Childhood Asthma Research and Education (CARE) Network Trial - Best Add-On Therapy Giving Effective Response (BADGER)
Childhood Asthma Research and Education (CARE) Network Trial - Best Add-On Therapy Giving Effective Response (BADGER)
Asthma is a common, serious illness among children in the United States. While a low dose of
 inhaled corticosteroids (ICS) may effectively control symptoms, some children may require
 additional medications to maintain adequate asthma control. This study compares the
 effectiveness of a higher dose of ICS, ICS combined with a long-acting beta-agonist (LABA)
 medication, and ICS combined with a leukotriene receptor antagonist (LTRA) medication at
 reducing the impact and severity of asthma exacerbations that occur in children with mild to
 moderate persistent asthma.
Almost 9 million children in the United States have asthma, and it is a leading cause of
 hospitalizations and school absenteeism. Common asthma symptoms include wheezing, shortness
 of breath, chest tightness, and coughing. While there is no cure for asthma, most children
 who receive proper treatment are able to control symptoms and lead a normal life. Low doses
 of ICS are commonly prescribed to prevent symptoms and keep asthma under control. While this
 is usually sufficient to prevent asthma attacks, some children do not respond well to low
 dose ICS alone. For these children, their asthma symptoms may be more effectively controlled
 by either receiving a higher dose of ICS or receiving LABA or LTRA medications in combination
 with a low dose of ICS. Both LABA and LTRA medications are used to help control moderate to
 severe asthma. The purpose of this study is to compare the effectiveness of a high dose of
 ICS versus a low dose of ICS plus either LABA or LTRA medication at improving asthma control
 and reducing the severity of symptoms that occur in children with mild to moderate persistent
 asthma.

 This study began with an 8-week screening period during which participants were monitored
 while they used an inhaler with a low dose of ICS medication. During this time, participants
 also attended one or two study visits. At each visit, participants underwent a physical
 examination, exhaled nitric oxide analysis, and lung function and airway pressure testing.
 After enrollment criteria were met, participants underwent these same evaluations again, and
 they completed questionnaires to assess asthma control, quality of life, and home
 environmental factors. Blood was collected and a methacholine challenge test was completed,
 which artificially triggers an asthma attack to determine the severity of an individual's
 asthma. Participants then were randomly assigned to one of six treatment sequences, each of
 which includes the following three regimens in a different order:

 -  Low dose of ICS and salmeterol, a LABA medication

 -  Low dose of ICS and montelukast, a LTRA medication

 -  Double dose of ICS

 Each treatment period lasted 16 weeks, with study visits occurring weekly. A physical
 examination, blood collection, lung function and airway pressure testing, a methacholine
 challenge test, and questionnaires occurred at selected visits. Throughout the study,
 participants recorded asthma symptoms, peak expiratory flow rates, and rescue medication
 usage in a daily diary. The entire length of the study did not exceed 56 weeks.
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