Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: Results of a 6-month randomized clinical trial

Abstract

Background: The combination of an inhaled corticosteroid (ICS) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. Budesonide/formoterol dry powder inhaler (DPI) has demonstrated efficacy and tolerability in patients with COPD. Objective: To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) in patients with COPD. Methods: This was a 6-month, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre study (NCT00206154) of 1704 patients aged ≥40 years with moderate to very severe COPD conducted in 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa. After 2 weeks of treatment based on previous therapy (ICSs and short-acting bronchodilators allowed during the run-in period), patients received one of the following treatments administered twice daily: budesonide/formoterol pMDI 160/4.5 μg x two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg x two inhalations (160/9 μg); budesonide pMDI 160 μg x two inhalations (320 μg) plus formoterol DPI 4.5 μg x two inhalations (9 μg); budesonide pMDI 160 μg x two inhalations (320 μg); formoterol DPI 4.5 μg x two inhalations (9 μg); or placebo. Main outcome measures: The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1. Results: Budesonide/formoterol 320/9 μg demonstrated significantly greater improvements in pre-dose FEV1 versus formoterol (p = 0.026; pre-specified primary comparator) and 1-hour post-dose FEV1 versus budesonide (p < 0.001; pre-specified primary comparator); budesonide/formoterol 160/9 μg demonstrated significantly greater improvements versus budesonide (p < 0.001) for 1-hour post-dose FEV1 but not versus formoterol for pre-dose FEV1. Dyspnoea (measured using the Breathlessness Diary) and health-related quality-of-life (HR-QOL) scores (based on the St George's Respiratory Questionnaire total score) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide, formoterol and placebo (p ≤ 0.044 for all). Although not powered a priori for comparisons, the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and/or hospitalization was numerically (20-25%) lower with the budesonide-containing treatments (0.710-0.884) versus formoterol (1.098) and placebo (1.110). This result was driven by the exacerbations requiring treatment with oral corticosteroids (79-120 events). The number of exacerbations resulting in hospitalization was very low across treatment groups (11-22); the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 μg (0.158) versus other treatment groups (0.081-0.108) except budesonide/formoterol 160/9 μg (0.139), and for budesonide/formoterol 160/9 μg versus formoterol (0.081) [p ≤ 0.05]. All treatments were generally well tolerated. The incidence of individual non-fatal serious adverse events was similar across all treatment groups, except COPD, which was highest in the budesonide/formoterol 320/9 μg group (6.1%) and lowest in the budesonide (3.6%) and formoterol (3.9%) groups, with a range of 4.3-4.6% in the budesonide/formoterol 160/9 μg, budesonide plus formoterol and placebo groups. Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo. There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo. Conclusions: Budesonide/formoterol pMDI 320/9 μg demonstrated significantly greater efficacy for pulmonary function on both co-primary endpoints versus the pre-specified comparators (formoterol DPI 9 μg for pre-dose FEV1 and budesonide pMDI 320 μg for 1-hour post-dose FEV1). Budesonide/formoterol pMDI 160/9 μg demonstrated significantly greater efficacy for 1-hour post-dose FEV1 versus budesonide pMDI 320 μg. Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo. Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo. © 2008 Adis Data Information BV. All rights reserved.