Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 1-Year Safety Study of Medium and High Doses of Mometasone Furoate/Formoterol Combination Formulation and Medium and High Doses of Fluticasone/Salmeterol in Persistent Asthmatics Previously Treated With Medium to High Doses of Inhaled Glucocorticosteroids
Brief Summary: The purpose of this study is to evaluate the long-term safety of mometasone furoate/formoterol (MF/F) metered dose inhaler (MDI) 200/10 mcg twice-a-day (BID) and MF/F MDI 400/10 mcg BID and two doses of fluticasone/salmeterol combination (F/SC) (250/50 mcg BID and 500/50 mcg BID) in subjects with persistent asthma who require maintenance treatment on inhaled glucocorticosteroids (ICS); evaluator-blind.

In addition, the extrapulmonary effects on 24-hour plasma cortisol area under curve (AUC), of MF/F MDI 200/10 mcg BID, MF/F MDI 400/10 mcg BID, F/SC MDI 250/50 mcg BID, and F/SC MDI 500/50 mcg BID will be evaluated.


Options:
A: Inclusion Criteria:

* A subject must be at least 12 years of age, of either sex, and of any race, with a diagnosis of asthma of at least 12 months duration that is consistent with the following definition:

  * The diagnosis of asthma is based upon clinical history and examination, pulmonary function parameters, and response to beta2-agonists, according to international guidelines.
* A subject must have been using a high dose of inhaled glucocorticosteroid (ICS) either alone or in combination with a long-acting beta2 agonist (LABA) for at least 12 weeks prior to Screening, with no use of oral glucocorticosteroids within 30 days prior to Screening. A subject must have been on a stable asthma regimen (daily dose unchanged) for at least 2 weeks prior to Screening. High daily doses of ICS are defined as follows:

  * \>1000 mcg beclomethasone chlorofluorocarbon (CFC)
  * \>500 mcg beclomethasone hydrofluoroalkane (HFA)
  * \>1000 mcg budesonide dry powder inhaler (DPI)
  * \>2000 mcg flunisolide
  * \>500 mcg fluticasone
  * \>400 mcg MF
  * \>2000 mcg triamcinolone acetonide
  * \>320 mcg ciclesonide

Note: Dose delivery by method or modality other than those noted above must be equivalent.

* A subject must have experienced at least one severe exacerbation requiring a course of oral glucocorticosteroid 2 to 12 months prior to Screening.
* If, based upon the medical judgment of the investigator, there is no inherent harm in changing the subject's current asthma therapy, then the subject (and parent/guardian, if applicable) must be willing to discontinue his/her prescribed ICS or ICS/LABA prior to initiating MF MDI run-in medication.
* To document the diagnosis of asthma and assure the subject's responsiveness to bronchodilators before randomization, one of the following methods can be used at the Screening Visit, Day-14, or thereafter, but prior to the Baseline Visit:

  * The subject must demonstrate an increase in absolute FEV1 of at least 12% and at least 200 mL within approximately 15 to 20 minutes after administration of four inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg).
  * The subject must demonstrate a peak expiratory flow (PEF) variability of more than 20% expressed as a percent of the best and lowest morning pre-bronchodilator PEF over at least 1 week.
  * The subject must demonstrate a diurnal variation in PEF of more than 20% based on the difference between the prebronchodilator (before taking albuterol/salbutamol) morning value and the postbronchodilator value (after taking albuterol/salbutamol) from the evening before, expressed as a percentage of the mean daily PEF value. Note: If a subject is to qualify using diurnal variation, the subject should be instructed to perform his/her PEF evaluation after using his/her bronchodilator in the evening.
* At the Screening Visit, the subject's FEV1 must be \>=50% predicted when all restricted medications have been withheld for the appropriate intervals.
* At the Baseline Visit, the subject's FEV1 must be \>=50% and \<=85% predicted when all restricted medications have been withheld for the appropriate intervals.
* The subject (and parent/guardian for a subject under the age of legal consent) must be willing to give written informed consent and be able to adhere to dose and visit schedules.
* A female subject of childbearing potential must be using a medically acceptable, adequate form of birth control. This includes:

  * hormonal contraceptive as prescribed by a physician (oral combined, hormonal vaginal ring, hormonal implant or depot-injectable);
  * medically prescribed intra-uterine device (IUD);
  * medically prescribed topically-applied transdermal contraceptive patch;
  * condom in combination with a spermicide (double-barrier method);
  * monogamous relationship with a male partner who has had a vasectomy. The subject must have started this birth control method at least 3 months prior to Screening (with the exception of condom in combination with spermicide), and must agree to continue its use for the duration of the study. A female subject of childbearing potential who is not currently sexually active must agree and consent to using a medically acceptable method should she become sexually active during the course of this study. 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 the open-label MF MDI Run-in Period.

