Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Long-term, Randomized, Double-blind, Multicenter, Parallel-group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT007 Administered as Needed in Response to Symptoms in Symptomatic Adults and Children 4 Years of Age or Older With Asthma
Brief Summary: This is a randomized, double-blind, multicenter, parallel-group, variable-length study to compare 2 doses of BDA MDI (PT027) with AS MDI (PT007) on the time to first severe asthma exacerbation in adult, adolescent, and pediatric subjects with moderate to severe asthma.


Options:
A: INCLUSION CRITERIA

* Black or Hispanic based on self-identification (Hispanic if identify as both)
* Male and female, ages 18-75 years
* Ability to provide informed consent
* Clinical history consistent with asthma for \> 1 year.
* Prescribed ICS as daily maintenance therapy
* Participant must also have an ACT score of 19 or less, or a history of one or more exacerbations in the past year that required patient report of systemic corticosteroid use.

EXCLUSION CRITERIA

* Life expectancy less than one year
* Known allergy to the ICS inhaler used in the study
* Having COPD or other chronic lung disease other than asthma; with the exception of the following:

  * Dx of COPD in a never smoker without any other lung disease or any other disease that might cause airway obstruction such as: Cystic Fibrosis, Connective Tissue Disease, premature birth, organ transplantation, bronchiectasis, sarcoid, and obliterative bronchiolitis
  * Dx of COPD in former smoker with normal PFTs done after the person quit smoking
  * Dx of COPD in current smoker with normal PFTs done in past 24 months
  * Dx of COPD IN CURRENT OR FORMER SMOKER with obstruction on PFTs: normal diffusing capacity in past 24 months and demonstrated reversibility of 12% or more at any time
* Regular systemic corticosteroid use daily or every other day for any reason-including asthma or other medical reasons
* Use of systemic corticosteroid, or visit to the doctor's office, emergency department (ED) or urgent care, or overnight hospitalization for an asthma exacerbation in the past month (can wait and re-check eligibility after one month)
* Use of biologics (injections or infusion medicines): with the exception of the following:

  * the patient has been on a stable dose of a biologic for at least 6 months and,
  * must have had an exacerbation at least 2 months after starting on a biologic to be considered eligible OR
  * must have a current ACT score \<=19 to be considered eligible.
* Bronchial thermoplasty less than 6 months ago (can re-check eligibility 6 months after procedure)
* Another family member living in the same household already enrolled in study
B: Inclusion Criteria:

1. Female or male aged ≥4 years at the time of informed consent
2. Physician diagnosis of asthma documented for at least 1 year
3. Receiving 1 of the following scheduled asthma maintenance therapies for 3 months with stable dosing for at least the last 4 weeks before Visit 1:

   * Medium-to-high-dose inhaled corticosteroid (ICS)
   * Medium-to-high-dose ICS and 1 additional maintenance therapy from the following: leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA), or theophylline
   * Low-to-high-dose ICS in combination with long-acting β2-adrenoreceptor agonist (LABA) with or without one additional maintenance therapy from the following: LTRA, LAMA, or theophylline
4. Prebronchodilator forced expiratory volume in 1 second (FEV1) of ≥40 to \<90% predicted normal value for adults and adolescents, and ≥60 to \<100% predicted normal value for subjects aged 4 to 11 years after withholding specified medications including short/rapid-acting β2-adrenoreceptor agonist (SABA)
5. Demonstrate reversibility at Visit 1, with an increase in FEV1 ≥12% (and ≥200 mL for subjects aged ≥18 years) relative to baseline after administration of sponsor provided Ventolin via central spirometry. One re-test for reversibility testing is allowed within the screening period in advance of Visit 2
6. Demonstrate acceptable spirometry performance (i.e., meet American Thoracic Society/European Respiratory Society acceptability/repeatability criteria)
7. A documented history of at least 1 severe asthma exacerbation within 12 months before Visit 1
8. Able to perform acceptable and reproducible peak expiratory flow (PEF) measurements as assessed by the investigator

Exclusion Criteria:

1. Chronic obstructive pulmonary disease or other significant lung disease (e.g., chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or bronchopulmonary dysplasia)
2. Oral corticosteroid/SCS use (any dose and any indication) within 6 weeks before Visit 1
3. Chronic use of oral corticosteroids (OCS, ≥3 weeks use in 3 months prior to Visit 1)
4. Having received any marketed (e.g., omalizumab, mepolizumab, reslizumab, benralizumab) or investigational biologic within 3 months or any other prohibited medication
5. Current smokers, former smokers with \>10 pack-years history, or former smokers who stopped smoking \<6 months before Visit 1 (including all forms of tobacco, e-cigarettes \[vaping\], and marijuana)
6. Life-threatening asthma defined as any history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s) within 5 years of Visit 1
7. Historical or current evidence of a clinically significant disease
8. Cancer not in complete remission for at least 5 years
9. Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1
10. History of psychiatric disease, intellectual deficiency, poor motivation, or other conditions if their magnitude is limiting informed consent validity
11. Significant abuse of alcohol or drugs
C: Inclusion Criteria:

