Budesonide/formoterol as effective as prednisolone plus formoterol in acute exacerbations of COPD. A double-blind, randomised, non-inferiority, parallel-group, multicentre study

Abstract

Background: Oral corticosteroids and inhaled bronchodilators with or without antibiotics represent standard treatment of COPD exacerbations of moderate severity. Frequent courses of oral steroids may be a safety issue. We wanted to evaluate in an out-patient setting whether a 2-week course of inhaled budesonide/formoterol would be equally effective for treatment of acute COPD exacerbations as standard therapy in patients judged by the investigator not to require hospitalisation.

Methods: This was a double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatment strategies; two weeks' treatment with inhaled budesonide/formoterol (320/9 microg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 microg bid) in patients with acute exacerbations of COPD attending a primary health care centre. Inclusion criteria were progressive dyspnoea for less than one week, FEV1 30-60% of predicted normal after acute treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromide and no requirement for subsequent immediate hospitalisation, i.e the clinical status after the acute treatment allowed for sending the patient home.A total of 109 patients (mean age 67 years, 33 pack-years, mean FEV1 45% of predicted) were randomized to two weeks' double-blind treatment with budesonide/formoterol or prednisolone plus formoterol and subsequent open-label budesonide/formoterol (320/9 microg bid) for another 12 weeks. Change in FEV1 was the primary efficacy variable. Non-inferiority was predefined.

Results: Non-inferiority of budesonide/formoterol was proven because the lower limit of FEV1-change (97.5% CI) was above 90% of the efficacy of the alternative treatment. Symptoms, quality of life, treatment failures, need for reliever medication (and exacerbations during follow-up) did not differ between the groups. No safety concerns were identified.

Conclusion: High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in non-hospitalized COPD patients. An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids are used.

Clinical trial registration: NCT00259779.

Figures

Figure 1

Change in FEV1 as % predicted, measured at the clinic, from baseline to one and two weeks for all patients (main graph) and log ratio between treatments (inset graph). Data are presented as means and ± 95% CIs. * The treatment with budesonide/formoterol was non-inferior to the standard treatment with prednisolone plus formoterol because the predefined limit of at least 90% effect with budesonide/formoterol was superseded by the value (92.0%) of the lower limit of the 97.5% CI. The mean effect of budesonide/formoterol was 99.4% of standard treatment and the upper 97.5% CI limit was 107.4%.

Figure 2

Change in FEV1 as % of predicted from daily measurements at home during the double-blind period. Bars to the right are presented as means and ± 95% CIs.

Figure 3

Change from baseline in four COPD symptom scores during double-blind treatment: difficulty in breathing, cough, chest tightness and night-time awakenings. Bars to the right are means and ± 95% CIs. Lower values represent improvements.

Figure 4

Time to first exacerbation during the open-label treatment period. Day 0 corresponds to the end of the double-blind treatment period. The groups shown represent the treatment arms for the double-blind treatment period.

Figure 5

Serum C-reactive protein levels at baseline and after one, two and 14 weeks' treatment. Data are presented as means and standard errors of the mean. Between week two and week 14 all patients were treated with budesonide/formoterol, 320/9 μg, one dose twice daily.