Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma

BACKGROUND: The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call. RESULTS: A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups. CONCLUSIONS: In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated.