Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial

Abstract

Background: Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study.

Objective: This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD.

Methods: This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1, 964 patients aged >or =40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 microg x two inhalations (320/9 microg); budesonide/formoterol pMDI 80/4.5 microg x two inhalations (160/9 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); 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 microg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001). The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p <or= 0.004). Both budesonide/formoterol doses were more effective than placebo (p <or= 0.006) for controlling dyspnoea and improving health status (St George's Respiratory Questionnaire). All treatments were generally well tolerated. The incidence of pneumonia was not different for active (3.4-4.0%) and placebo (5.0%) groups.

Conclusions: Budesonide/formoterol pMDI (320/9 microg and 160/9 microg) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD. Only budesonide/formoterol pMDI 320/9 microg demonstrated greater efficacy for both co-primary variables compared with formoterol DPI 9 microg. Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo.

Fig. 1

Study design. To maintain blinding, patients received both a pressurized metered-dose inhaler (pMDI) and a dry powder inhaler (DPI) containing either active treatment or double-dummy placebo (PL) as appropriate. This study used formoterol (FM) DPI (Oxis® Turbuhaler®, AstraZeneca, Lund, Sweden) as the FM comparator because FM is not available as a hydrofluoroalkane pMDI in the US. A previous study in asthma patients reported equivalent FM-related bronchodilatory effects when FM was administered in combination with budesonide (BUD) via pMDI or alone via DPI.[5] Patients were asked to return to the clinic for follow-up visits 3–8 at the end of months 1, 2, 4, 6, 9 and 12, and received a telephone call 4 weeks after the last clinic visit. bid = twice daily; R = randomization.

Fig. 2

Patient disposition. AE = adverse event; bid = twice daily; BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; med = medication; PL = placebo; pMDI = pressurized metered-dose inhaler.

Table I

Patient demographic and baseline clinical characteristics of randomized patients

Fig. 3

Co-primary efficacy endpoints. Least squares mean change from baseline by study visit over the randomized treatment period in (a) pre-dose forced expiratory volume in 1 second (FEV₁) and (b) 1-hour post-dose FEV₁. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; pMDI = pressurized metered-dose inhaler. * p < 0.001 vs placebo; † p ≤ 0.023 vs FM.

Table II

Mean (SD) changes from baseline in additional pulmonary function assessments

Fig. 4

Mean percentage change from baseline in forced expiratory volume in 1 second (FEV₁) over 12 hours at randomization and end of treatment (EOT) for (a) budesonide (BUD)/formoterol (FM) 320/9 μg twice daily (bid) vs placebo, (b) BUD/FM 160/9 μg bid vs placebo and (c) FM 9 μg bid vs placebo. DOR = day of randomization; DPI = dry powder inhaler; pMDI = pressurized metered-dose inhaler.

Fig. 5

Least squares mean change from baseline by study visit over the randomized treatment period in (a) pre-dose inspiratory capacity (IC) and (b) 1-hour post-dose IC. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; pMDI = pressurized metered-dose inhaler. * p < 0.001 vs placebo; † p = 0.01 vs FM; ‡ p < 0.05 vs FM; § p < 0.01 vs placebo.

Fig. 6

Kaplan-Meier probability curve for the time to first chronic obstructive pulmonary disease exacerbation during randomized treatment. BUD = budesonide; DPI = dry powder inhaler; FM = formoterol; pMDI = pressurized metered-dose inhaler. * p ≤ 0.004 vs placebo; † p = 0.026 vs FM.

Table III

Mean changes (SD) in SGRQ total and domain scores from baseline^a to end of treatment^b

Table IV

Mean (SD) changes in chronic obstructive pulmonary disease (COPD) symptom variables from baseline^a to the average over the randomized treatment period

Table V

Overall adverse events (AEs) [irrespective of relationship to study medication] reported by ≥3% of patients