For all patients:

1. The patient understands the study procedures and agrees to participate by signing the consent form.
2. The patient is male or female, at least 18 years of age but no more than 80 years of age at the entry into the study (screening visit).

For patients with asthma (groups 1 and 2)

1. The patient has a history of intermittent or persistent symptoms of wheezing, breathlessness, chest tightness and cough. The diagnosis of asthma must have been confirmed by a specialist in pulmonary medicine.
2. The patient fulfils one or several of the following criteria for reversible airway obstruction, as documented during the last 5 years before the study or at screening visit:

   1. An increase in FEV1 more than 9% of predicted (or improvement by 200 mL) after administration of 4 puffs of 100 microg salbutamol dose-aerosol inhaler via a spacer, or after additional inhalation of four puffs of 20 microg ipratropium bromide (Atrovent) administered through a large volume spacer.
   2. A mean diurnal variation in Peak Expiratory Flow (PEF) of more than 15% on more than 4 days/week for at least 2 weeks, as calculated by the following equation:

      (highest PEF-lowest PEF)/mean PEF
   3. An increase in FEV1 of at least 400 mL after a course of prednisolone 0.5mg/kg/day for 14 days.
   4. In patients with a FEV1 more than 70% predicted, demonstrated bronchial hyperresponsiveness to histamine, methacholine, isocapnic hyperventilation, exercise or other indirect challenges (according to established local methods).
3. The patient is a non-smoker or has a total smoking history of less than 5 pack years. In the case the patient is smoking, it must be less than 10 cigarettes a day and the asthma must have started before smoking.

Specific for patients with mild to moderate asthma (group 1)

1. The patient has stable disease with minimal symptoms, no exacerbations or hospitalisations during the last year.
2. The patient uses inhaled steroids regularly, but not more than 800 microg/day budesonide or beclomethasone, or up to 500 microg/day fluticasone.
3. The patient uses prescribed short-acting beta agonists as needed.
4. The patient does not require treatment with long-acting beta-agonists.

Specific for patients with severe asthma (group 2)

1. The patient has been under specialist treatment for at least one year.
2. The patient requires continuous treatment with high doses of inhaled steroids. If the patient does not take oral steroids, the inhaled dose of steroids must be more than 1600 microg/day budesonide or beclomethasone, or more than 800 microg/day fluticasone or equivalent. In case the patient does take oral steroids, the inhaled dose of steroids must be more than 800 microg/day budesonide or beclomethasone, or more than 400 microg/day fluticasone or equivalent.
3. The patient requires continuous treatment with long acting inhaled beta-agonists or oral theophylline, as documented for at least one year.
4. The patient experienced at least one asthma exacerbation during the previous year.

Specific for patients with COPD (group 3)

1. The diagnosis of COPD must have been made by a specialist in pulmonary medicine. The patient may or may not have chronic symptoms (cough, sputum production, dyspnoea).
2. The patient has a FEV1/Forced Vital Capacity (FVC) ratio of less than 70%.
3. The patient's post bronchodilator FEV1 value is more than 30% but less than 80% of predicted.
4. The patient has a smoking history of more than 15 pack years, either as current or ex-smoker.
5. The patient displays a negative reversibility test to inhaled bronchodilators as defined by an increase in FEV1 of less than 9% of predicted (or an improvement by less than 200 mL) after administration of 4 puffs of 100 microg salbutamol dose-aerosol inhaler via a spacer, and four puffs of 20 microg ipratropium bromide (Atrovent) administered through a large volume spacer.
6. The patient has no history of asthma.
7. The patient has no current allergy, as shown by a negative skin-prick test.
8. The patient has used inhaled steroids in the range 800-1600 microg/day (budesonide or equivalent) for at least 3 months prior to the study.

Exclusion Criteria:

General exclusions

1. The patient is pregnant.
2. The patient has a recent history of incapacitating psychotic disorders.
3. The patient is a current or recent past abuser of alcohol or illicit drugs.
4. The patient has a history of malignancy, is known to be positive for HIV, or other states that are considered to interfere with study conduct or scientific interpretations.
5. The patient cannot read or comprehend written material, or is in the opinion of the investigator, for other reasons unlikely to understand and follow the study procedures.
6. The patient is mentally or legally incapacitated preventing informed consent from being obtained.

