requiring oral corticosteroids within 12 weeks of Visit 1 or resulting in an overnight hospitalization requiring additional treatment for asthma within 6 months prior to Visit 1.
* A subject must not have current evidence of Atlectasis, Bronchopulmonary dysplasia, Chronic bronchitis, Chronic obstructive pulmonary disease, Pneumonia, Pneumothorax, Interstitial lung disease, or any evidence of concurrent respiratory disease other than asthma
* A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the results if the condition/disease exacerbated during the study.
* A subject must not have used any investigational drug within 30 days prior to Visit 1 or within five half-lives (t½) of the prior investigational study, whichever is longer of the two.
* Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of RELVAR™ ELLIPTA inhaler, SERETIDE™ ACCUHALER/DISKUS inhaler or FP 250.
* History of severe milk protein allergy.
* Administration of prescription or non-prescription medication that would significantly affect the course of asthma, or interact with study drug.
* A subject must not be using or require the use of immunosuppressive medications during the study.
* A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, disease, or geographical location which seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol, including visit schedule and completion of the daily diaries.
* Current tobacco smoker or has a smoking history of 10 pack-years (20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products or inhaled marijuana within the past 3 months (e.g., cigarettes, cigars, electronic cigarettes, or pipe tobacco).
* 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.
B: Main Inclusion Criteria:

* ≥ Age 12 years at the Screening Visit.
* History of asthma for 12 months prior to the Screening Visit.
* Documented use of an inhaled corticosteroid for at least 4 weeks prior to the Screening Visit.
* Steroid-requiring patient
* patients must demonstrate (1) an FEV1 of 40% to 80% (inclusive) of predicted normal values at both the Screening and Baseline Visits and (2) documented reversibility within 12 months of the Screening Visit, defined as a ≥ 15%

Main Exclusion Criteria:

* Life-threatening asthma within the past year or during the Run-In Period.
* History of systemic (oral or injectable) corticosteroid medication within 3 months before the Screening Visit.
* An upper or lower respiratory infection within 4 weeks prior to the Screening Visit or during the Run-In Period.
* Significant, non-reversible, pulmonary disease (e.g., chronic obstructive pulmonary disease \[COPD\], cystic fibrosis, bronchiectasis).
* A smoking history equivalent to "10 pack years" (i.e., at least 1 pack of 20 cigarettes /day for 10 years or 10 packs/day for 1 year, etc.).
* Current smoking history within 12 months prior to the Screening Visit.
* Previous exposure to FlutiForm
C: Inclusion criteria:

1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).
2. Male or female patients aged at least 18 years but not more than 75 years.
3. All patients must have at least a 5-year history of asthma at the time of enrolment into the trial and the diagnosis of asthma must have been made before the patient´s age of 40.
4. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent
5. All patients must have a history of one or more asthma exacerbation in the past year.
6. Patients must have evidence of treated, severe, persistent asthma in postbronchodilator pulmonary function tests.
7. Patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years
8. Patients must be able to use the Respimat® inhaler correctly
9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the electronic diary/peak flow meter.

Exclusion criteria:

1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient´s ability to participate in the trial.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry.
3. Patients with a recent history (i.e. six months or less) of myocardial infarction, hospitalisation for cardiac failure during the past year, any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year, known active tuberculosis, malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (treated basal cell carcinoma allowed), lung diseases other than asthma (e.g. COPD), significant alcohol or drug abuse within the past two years, patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1.
4. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).
5. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day.
6. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
7. Pregnant or nursing women or 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/salpingectomy, or post-menopausal for at least two years.
8. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.
9. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®), beta-blocker medication, oral beta-adrenergics, other non-approved and according to international guidelines not recommended ´experimental´ drugs for routine asthma therapy (e.g. TNF-alpha blockers, methotrexate, cyclosporin) within four weeks prior to the Screening Visit (Visit 1) or during the screening period.
10. Patients with any asthma exacerbation or respiratory tract infection in the four weeks prior to the trial.
11. Patients who have previously been randomised in this trial or in the respective twin trial (205.416 versus 205.417) or are currently participating in another trial.
12. Patients with a known narrow-angle glaucoma.

Note:

As with other anticholinergic drugs, tiotropium should be used with caution in patients with prostatic hyperplasia or bladder neck obstruction.

As with all predominantly renally excreted drugs, patients with moderate to severe renal impairment (known creatinine clearance of \<= 50 mL/min) treated with tiotropium should be monitored closely.
D: Inclusion Criteria:

