Childhood Asthma Research and Education (CARE) Network Trial - Best Add-On Therapy Giving Effective Response (BADGER)

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