Elsevier

The Lancet

Volume 377, Issue 9766, 19–25 February 2011, Pages 650-657
The Lancet

Articles
Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(10)62145-9Get rights and content

Summary

Background

Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment.

Methods

In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5–18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 μg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 μg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329.

Results

843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)—555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37–61), the frequency of exacerbations was lower in the daily (28%, 18–40, p=0·03), combined (31%, 21–43, p=0·07), and rescue (35%, 24–47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14–43) in the placebo group, compared with 5·6% (1·6–14) in the combined (p=0·012), 2·8% (0–10) in the daily (p=0·009), and 8·5% (2–15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis.

Interpretation

Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided.

Funding

National Heart, Lung and Blood Institute.

Introduction

In children with mild persistent asthma, guidelines recommend the daily use of inhaled corticosteroids in low doses as the preferred treatment for the control of symptoms and asthma exacerbations.1, 2 Often, parents or children have great difficulty adhering to twice daily treatment during long asymptomatic periods, and either use inhaled corticosteroids sparingly or interrupt treatment altogether.3 Moreover, for children whose illness is well controlled with such treatment, no studies have established the optimum period for which treatment should be maintained, or at which point an individual should be weaned from treatment. Guidelines1 suggest weaning or withdrawal (step-down) of treatment after asthma control is achieved and maintained, without any clear evidence to support these recommendations.

Even when good day-to-day control is achieved with inhaled corticosteroids, children with mild persistent asthma can have a high frequency of exacerbations.4, 5 Thus, two essential and related challenges exist in the treatment of childhood asthma. First, what is the best strategy for discontinuing treatment in children with well controlled, mild asthma, but who are still at risk for exacerbations. Second, is there a treatment regimen that will decrease the risk of exacerbations in children with mild disease to a greater extent than is achieved with daily inhaled corticosteroids? Does this regimen need to be added to continued treatment with daily inhaled corticosteroids or can it be given on an as-needed basis?

Use of inhaled corticosteroids as rescue medication in combination with a bronchodilator can substantially decrease the frequency of asthma exacerbations that require prednisone.6, 7, 8, 9 Use of budesonide plus formoterol as rescue, when added to daily treatment with either budesonide or budesonide plus formoterol, substantially reduces the frequency of asthma exacerbations in both children and adults.6, 7, 8 In adults with mild asthma who took placebo twice daily, the use of beclomethasone plus albuterol as rescue was associated with substantially fewer exacerbations than was treatment with rescue albuterol alone, and with a similar frequency of exacerbations as with beclomethasone twice daily.9 These results suggest that inhaled corticosteroids used together with a bronchodilator as rescue could provide additional protection against exacerbations in children who are taking daily inhaled corticosteroids, and might also decrease the frequency of exacerbations in those who are not.

The goals of this TREXA study were to establish whether discontinuation of daily inhaled corticosteroids in children with well controlled, mild persistent asthma is associated with an increased risk of exacerbations, and whether or not the use of beclomethasone plus albuterol for relief, with or without concomitant use of daily beclomethasone, provides better protection against exacerbations than does a rescue strategy that uses albuterol alone.

Section snippets

Participants

Between January, 2007, and May, 2009, we recruited children and adolescents aged between 6 and 18 years from five clinical centres in the USA: Denver, CO; Madison, WI; Saint Louis, MO; San Diego, CA; and Tucson, AZ (satellite centres in Milwaukee, WI, and Albuquerque, NM, also recruited participants). All individuals recruited had a history of mild persistent asthma during the previous 2 years, and qualified for interruption or discontinuation of controller treatment because their illness was

Results

843 children were enrolled into the trial, of whom 288 (34%) were assigned to one of the four treatment groups (figure 1). Sociodemographic and clinical characteristics were much the same between participants who were randomised and those who were enrolled but were not eligible for the treatment phase (n=555; webappendix p 4). Baseline characteristics were much the same between individuals in the four treatment groups (table 1).

Figure 2 shows the Kaplan-Meier plots for time to first

Discussion

In this trial, we noted that, compared with treatment with only albuterol as rescue, daily beclomethasone reduced the risk for a first exacerbation by half, whereas rescue beclomethasone decreased the risk by more than a third, but this effect was not significant. Treatment failures were also substantially decreased in both groups that used daily beclomethasone and in the rescue beclomethasone group. Our results therefore suggest that rescue beclomethasone can lower the risk of exacerbations

References (26)

  • FA McAlister et al.

    Analysis and reporting of factorial trials: a systematic review

    JAMA

    (2003)
  • J Lubsen et al.

    Factorial trials in cardiology: pros and cons

    Eur Heart J

    (1994)
  • AC Plint et al.

    Epinephrine and dexamethasone in children with bronchiolitis

    N Engl J Med

    (2009)
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