1. Best pre-bronchodilator forced expiratory volume in 1 second (FEV1) of greater than 40% of their predicted normal value.
2. Patients must have a treatment regimen that includes a short-acting β2 agonist (SABA) (albuterol) for use as needed and either an inhaled corticosteroid (ICS) or an ICS/long-acting β2 agonist (LABA) as a preventative treatment for a minimum of 8 weeks before the SV. Patients currently taking low-dose ICS without LABA are not eligible for this study. Patients currently taking low-dose ICS/LABA may only be entered into the mid ICS strength. All patients must have been maintained on a stable dose of ICS or ICS/LABA for 4 weeks prior to the SV (or pre-SV if necessary) at 1 qualifying doses
3. To meet reversibility of disease criteria, the patient must demonstrate a ≥12% reversibility of FEV1 (and 200 mL for patients aged18 years and older) within 30 minutes following 4 inhalations of albuterol at the SV. Historic reversibility within the past 12 months of the SV may be used to meet this criterion.
4. Written informed consent/assent is obtained. For adult patients (aged 18 years and older, or as applicable per local regulations), the written informed consent form (ICF) must be signed and dated by the patient before conducting any study-related procedure. For minor patients (aged 12 to 17 years, or as applicable per local regulations), the written ICF must be signed and dated by the parent/legal guardian and the written assent form must be signed and dated by the patient (if applicable) before conducting any study-related procedure. Note: Age requirements are as specified by local regulations.
5. Outpatient \>= 12 years of age on the date of consent/assent. .
6. Asthma diagnosis: The patient has a diagnosis of asthma as defined by the National Institutes of Health (NIH). The asthma diagnosis has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in medication) for at least 30 days before providing informed consent.
7. The patient is able to perform acceptable and repeatable spirometry.
8. The patient is able to perform peak expiratory flow (PEF) with a handheld peak flow meter.
9. The patient is able to use a metered-dose inhaler (MDI) device without a spacer device and a MDPI device.
10. The patient is able to withhold (as judged by the investigator) his or her regimen of ICS or study drug, and rescue medication for at least 6 hours before the SV and before all treatment visits where spirometry is performed.
11. The patient/parent/legal guardian/caregiver is capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements.
12. SABAs: All patients must be able to replace their current SABA with albuterol/salbutamol HFA inhalation aerosol at the SV for use as needed for the duration of the study.
13. Female patients may not be pregnant, breastfeeding, or attempting to become pregnant.

    * -Other criteria may apply, please contact the investigator for more information

Exclusion Criteria:

1. The patient has a history of a life-threatening asthma exacerbation that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures.
2. The patient is pregnant or lactating, or plans to become pregnant during the study period or for 30 days after the study.
3. The patient has participated as a randomized patient in any investigational drug study within the 30 days preceding the SV (or prescreening visit, as applicable) or plans to participate in another investigational drug study at any time during this study.
4. The patient has previously participated in an Fp MDPI or FS MDPI study.
5. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the study drug or rescue medication formulation (ie, lactose).
6. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, azole antifungals, ritonavir, or clarithromycin) within 30 days before the SV or plans to be treated with any strong CYP3A4 inhibitor during the study.
7. The patient has been treated with any of the prohibited medications during the prescribed (per protocol) washout periods before the SV.
8. The patient currently smokes or has a smoking history of 10 pack-years or more (a pack-year is defined as smoking 1 pack of cigarettes/day for 1 year). The patient may not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).
9. The patient has a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the SV.
10. The patient has a history of alcohol or drug abuse within 2 years preceding the SV.
11. The patient has had an asthma exacerbation requiring systemic corticosteroids within 30 days before the SV, or has had any hospitalization for asthma within 2 months before the SV.
12. Initiation or dose escalation of immunotherapy (administered by any route) is planned during the study period. However, patients who initiated immunotherapy 90 days or more before the SV and have been on a stable (maintenance) dose for 30 days or more before the SV may be considered for inclusion.
13. The patient has used immunosuppressive medications within 4 weeks before the SV.
14. The patient is unable to tolerate or unwilling to comply with the appropriate washout periods and withholding of all applicable medications. (Patients that require continuous treatment with β-blockers, monoamine oxidase inhibitors, tricyclic antidepressants, anticholinergics, and/or systemic corticosteroids are excluded).
15. The patient has untreated oral candidiasis at the SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the study.
16. The patient has a history of a positive test for human immunodeficiency virus, active hepatitis B virus, or hepatitis C infection.
17. The patient is either an employee or an immediate relative of an employee of the clinical investigational center.
18. A member of the patient's household is participating in the study at the same time. However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened.
19. The patient has a disease/condition that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study.

    * Other criteria may apply, please contact the investigator for more information

Criteria for Randomization:

Patients were randomized into the study if they met all of the following criteria:

1. The patient continued to be in general good health, meeting the entry criteria.
2. The patient continued to have a predose/pre-albuterol FEV1 at the randomization visit (RV) that was ≥40% of predicted normal.
3. The patient had no clinically significant abnormal laboratory test results or ECG findings at the screening visit.
4. The patient had no significant changes in asthma medications during run-in, excluding the albuterol/salbutamol HFA (90 mcg ex actuator) or equivalent used as rescue medication as supplied per protocol.
5. The patient did not have a upper respiratory tract infection (URI) or lower respiratory tract infection (LRI) during the run in period. Patients who developed a URI or LRI during the run in period could be discontinued from the study and allowed to re-screen 2 weeks after resolution of symptoms.
6. The patient had no asthma exacerbation during the run in period, defined as any worsening of asthma requiring any significant treatment other than rescue albuterol/salbutamol HFA (90 mcg ex actuator) or equivalent or the patient's run-in MDPI. This included requiring the use of systemic corticosteroids and/or emergency department (ED) visit or hospitalization or an increase in the patient's regularly prescribed nonsteroidal maintenance treatment. Urgent care/ED visits where the treatment was limited to a single dose of nebulized albuterol/salbutamol did not meet the criteria of an asthma exacerbation.
7. The patient had no clinical visual evidence (on oropharyngeal examination) of oropharyngeal candidiasis.
8. The patient did not experience an adverse event that would result in failure to continue to meet selection criteria.
9. The patient did not use any of the prohibited concomitant medications during the run in period.
10. The patient complied with completion of the daily diary, defined as follows:

    * completion of AM and PM asthma symptom scores on 4 or more of the 7 days immediately preceding the RV.
    * completion of rescue medication use (whether used or not) on 4 or more of the 7 days immediately preceding the RV.
    * completion of AM peak expiratory flow (PEF) measurements on 4 or more of the 7 days immediately preceding the RV.
    * recording of AM and PM asthma inhalation therapy use on 4 or more of the 7 days immediately preceding the RV.

Answer: B