Please select the eligibility criteria that correspond to the clinical trial below.
Title: Step-up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations
Brief Summary: The objective of this study is to determine whether, in children receiving low-dose inhaled corticosteroids (ICS), quintupling the dose of inhaled corticosteroids at the onset of symptoms previously associated with upper respiratory illnesses and subsequent asthma exacerbations reduces the rate of severe asthma exacerbations treated with oral corticosteroids.


Options:
A: Main Inclusion Criteria:

* Written informed consent by the parents or legal guardians of the patient
* Outpatients
* Good health with the exception of asthma
* Documented diagnosis of asthma for more than 6 months
* Use of rescue medication only or pretreatment with a controller drug

Main Exclusion Criteria:

* Concomitant severe diseases
* Diseases contraindicated for the use of inhaled steroids
* Other relevant lung diseases causing impairment in pulmonary function
* Recurrent, episodic wheezing only
* History of life-threatening asthma
* History of any mechanical ventilation
* Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further clinical evaluation
* Premature birth (\< 32 weeks gestation)
B: Inclusion Criteria:

* Physician-diagnosed asthma
* At least 1 exacerbation treated with systemic (oral or injectable) corticosteroids in the past 12 months
* Able to perform reproducible spirometry
* Current treatment with step 2 controller therapy \[low-dose ICS, leukotriene receptor antagonist (LTRA)\] OR current treatment with step 3 controller therapy \[low-dose ICS + long-acting beta agonist (LABA), low-dose ICS + LTRA, or medium dose ICS\] with a childhood Asthma Control Test (c-ACT) score of \>19, no more than 2 prednisone treated exacerbations in the past 6 months, prebronchodilator Forced Expiratory Volume at 1 second (FEV1) ≥ 80% predicted and willing to step down therapy OR controller naïve and qualifying for step 2 controller therapy \[asthma symptoms or short acting beta agonist (SABA) use \> 2 days per week or night-time awakenings due to asthma \> 2 nights per month\]
* Prebronchodilator FEV1 ≥ 60% predicted
* Ability and willingness to provide informed assent
* For females of childbearing potential: not pregnant, non-lactating, and agree to practice an adequate birth control method.
* History of clinical varicella or varicella vaccine

Exclusion Criteria:

* Systemic (oral or injectable) corticosteroids within previous 2-week period
* Current or recent (previous 2-weeks) use of medications known to significantly interact with corticosteroid disposition, including but not limited to carbamazepine, erythromycin, phenobarbital, phenytoin, rifampin, and ketoconazole
* 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
* A history of cataracts, glaucoma, or any other medical disorder associated with an adverse effect to corticosteroids
* History of a life-threatening asthma exacerbation requiring intubation, mechanical ventilation, or resulting in a hypoxic seizure
* More than 5 prednisone treated exacerbations in the past 12 months
* More than 1 hospitalizations lasting \>24 hours for asthma in the past 12 months
* History of adverse reactions to ICS preparations or any of their ingredients
* Receiving hyposensitization therapy other than an established maintenance regimen (On maintenance regimen for ≥ 3 months)
* History of premature birth before 35 weeks gestation
C: Inclusion Criteria:

* Able to perform reproducible spirometry according to American Thoracic Society (ATS) criteria
* History of asthma symptoms that are adequately controlled in the 4 weeks prior to study entry, and meets at least one of the following criteria:

  1. History of mild persistent asthma symptoms (on average greater than 2 days per week with symptoms or albuterol use for symptoms or greater than 2 night-time awakenings per month during the year prior to study entry) and has been treated with a single-controller inhaled corticosteroid (ICS) dose less than or equal to 160 mcg per day of a beclomethasone-equivalent or a leukotriene receptor antagonist (LTRA) (in an age-appropriate dose) for the 4 weeks prior to study entry; individuals treated with a combination controller therapy (e.g. ICS+LTRA or ICS+long-acting beta-agonist (LABA)) in the past 8 weeks will not be eligible
  2. Not currently being treated with ICS, a history of mild persistent asthma, and 1 to 2 exacerbations in the year prior to study entry (but none in the 3 months prior to study entry)
* Forced expiratory volume in one second (FEV1) reversibility of greater than or equal to 12% following bronchodilator administration (4 puffs); individuals who do not meet this requirement may qualify for enrollment if their methacholine provocative concentration at 20% (PC20) is less than or equal to 12.5 milligrams per milliliter (mg/ml)
* 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

Participants will be eligible for the 44 weeks of treatment if, after the 4-week screening period, their asthma remains controlled, and they demonstrate at least 80% predicted pre-bronchodilator FEV1. Participants must meet ALL of the criteria stated below during the 8-week screening period to continue in the study:

* Meets the definition of acceptable asthma control, which is NOT having one or more of the following during ANY 2-week period:

  1. On average, on more than 2 days per week, experiences one or more 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 personal best defined as based on peak expiratory flow (PEF) value obtained at study visit 1
  2. More than 1 night-time awakening due to asthma
* Demonstrates adherence with taking study medications (at least 75% of scheduled doses), rescue medications (using both rescue inhalers for at least 75% of rescue doses), and completing patient diaries (at least 75% of days)
* Pre-bronchodilator FEV1 greater than or equal to 80% predicted at study visits 2 and 3
* Agrees to not use a spacer with beclomethasone/placebo study and rescue medications

NOTE: In January 2008, the Data and Safety Monitoring Board (DSMB) approved changes in the TREXA eligibility criteria, by which neither FEV1 reversibility ≥ 12% nor a participant's methacholine PC20 ≤ 12.5 mg/ml were required for randomization.

Exclusion Criteria:

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

  1. Oral - Use within 2-week period of the screening visit
  2. Injectable - Use within 2-week period of the screening visit
  3. Nasal corticosteroids 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
* Any hospitalization 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
* History of cataracts, glaucoma, or any other medical disorder associated with an adverse effect to corticosteroids
* Any asthma exacerbation in the past 3 months or more than 2 in the past year.
* History of a life-threatening asthma exacerbation requiring intubation, mechanical ventilation, or resulting in a hypoxic seizure
* History of adverse reactions to ICS preparations or any of its ingredients
* Receiving hyposensitization therapy other than an established maintenance regimen (continuous regimen for at least 3 months)
* Pregnant or breastfeeding
* Cigarette smoking or smokeless tobacco use in the year prior to study entry
* Refusal to consent to a genotype evaluation
* Current participation or participation within 1 month of 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
D: 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.

Answer: B