Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study

Abstract

Background: The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.

Methods: The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV1 95% of predicted) who previously demonstrated a > or = 30% fall in forced expiratory volume in 1 second (FEV1) after inhaling adenosine 5'-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 microg), formoterol (4.5 microg), salbutamol (2 x 100 microg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day.

Results: In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV1 within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV1.

Conclusions: A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

Trial registration: ClinicalTrials.gov NCT00272753.

Figure 1

Study design of the Test Days.

Figure 2

Mean FEV₁ over the test day with three AMP provocations followed by a single dose of budesonide/formoterol 160/4.5 μg (open diamonds), formoterol 4.5 μg (open squares), salbutamol 2 × 100 μg (filled triangles) or placebo (crosses) immediately after the first AMP provocation.

Figure 3

Mean FEF_25-75 over the Test Day with three AMP provocations followed by a single dose of budesonide/formoterol 160/4.5 μg (open diamonds), formoterol 4.5 μg (open squares), salbutamol 2 × 100 μg (filled triangles) or placebo (crosses) immediately after the first AMP provocation.

Figure 4

Mean Borg score over the Test Day with three AMP provocations followed by a single dose of budesonide/formoterol 160/4.5 μg (open diamonds), formoterol 4.5 μg (open squares), salbutamol 2 × 100 μg (filled triangles) or placebo (crosses) immediately after the first AMP provocation.