, Volume 68, Issue 14, pp 1975-2000,
Open Access This content is freely available online to anyone, anywhere at any time.
Date: 17 Sep 2012

Efficacy and Safety of Budesonide and Formoterol in One Pressurized Metered-Dose Inhaler in Patients with Moderate to Very Severe Chronic Obstructive Pulmonary Disease

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 × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); budesonide pMDI 160 μg × two inhalations (320 μg) plus formoterol DPI 4.5 μg × two inhalations (9 μg); budesonide pMDI 160 μg × two inhalations (320 μg); formoterol DPI 4.5 μg × 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.