Please select the eligibility criteria that correspond to the clinical trial below.
Title: Childhood Asthma Research and Education (CARE) Network Trial - Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST)
Brief Summary: Asthma affects about 4 million children in the United States and is a leading cause of hospitalizations and school absenteeism. Continuous wheezing in very young children may develop into asthma. Low doses of inhaled corticosteroids (ICS) are commonly prescribed to treat children with particularly bad wheezing episodes. This study will compare the safety and effectiveness of low doses of ICS taken daily versus higher doses of ICS taken only during respiratory tract illnesses for toddlers with continuous wheezing or coughing illnesses.


Options:
A: Inclusion Criteria at Screening Visit:

Participants who meet all of the following criteria are eligible for study entry. Participants may be reassessed if not initially eligible.

* Positive asthma predictive index (API) status
* A history of at least 4 wheezing episodes in the prior year with at least one physician diagnosed or at least 3 wheezing episodes in the prior year with at least one physician diagnosed and at least 3 months of asthma controller therapy in the prior year
* Experienced a severe exacerbation requiring systemic corticosteroids, urgent unscheduled or emergency visit, or hospitalization in the 12 months before the screening visit
* All immunizations must be completed, including varicella (unless the child has already had clinical varicella). If the child needs the varicella vaccine, this will be arranged with the primary care physician and must be received before study entry.
* Allows blood to be used for genetic analysis
* Willingness to provide informed consent by the child's parent or guardian

Exclusion Criteria at Screening Visit:

Participants who meet any of the following criteria are NOT eligible for enrollment, but they may be re-enrolled if these exclusion criteria disappear:

* Use of more than six courses of systemic corticosteroids in the 12 months before the screening visit
* More than two hospitalizations for wheezing illnesses in the 12 months before the screening visit
* Use of oral or systemic corticosteroids in the 2 weeks before the screening visit
* Current treatment with antibiotics for diagnosed sinus disease
* Current participation or has participated in the month before the screening visit in another investigational drug trial
* Evidence that the family may be unreliable or nonadherent, or may move from the clinical center area before trial completion
* Medically unable to use systemic corticosteroids
* Clinically relevant gastroesophageal reflux
* Inability of the child to cooperate with nebulizer therapy

Participants who meet any of the following criteria are NOT eligible for enrollment, and they may not be re-enrolled:

* Gestation less than late preterm, as defined as birth before 34 weeks gestational age
* Significant developmental delay/failure to thrive, defined as crossing of two major percentile lines during the last year for age and gender. If a child plots less than the 10th percentile for age and gender, a growth chart for the previous year will be obtained from the child's primary care provider.
* Head circumference less than the 3rd percentile or greater than the 97th percentile unless medical evaluation documents no associated illness
* Presence of lung disease other than asthma, such as cystic fibrosis and bronchopulmonary dysplasia (BPD). Evaluation during the screening process will assure that an adequate evaluation of other lung diseases has been performed.
* Presence of other significant medical illnesses (e.g., cardiac, liver, gastrointestinal, endocrine) that would place the child at increased risk of participating in the study
* Immunodeficiency disorders
* History of respiratory failure requiring mechanical ventilation
* History of hypoxic seizure
* History of significant adverse reaction to any study medication ingredient

Exclusion Criteria at Baseline Visit:

Participants will be ineligible to continue in the study and be randomly assigned to a treatment group if any of the following is documented during the 2-week observation period, but they may be re-enrolled if these exclusion criteria disappear:

* Persistent symptomatic asthma, as defined as experiencing symptoms requiring albuterol use on average three or more days per week or two or more night time awakenings due to asthma-associated symptoms
* Inadequate adherence (less than 75% of days) to diary card completion or nebulizer medication use
* Use of any asthma medication except albuterol (used on as needed basis)
B: 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
C: Inclusion Criteria:

* Children of asthmatic mothers form the COPSAC birth cohort study

Exclusion Criteria:

* Children born more than 4 weeks preterm
* children with other systemic illness that atopy/allergy
* Children requiring mechanical ventilation at any time since birth.
D: Inclusion Criteria:

Patients will be enrolled into the 2-week placebo run-in period if they meet all the following criteria:

* Age ≥ 1 year and ≤ 4 years.
* At least 3 episodes of wheeze or asthma-like symptoms in the 6 months preceding the study entry.
* A cooperative attitude and ability to be trained to inhale correctly from the device and to complete the diary cards.
* Written parental/guardian informed consent obtained.

Patients will be then randomised to the treatment period if they meet all the previous criteria plus:

* Presence in at least 7 days out of the 14 days of the run-in period of at least one of the following symptoms: wheeze, cough or shortness of breath; or had required at least one dose of relief salbutamol.

Exclusion Criteria:

* History of severe asthma exacerbation or exacerbations requiring hospitalisation in the previous 4 weeks.
* Symptomatic infection of the airways requiring treatment with antibiotics or antimycotics in the previous 4 weeks.
* Treatment with inhaled steroids in the previous 4 weeks or oral steroids in the previous 8 weeks.
* Treatment with methyl-xantine derivatives in the previous 4 weeks.
* Treatment with long-acting β2-agonists in the previous 2 weeks.
* Changes in asthma medications taken on regular basis in the previous 4 weeks.
* Symptoms of asthma limited to seasonal allergen exposure.
* History of clinically significant cardiac, renal, neurologic, hepatic, endocrine or pulmonary disease (except asthma), or laboratory testing abnormalities, whose sequelae and/or treatments can interfere with the results of the present study.
* Evidence of pulmonary malformations.
* Evidence of immunological deficiency (patients to be withdrawn if diagnosed during the study).
* Cancer or any other chronic disease with prognosis \< 2 years.
* Hypersensitivity to inhaled corticosteroids.
* Participation in another trial in the last 4 weeks.

Answer: A