Exclusions because of pulmonary disorders

1. The patient is unable to perform acceptable spirometry, peak flow measurements and/or complete diary cards in a satisfactory way during the period between visit 1 and visit 3B (optimisation period and prednisolone/placebo trial). If the patient is unable to use the electronic Peak Flow meters/Diary cards, it is acceptable to use an ordinary mechanical meter (e.g. Mini-Wright) together with a paper version of the diary card. Patients that are unable to use the mechanical meter and paper diary card during the period between visit 1 and 3B cannot enter the follow-up year.
2. The patient has, in addition to asthma or COPD, any other pulmonary disorder that according to the investigator would interfere with the study procedures or scientific evaluation (e.g. tuberculosis).
3. The patient suffers from chronic hypercapnic respiratory failure as indicated by an elevated pCO2 (\>47 mm Hg or 6,25 kPa). In case of doubt this should be confirmed with pulse oximetry or blood gas sampling.

Exclusions because of medications

1. The patient has received immunosuppressants other than corticosteroids (i.e., methotrexate, gold, troleandomycin, cyclosporin or any other experimental anti-inflammatory drug) within three months of study entry.
2. The patient is currently undergoing immunotherapy.
3. The patient receives chronic oxygen therapy.

Specific exclusion criterion for patients with asthma (groups 1 \& 2)

1. The patient has smoked more than five (5) pack years.

Specific exclusion criterion for patients with mild asthma (group 1) 1. The patient requires treatment with long-acting beta-agonists.

Specific exclusion criteria for patients with severe asthma (group 2)

1. The patient is not treated with high doses of inhaled steroids (see above).
2. The patient has not had an exacerbation of asthma during the last year.
3. The patient does not require treatment with long-acting beta-agonists or theophylline as documented during one year.

Specific exclusion criterion for patients with COPD (group 3)

1. The patient has a history of asthma confirmed by a specialist in pulmonary medicine.

Specific exclusion criteria for bronchoscopy (all groups)

1. The patient has had a severe exacerbation of asthma requiring high doses of oral steroids during the last three (3) months.
2. The patient has had a severe exacerbation of COPD requiring intensive outpatient treatment or hospitalisation during the last three (3) months.
3. The patient has had three or more severe exacerbations of asthma or COPD during the last year.
4. The patient displays more than 10% fall in FEV1 at 2 minutes after inhalation of 0.9% saline (during induction of sputum at visit 2).
5. The patient has shown signs of uncontrolled disease during the last three days, e.g. the patient has required more than four puffs/day of rescue medication above baseline use during the last three days. (In the case criteria 1-4 are not met, such patients may be rescheduled for bronchoscopy in two weeks time. The start of the oral prednisolone intervention will then be postponed by the number of days passing before the bronchoscopy).
6. If a patient who otherwise has qualified for bronchoscopy has received more than 6 mg per kg BW of lidocaine during the preparation for the procedure, the bronchoscopy must be terminated and cannot be continued the same day.
7. Patients who have experienced severe bronchoconstriction or other adverse reactions at previous attempts to perform bronchoscopy.
8. The patient has a post-bronchodilator FEV1 \< 40% predicted.
9. Do not start or proceed bronchoscopy if:

   * Transcutaneous oxygen saturation by pulse-oximeter \< 90% (despite giving oxygen by nasal cannula when saturation is \< 94%)
   * Heart frequency \> 130
   * Heart rhythm disturbances.

Specific exclusion criteria for induced sputum (all groups)

1. A post-bronchodilator (after administration of 4 puffs of 100 microg salbutamol dose-aerosol inhaler via a spacer) FEV1 percent of predicted being less than 60%, or in absolute values less than 1.0 L.
2. A peak flow variability of more than 30% during the previous four days.
3. Patients who display more than a 15% fall in FEV1 at 2 minutes after inhalation of saline (0.9% NaCl) during induction of sputum..
4. Patients who have experienced severe bronchoconstriction or other adverse reactions at previous attempts to induce sputum.
D: Inclusion Criteria:

* Able to perform reproducible spirometry according to American Thoracic Society (ATS) criteria
* History of asthma symptoms (e.g., cough, wheezing, shortness of breath) and meets at least one of the following criteria:

