Daily or intermittent budesonide in preschool children with recurrent wheezing

Abstract

Background: Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy.

Methods: We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy.

Results: The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen.

Conclusions: A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST ClinicalTrials.gov number, NCT00675584.).

Figure 1. Study Design and Enrollment

Panel A shows the study design and treatments. Intermittent high-dose nebulized budesonide inhalation suspension was administered at a dose of 1 mg twice daily in the form of Pulmicort Respules for 7 days at the onset of a predefined respiratory tract illness. A matched placebo was administered once nightly on all other days. Daily low-dose nebulized budesonide inhalation suspension was administered at a dose of 0.5 mg once nightly, also in the form of Pulmicort Respules. During respiratory tract illnesses, an appropriately matched morning placebo was used for 7 days. To maintain blinding during respiratory tract illnesses, daily treatments were discontinued for 7 days and respiratory illness kits that were based on the study-group assignment were administered for 7 days. After 7 days, regular daily treatments were restarted. Open-label rescue albuterol was administered per protocol during a respiratory tract illness and as needed. Study medications were administered with the use of a Pari Ultra II compressor with a Pari LC Sprint reusable nebulizer and a mask (Bubbles the Fish II or Pari Baby mask), if needed, or a mouthpiece, depending on the age of the child. Rescue albuterol was administered at a dose of 180 μg per treatment by metered-dose inhalation (Ventolin HFA, GlaxoSmithKline) through AeroChamber Z-STAT Plus with FlowSIGnal Whistle with ComfortSeal Mask (Monaghan Medical) or a solution of 2.5 mg of albuterol per treatment by nebulization according to protocol during a respiratory tract illness (four times daily, while the child was awake, for the first 48 hours) and as needed. Panel B shows the numbers of patients who were enrolled in the study, underwent randomization, and completed the study.

Figure 2. Exacerbations of Wheezing and Respiratory Tract Illness

P values are based on exact Wilcoxon–Mann–Whitney tests for Panels A and C and on Wald tests from a proportional-hazards regression model for Panels B and D. All comparisons have been adjusted for clinical center and age.

Figure 3. Profiles of Symptom Severity during Respiratory Tract Illness

Day zero corresponds to the start of treatment for a respiratory tract illness. P values are for comparisons of symptom levels during the first 14 days after the initiation of treatment for respiratory tract illness, with adjustment for baseline symptom levels (on days 13 to 7 before the initiation of treatment). Plotted values are means for the indicated day. Scores range from 0 to 5, with higher scores indicating more severe symptoms.