Results

All statistical analyses were performed on the intent-to-treat population which consisted of 45 of the 52 subjects screened. A further five subjects withdrew from the study after randomisation. Three of the withdrawn subjects failed to return. These subjects were randomised to treatment sequences ACB, CAB, and ACB (where A = salmeterol 50 μg, B = salmeterol 100 μg, and C = salbutamol 200 μg) and withdrew during periods 1, 2, and 2, respectively. One subject, randomised to sequence ACB, withdrew due to non-compliance in the third period. The other withdrawal, randomised to sequence BCA, withdrew due to lack of efficacy in the first period. All subjects returned at least 80% of the prescribed study medication with the blisters pierced.

Thirty one (69%) of the 45 subjects in the intent-to-treat population were boys with 24 (77%) being less than 12 years of age. Of the 14 girls, 10 (71%) were less than 12 years of age. The overall mean (SD) age of the subjects was 9 (2.8) years.

Eighty two percent of the subjects had a family history of asthma, 80% had a history of seasonal rhinitis, and 60% had a positive skin test to common allergens. All children had at least one exacerbation requiring a change in medication in the previous year, but only five had been admitted to hospital in that period. The main asthma triggers identified were exercise (96%) and cold air (91%).

The overall incidence of adverse events experienced during treatment was slightly higher with salbutamol 200 μg (79%) than with salmeterol 50 μg (64%) or 100 μg (70%). However, for the most common adverse events (asthma, upper respiratory tract infection, cough, headache, and sore throat) there were no statistically significant differences between the treatment groups. Headache was the most commonly reported drug related adverse event in all three treatment groups. Nine patients in the intent-to-treat population experienced at least one serious adverse event during the run in period, study period, or follow up. Two subjects had serious adverse events that were considered to be possibly or probably related to study medication. However, on further follow up the investigator concluded that one these was unlikely to be related to study medication. No subjects died in the study and no patients were withdrawn because of an adverse event.

The primary efficacy analysis identified the two salmeterol treatments to be significantly more effective at increasing the mean morning PEF than salbutamol. For salmeterol 50 μg versus salbutamol 200 μg the estimated treatment difference was 9.6 l/min (95% confidence interval (CI) 2.1 to 17.1), p = 0.013. For salmeterol 100 μg versus salbutamol 200 μg the estimated treatment difference was 13.8 l/min (95% CI 6.0 to 21.5), p = 0.001. No significant difference was found between the two doses of salmeterol (p = 0.280, table2).

Analysis of the percentage predicted mean morning PEF gave similarly significant results to the treatment differences. However, for the mean evening PEF and percentage predicted mean evening PEF, no significant treatment differences were identified. The clinic visit FEV₁ also showed no differences between treatments. Only 14 subjects were tested for bronchial hyperreactivity (PC₂₀) on salmeterol 50 μg, 15 on salmeterol 100 μg, and 16 on salbutamol 200 μg and no significant differences were found between the treatment groups.

The median percentage of days during which no rescue medication was required was greatly increased from baseline (42%) for all three treatments: 61% for salmeterol 50 μg, 72% for salmeterol 100 μg, and 65% for salbutamol 200 μg. However, Koch's method provided no evidence to suggest that any one treatment was more effective in increasing the percentage of days with no rescue medication. No significant differences were found between the treatment groups for the percentage of nights during which no rescue medication was required.

The median daytime symptom score improved from a baseline score of 1 to a score of 0 for all three treatments and the daytime symptom score remained at 0 for all treatments throughout the study. The percentage of symptom free days increased from baseline for all three treatments but there were no significant differences between them. The physician and child assessments of efficacy were the same for all study periods, with more than 50% rating the study medication as effective or very effective. These results provide no further evidence of any differences between treatments.

Discussion

This study has shown that, in addition to inhaled corticosteroids in doses of at least 400 μg/day, the use of salmeterol 50 μg bd and salmeterol 100 μg bd provides significantly greater improvement in mean morning PEF (9.6 l/min and 13.8 l/min, respectively) than regular salbutamol 200 μg qds in children with symptomatic asthma over a four week period. There was no significant difference in efficacy between the two doses of salmeterol. There were no significant treatment differences for the symptom scores, evening peak expiratory flow, use of rescue medication, spirometric indices, and histamine challenge.

This study was double dummy and double blind with a random order of treatments to control for the tendency for children with asthma to improve spontaneously over time. There are potential limitations to any conclusions that can be drawn because of the nature of the study design. Firstly, the treatment periods were for four weeks only, and thus we cannot exclude that a longer time period would have revealed loss of efficacy or increased side effects in any of the treatments. We decided to opt for a shorter treatment period because of concerns about the possible ill effects of regular short acting β₂agonists during the control period, and also to enable us to complete a dose response study in a reasonable length of time. The alternative would have been a parallel group design over 12 weeks but this would have required far more patients to achieve comparable statistical power. However, inspection of the raw data showed no compelling evidence of any trends for improvement or deterioration with time during the last three weeks of the treatment periods, implying that a plateau had been reached which is, to some extent, reassuring (fig 1). Furthermore, Russell et al 5showed no loss of benefit in their parallel group study over a 12 week period and Verberne et al 9showed no deterioration in bronchoprotection with salmeterol treatment over a four month period in 30 children with mild asthma. A more recent study10 did show a reduction in the duration of the protective action of salmeterol against exercise induced bronchoconstriction. The short duration of the study means that we were precluded from detecting any effect (positive or negative) on acute exacerbations of asthma.