  1. Naïve to controller therapy and meeting National Asthma Education and Prevention Program (NAEPP) criteria for mild-moderate persistent asthma (symptoms at least 2 days per week and/or night-time awakenings due to asthma at least 2 nights per month)
  2. Current uncontrolled asthma (meets NAEPP criteria for mild-moderate persistent asthma) while receiving an ICS dose greater than or equal to 200 ug per day of fluticasone equivalent or some form of non-ICS controller therapy (e.g., montelukast, theophylline, cromolyn)
  3. Asthma is currently under control while receiving an ICS dose between 300 to 400 ug per day of fluticasone equivalent and willing to consider changing current treatment to monotherapy with one dose of ICS (current standard of care)
  4. Asthma is currently under control while receiving some form of combination therapy, such as ICS less than or equal to 200 ug per day of fluticasone equivalent in addition to a non-ICS controller therapy (e.g., LABA, montelukast, theophylline, cromolyn), and willing to consider changing current treatment to monotherapy with one dose of ICS (current standard of care)
* FEV1 reversibility of at least 12% following bronchodilator administration (4 puffs) at study visit 1. Individuals will need to hold albuterol, montelukast, theophylline, ipratropium bromide (or other anticholinergics) and LABAs per study instructions prior to reversibility testing. If an individual is receiving these types of medications prior to study visit 1, he/she may be brought back to the clinical center within 1 week following appropriate medication withholding to attempt qualification by reversibility criteria. If the individual does not meet this requirement, they may qualify for enrollment if their PC20 methacholine FEV1 is less than or equal to 12.5 mg/ml at the time of randomization. If FEV1 is less than 70%, thus precluding the methacholine challenge at this visit, then completion of the visit will be postponed several days and an additional attempt to obtain a methacholine challenge test will be made. If the methacholine challenge still cannot be performed, an individual may still qualify by reversibility criteria at this visit.
* History of clinical varicella or varicella vaccine; individuals needing the vaccine may receive it from their primary care physician prior to study entry
* Ability of parent to provide informed consent; verbal assent must be obtained from children less than 7 years of age and written assent must be obtained from children between 7 and 18 years of age
* If female, willing to use an effective form of contraception

Prior to being randomly assigned to a treatment group, participants must meet the following criteria to remain in the study:

* Lack of acceptable asthma control during the 8-week screening period as defined by the following criteria:

  1) On average, on more than 2 days per week, one or all of the following:
  1. Diary-reported symptoms
  2. The use of inhaled bronchodilator (not including pre-exercise)
  3. Peak flows in the yellow zone (less than 80% of post bronchodilator PEF value obtained at study visit 1) OR
* On average, more than 1 night-time awakening due to asthma, during each 2-week period

Exclusion Criteria:

* Corticosteroid treatment for any condition prior to study entry within the following defined timepoints:

  1. Oral - Use within 2 weeks of the screening visit
  2. Injectable - Use within 2 weeks of the screening visit
  3. Nasal - May be used at any time during the study at the discretion of the study investigator or primary care physician
* Current or prior use of medications known to significantly interact with corticosteroid disposition (within a 2-week period of study visit 1), including but not limited to carbamazepine, erythromycin or other macrolide antibiotics, phenobarbital, phenytoin, rifampin, or ketoconazole
* Pre-bronchodilator FEV1 less than 60% predicted at study visit 1
* More than three hospitalizations for asthma in the year prior to study entry
* Presence of chronic or active lung disease other than asthma
* Significant medical illness other than asthma, including thyroid disease, diabetes mellitus, Cushing's disease, Addison's disease, hepatic disease, or concurrent medical problems that could require oral corticosteroids during the study or would place the participant at increased risk while participating in the study
* History of cataracts, glaucoma, or any other medical disorder associated with an adverse effect to corticosteroids
* Gastroesophageal reflux symptoms not controlled by standard medical therapy
* History of significant asthma exacerbation within 2 weeks of study visit 1 or more than 5 courses of systemic corticosteroids in the year prior to study entry
* History of a life-threatening asthma exacerbation requiring intubation, mechanical ventilation, or resulting in a hypoxic seizure within the 5 years prior to study entry
* History of adverse reactions to ICS, LTRA, or LABA preparations or any of their ingredients
* Receiving hyposensitization therapy other than an established maintenance regimen (i.e., continuous regimen for at least 3 months prior to study entry)
* Pregnant or breastfeeding
* Inability to perform study procedures
* Refusal to consent to a genotype evaluation
* Inability of the child to ingest the study drug
* Cigarette smoking or smokeless tobacco use in the year prior to study entry
* Current participation or participation in the month prior to study entry in another investigational drug trial
* Evidence that the family may be unreliable or nonadherent, or may move from the clinical center area before study completion

Answer: B