Exclusion Criteria:

* A subject who demonstrates a change (increase or decrease) in absolute FEV1 of \>20% at any time from the Screening Visit up to and including the Baseline Visit. Pulmonary function tests (PFTs) will be performed in the morning.
* A subject who requires the use of \>8 inhalations per day of short-acting beta agonists (SABA) MDI or \>=2 nebulized treatments per day of 2.5 mg SABA, on any 2 consecutive days from the Screening Visit up to and including the Baseline Visit.
* A subject who experiences a decrease in AM or PM peak expiratory flow (PEF) below the Run-in Period stability limit on any 2 consecutive days prior to randomization.
* A subject who experiences a clinical asthma exacerbation (defined as a deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with additional, excluded asthma medication \[including oral or other systemic corticosteroids, but allowing SABAs\]), at any time from the Screening Visit up to and including the Baseline Visit.
* A subject who has been treated in the emergency room (for a severe asthma exacerbation), or admitted to the hospital for management of airway obstruction, within the last 3 months.
* A subject who has ever required ventilator support for respiratory failure secondary to asthma.
* A subject who has experienced an upper or lower respiratory tract infection (viral or bacterial) within the previous 2 weeks prior to Screening and Baseline Visits. Visits can be rescheduled 2 weeks after complete resolution of the event to re-assess eligibility.
* A subject who is a smoker or ex-smoker and has smoked within the previous year or has had a cumulative smoking history \>10 pack-years.
* A subject with a clinically significant abnormal vital sign.
* A subject with evidence (upon visual inspection, laboratory culture is not required) of clinically significant oropharyngeal candidiasis at Baseline (Visit 3) with or without treatment. If there is evidence of oropharyngeal candidiasis at Screening or Pre-Baseline Visit, the subject may be treated as appropriate and the Baseline Visit can be scheduled upon resolution. If there is evidence of oropharyngeal candidiasis at the Baseline Visit, the subject may be treated as appropriate and the visit can be rescheduled upon resolution.
* A subject with a history of clinically significant renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular, or other significant medical illness or disorder which, in the judgment of the investigator, could interfere with the study, or require treatment that might interfere with the study. Specific examples include (but are not limited to) insulin-dependent diabetes, hypertension being treated with beta blockers, active hepatitis, coronary artery disease, arrhythmia, 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 clinically diagnosed chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, etc. Other conditions that are well-controlled and stable (eg, hypertension not requiring beta blockers) will not prohibit participation if deemed appropriate per the investigator's judgment.
* A subject who is known to be allergic to or intolerant of ICS, beta2 agonists, or any of the excipients present in the medications used in this study.
* A female subject who is breast-feeding, pregnant, or intends to become pregnant while participating in this study.
* A subject who is a known illicit drug user.
* A subject who is known to be human immunodeficiency virus (HIV) positive (HIV testing will not be conducted in this study).
* A subject who is unable to correctly use an oral MDI inhaler.
* A subject who has been taking any of the restricted medications prior to Screening without meeting the required washout timeframes.
* A subject who cannot adhere to the permitted concomitant medications and prohibited medications.
* A subject participating in this study may not participate in this same study at another investigational site. In addition, a subject cannot participate in a different investigational study at any site, during the same timeframe of this study.
* A subject must not be randomized into this study more than once.
* No person directly associated with the administration of the study may participate as a study subject. No family member of the investigational study staff may participate in this study.
* A subject who previously participated in a trial with MF/F.
* Subjects with a history of significant QTC prolongation (ie, QTc\>500 msec) are excluded from participation in the study.
B: Inclusion Criteria:

* Subjects of either sex and any race, at least 12 years of age, with a diagnosis of asthma of at least 12 months.
* Use of medium or high daily dose of ICS (alone or in combination with long-acting beta-agonist \[LABA\]) for at least 12 weeks prior to Screening and have been on a stable regimen for at least 2 weeks prior to Screening.

