Objectives

To compare the effectiveness of a high dose of inhaled corticosteroids (ICS) versus a low dose of ICS plus either long-acting beta-agonist (LABA) medication or leukotriene receptor antagonist (LTRA) medication at improving asthma control and reducing the severity of symptoms that occur in children with mild to moderate persistent asthma.

Background

Asthma is a condition that afflicts almost 9 million children in the United States each year. It is the leading cause of pediatric hospitalization and school absenteeism, and is characterized by symptoms of wheezing, coughing, and shortness of breath. There is no cure for asthma but symptoms are typically managed with inhaled corticosteroids as a preventative medication and albuterol as a rescue medication. However, children commonly experience uncontrolled asthma while under treatment with low-dose inhaled corticosteroids and there is limited and inconsistent evidence available to guide practitioners about how to treat such patients.

Participants

480 pediatric participants, ages 6 to 18 were enrolled in the study. Participants were eligible for enrollment if they had mild-to-moderate asthma, an ability to perform reproducible spirometry, an FEV1 of at least 60% before bronchodilation, and an increase in the FEV1 of at least 12% (bronchodilator reversibility) or a methacholine provocation concentration causing a 20% fall in the FEV1 of 12.5 mg/mL or less. Of these, 182 participants underwent randomization. A patient became eligible for randomization after the documentation of uncontrolled asthma, which was defined as the occurrence of at least one of the following for more than 2 days per week on average during a 2-week period: diary-reported symptoms (coughing rated as moderate or severe or wheezing rated as mild, moderate, or severe), rescue use of an inhaled bronchodilator with two or more puffs per day, or peak flows under 80% of the predetermined reference value.

Participants were considered excluded during enrollment or run-in period for any of the following conditions or concerns: current or prior use of medications and/or significant medical diagnoses known to significantly interact with corticosteroid disposition; pre-bronchodilator FEV1 less than 60% predicted at study visit 1; inability to perform study procedure or use of study drugs; refusal to consent to a genotype evaluation; cigarette smoking or smokeless tobacco use in the year prior to study entry.

Design

CARE-BADGER was a randomized, double-blind, three-treatment, three-period crossover trial for a total of 48 weeks. During the run-in period of 2 to 8 weeks participants received one puff of 100 µg of fluticasone twice daily and attended 1-2 study visits that included a physical examination, exhaled nitric oxide analysis, and lung function and airway pressure testing. A patient became eligible for randomization after the documentation of uncontrolled asthma, as described above.

The study assigned participants to receive each of the three blinded step-up therapies in random order for 16 weeks:

• ICS step-up group: 250 µg of fluticasone twice daily
• LABA step-up group: 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist (salmeterol) twice daily
• LTRA step-up group: 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist (montelukast) daily

Study visits were conducted at 4-week intervals during each 16 week treatment period. A physical examination, lung function and airway pressure testing, methacholine challenge test, phlebotomy, and questionnaires occurred at selected visits. Participants recorded asthma symptoms, peak expiratory flow rates, and rescue medication usage in a daily diary during the entire 56 week study period.

The primary outcome was the differential response to each therapy based on the following criteria for asthma control: the need for treatment with oral prednisone for acute asthma exacerbations, the number of asthma-control days, and the FEV1. Each of these were measured during the last 12 weeks of each 16-week treatment period.

Conclusions

The CARE-BADGER study showed a clinically significant differential response in nearly all the children (98%) with the best response during LABA step-up occurring significantly more frequently than during LTRA or ICS step-up.

Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362(11):975‐985. doi:10.1056/NEJMoa1001278

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