Distribution of therapeutic response in asthma control between oral montelukast and inhaled beclomethasone

Abstract

The distribution of responses in study populations provides a novel method of comparing the benefit of two treatments. This 6-week, randomised, placebocontrolled, double-blind study compared the effectiveness of oral montelukast with inhaled beclomethasone in chronic asthma by assessing the distribution and overlap of patient responses to therapy, as measured by a clinical outcome (asthma control days).A total of 730 adult patients with asthma, age 15-65 yrs, with a forced expiratory volume in one second (FEV1) at baseline of 50-85% of predicted and o15% improvement in FEV1 after inhaled b-agonist were enrolled. After a 2-week placebo run-in period, patients were randomly allocated to receive montelukast (10 mg once daily), inhaled beclomethasone (200 mg twice daily) or placebo. The primary end-point (per cent of asthma control days) was compared between treatments as the overlap in the response distributions.The overlap of the distribution of responses between the montelukast and beclomethasone groups was 89% for per cent asthma control days and 96% for change from baseline in FEV1. The mean (¡SD) per cent asthma control days in the montelukast and beclomethasone groups was significantly higher than that in the placebo group (placebo 40.0 ¡ 35.8, montelukast 50.7 ¡ 37.1, beclomethasone 57.9 ¡ 36.1). The mean differences between montelukast and placebo, beclomethasone and placebo, and montelukast and beclomethasone were significant. The mean per cent change (¡SD) from baseline in FEV1 was 12.1¡18.7 and 13.9¡20.8 in the montelukast and beclomethasone groups, respectively, and significantly greater than that in the placebo group (6.4¡20.1); there was no significant difference between the montelukast and beclomethasone groups in mean values or response distribution. There was also no difference among treatment groups in the frequency of adverse experiences.A comparison of the response distribution is an important approach to comparing therapies; montelukast and beclomethasone provided similar response distributions for the end-point of per cent asthma control days over a 6-week treatment period. Eur Respir J 2003; 21: 123-128

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

“…In addition, the use of intermittent courses of oral corticosteroids to treat exacerbations without any maintenance treatment appears to be as effective as using ICS regularly [118], however, the size of cohort used was probably not big enough to show any differential effect. Another issue with the response of ICS is that at least the bronchodilator response as measured by FEV 1 is not uniform across a population of patients with mild to moderate asthma, and a percentage of patients do not respond to ICS [116,119]. In the study of Martin et al, 46 % of patients with mild to moderate asthma did not respond to low-dose ICS defined as an FEV 1 response of less than 5% of baseline, and the non-responders were associated with a lesser bronchodilator response to salbutamol but without any greater inflammatory index as measured by sputum eosinophils or exhaled nitric oxide levels [119].…”

“…However, LTRA do not provide as good a benefit as low-dose inhaled CS therapy [115,116] although they remain an alternative therapy, particularly in pediatric patients. One study indicated that the intermittent use of ICS combined with a short-acting β-agonist (SABA) as needed was as effective as the regular use of ICS twice daily with SABA as needed [117].…”

Distribution of therapeutic response in asthma control

“…Using traditional measures of asthma, the study by BAUMGARTNER et al [1] showed significant differences in favour of beclomethasone in several variables and a trend in all others, suggesting a true finding. The proposed new analysis method suggests the two treatments are equivalent.…”

“…The only design that allows the within-patient difference to be addressed is the crossover design, and its sophisticated version, N of 1 [4]. The use of crossover studies in asthma is a challenge, but we should also recognise that the approach proposed by BAUMGARTNER et al [1] is not suitable for parallel group designs.…”

“…The paper by BAUMGARTNER et al [1] raises very important questions pertaining to the interpretation and usefulness of randomised clinical trials, the use of surrogates of little relevance to the patient and the comparison of results using group average values. However, these problems are not adequately addressed.…”