  * Medium daily doses of ICS:

    * \> 500 to 1000 mcg beclomethasone chlorofluorocarbon (CFC)
    * \> 250 to 500 mcg beclomethasone hydrofluoroalkane (HFA)
    * \> 600 to 1000 mcg budesonide dry powder inhaler (DPI)
    * \> 1000 to 2000 mcg flunisolide
    * \> 250 to 500 mcg fluticasone
    * 400 mcg MF
    * \> 1000 to 2000 mcg triamcinolone acetonide
  * High daily doses of ICS:

    * \> 1000 mcg beclomethasone CFC
    * \> 500 mcg beclomethasone HFA
    * \> 1000 mcg budesonide DPI
    * \> 2000 mcg flunisolide
    * \> 500 mcg fluticasone
    * \> 400 mcg MF
    * \> 2000 mcg triamcinolone acetonide
* If there is no inherent harm in changing the subject's current asthma therapy, the subject must discontinue prescribed ICS or ICS/LABA combination at Baseline.
* Must show evidence of reversibility within the last 12 months or during the Screening Period. Historical reversibility defined as an increase in absolute forced expiratory volume in 1 second (FEV1) of \>= 12% and \>= 200 mL will qualify if performed within 12 months of Screening. If no historical reversibility, subject must demonstrate an absolute FEV1 of \>= 12% and \>= 200 mL within 10 to 15 minutes after four puffs of salbutamol at Visit 1 or anytime prior to Baseline.
* At Screening and Baseline, FEV1 must be \>= 50% predicted, when restricted medications are withheld for the appropriate intervals.
* Complete blood count, blood chemistries, urinalysis, and electrocardiogram (ECG) conducted at Screening must be within normal limits or clinically acceptable to the investigator/sponsor. A chest x-ray performed at Screening or within 12 months prior must be clinically acceptable.
* A female of childbearing potential must be using a medically acceptable, adequate form of birth control:

  * prescribed hormonal contraceptives;
  * medically prescribed intrauterine device (IUD);
  * medically prescribed transdermal contraceptive;
  * condom in combination with spermicide;
  * monogamous relationship with a male partner who has had a vasectomy.

Birth control must have started at least 3 months prior to Screening. Subject must agree to continue its use for the duration of the study. A subject of childbearing potential who is not currently sexually active must agree to use a medically acceptable method should she become sexually active during the study. Women who have been surgically sterilized or are at least 1 year postmenopausal are not considered to be of childbearing potential. A subject of childbearing potential must have a negative serum pregnancy test at Screening.

Key Exclusion Criteria:

* A change (increase or decrease) in absolute FEV1 of \> 20% at any time from the Screening Visit up to, and including, the Baseline Visit.
* A subject who requires the use of \> 12 inhalations per day of short-acting beta-agonist (SABA) MDI or \> 2 nebulized treatments per day of 2.5 mg salbutamol, on any 2 consecutive days from the Screening Visit up to, and including, the Baseline Visit.
* A subject who experiences a clinical asthma exacerbation (defined as a deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with additional, excluded asthma medication \[other than SABA\]) at any time from the Screening Visit up to, and including, the Baseline Visit.
* A subject who has ever required ventilator support for respiratory failure secondary to asthma.
* A subject who is a smoker or ex-smoker and has smoked within the previous year or has had a cumulative smoking history \> 10 pack-years.
C: 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.
D: Inclusion Criteria:

* Outpatient at least 12 years of age
* Both genders; females of childbearing potential must be willing to use birth control method
* Clinical diagnosis of asthma for ≥12 weeks
* Best pre-bronchodilator FEV1 of 40%-90% predicted
* Reversibility of FEV1 of at least 12% and 200mls
* Current asthma therapy that include an inhaled corticosteroid for at least 12 weeks prior to 1st visit
* Ability to use replace current short-acting rescue treatment with albuterol and ability to withhold albuterol use for at least 6 hours prior to study visits

Exclusion Criteria:

* History of life-threatening asthma
* Respiratory infection within last 4 weeks leading to change in asthma management
* Asthma exacerbation within last 3 months
* Concurrent respiratory disease or other disease that would confound study participation or affect subject safety
* Allergies to study drugs, study drugs' excipients, or medications related to study drugs
* Taking another investigational medication or medication prohibited for use during the study.
* Previous participation in a vilanterol (GW642444) study

Answer: B