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Figure 1

Mean morning peak expiratory flow rate (PEFR) over the four week treatment period, using the raw data.

Secondly, the study lacked a placebo period. However, in these very symptomatic children we felt that a placebo period would not be ethical and that a two week run in was the longest acceptable time without instituting a change in treatment. We accept that an alternative study design would have been to provide as needed rather than regular salbutamol,5 but the children were already in effect using this strategy before joining the study and were still symptomatic, so we felt we had to offer an alternative strategy. The further alternative, that of doubling the dose of inhaled corticosteroids, would have been likely to require a longer study period and the comparison of these two strategies was not the aim of this study. We do not have any direct data on changes in airway inflammation. Clearly we could not have carried out bronchoscopy, lavage, and biopsy at the end of each treatment period in this group of children. At the time the study was carried out we did not have access to measurements of exhaled nitric oxide11 ,12 or induced sputum13 that would undoubtedly have supplemented our findings. However, even these techniques would have been difficult to apply in some of the younger children. We were able to measure bronchial hyperreactivity as a surrogate for airway inflammation14 ,15 in about one third of the group, and reassuringly there was no change with treatment. However, this study cannot exclude the possibility of either short term or long term worsening of airway inflammation in any treatment arm.

Nonetheless, within the constraints of the study, the data provided no evidence of a significant advantage, in terms of the primary or secondary end points, of doubling the conventional dose of salmeterol. Previous dose response studies have compared salmeterol in doses up to 50 μg bd16-18 with conflicting results. Lenneyet al 16 compared 25 μg with 50 μg bd and showed that symptoms and morning and evening peak flow were higher with salmeterol 50 μg bd. By contrast, de Benedictiset al 17 found that a single dose of 25 μg salmeterol was equally as good as 50 μg in preventing exercise induced bronchoconstriction. Weinsteinet al 18 reported a trend to greater bronchodilatation with 42 μg than with 21 μg salmeterol in 243 children but found no statistically different changes between the two doses. Primhak et al 19did show additional bronchoprotective effect against methacholine induced wheeze with an increase in a single salmeterol dose from 25 to 100 μg, but this was in younger children using a mask and spacer. It is difficult to compare airway deposition with this device and a dry powder device. Some of these apparent contradictions may be because the plateau of the dose response curves are at different doses for bronchodilatation and bronchoprotection. Our data imply that, at least for bronchodilatation, symptom score and use of rescue medication, the plateau has been reached by 50 μg salmeterol twice daily in most individuals. This does not exclude the possibility that some individuals may benefit from a higher dose and, indeed, four children (10%) did appear to show additional benefit at the higher dose.

The role of long acting β₂ agonists in paediatric asthma is still to be defined. They should only be used in children already taking inhaled corticosteroids, and not used as sole preventive treatment.20 ,21 Several previous investigators have demonstrated benefit in children with asthma who had inadequate control on moderate doses of inhaled corticosteroids.16 ,22 ,23However, the role of long acting β agonists in paediatric asthma was called into question by Verberne et al 6 who performed a randomised, double blind, parallel group study comparing beclomethasone 200 μg bd plus placebo, beclomethasone 200 μg bd plus salmeterol 50 μg bd, and beclomethasone 400 μg bd in 177 children. They showed no difference in lung function, bronchial hyperreactivity, and asthma control in any of the three groups. This may be because they were studying children whose asthma was already well controlled (average rescue bronchodilator usage <1 dose/week). In our study, in which a much more symptomatic group of patients was studied, differences in the mean morning PEF were seen over the four week period with the different treatments, both doses of salmeterol giving significantly greater improvements in PEF than salbutamol. The symptomatic control of patients and use of rescue therapy improved over the four week period in all treatment groups, although the differences were not significant.

What then is the role of long acting β₂ agonists in paediatric asthma? They should never be used as monotherapy but, when added to inhaled corticosteroids, there is evidence for improved asthma control and better lung function with no deterioration in bronchial hyperreactivity, at least in the short term. For most children there will be no additional benefit in increasing the dose of salmeterol above 50 μg bd, although a few children may benefit from a trial of 100 μg bd. Although benefit can be obtained with regular short acting β₂ agonists, the improvement is less and the inconvenience of a four times daily regime is likely to make it less acceptable. The stage at which long acting β₂ agonists should be added rather than the dose of inhaled steroids increased remains to be agreed, at least in paediatric asthma.