Safety and efficacy of fluticasone/formoterol combination therapy in adolescent and adult patients with mild-to-moderate asthma: a randomised controlled trial

Abstract

Background: This study investigated the efficacy and safety of a new asthma therapy combining fluticasone propionate and formoterol fumarate (fluticasone/formoterol; flutiform®), administered twice daily (b.i.d.) via a single aerosol inhaler, compared with its individual components administered separately and placebo, in patients with mild-to-moderate asthma.

Methods: Patients aged ≥ 12 years were evenly randomised to 12 weeks of treatment with fluticasone/formoterol (100/10 μg b.i.d.), fluticasone (100 μg b.i.d.), formoterol (10 μg b.i.d.), or placebo, in this double-blind, parallel group, multicentre study. The three co-primary endpoints were: a) change in forced expiratory volume in the first second (FEV(1)) from morning pre-dose at baseline to pre-dose at week 12 for the comparison with formoterol; b) change in FEV(1) from morning pre-dose at baseline to 2 hours post-dose at week 12 for the comparison with fluticasone, and c) time to discontinuation due to lack of efficacy from baseline to week 12 for the comparison with placebo. Safety was assessed based on adverse events, clinical laboratory tests and vital sign evaluations.

Results: Statistically significant differences were demonstrated for all the three co-primary endpoints. Fluticasone/formoterol combination therapy showed significantly greater improvements from baseline to end of study in the change in pre-dose FEV(1) compared with formoterol (Least Squares (LS) mean treatment difference: 0.101 L; 95% Confidence Interval (CI): 0.002, 0.199; p = 0.045) and the change in pre-dose compared with 2 hours post-dose FEV(1) versus fluticasone (LS mean treatment difference: 0.200 L; 95% CI: 0.109, 0.292; p < 0.001). The time to discontinuation due to lack of efficacy was significantly longer for patients in the combination therapy group compared with those receiving placebo (p = 0.015). Overall, the results from multiple secondary endpoints assessing lung function, asthma symptoms, and rescue medication use supported the superior efficacy of the combination product compared with fluticasone, formoterol, and placebo. The fluticasone/formoterol combination therapy had a good safety and tolerability profile over the 12 week treatment period.

Conclusions: Fluticasone/formoterol had a good safety and tolerability profile and showed statistically superior efficacy for the three co-primary endpoints compared to fluticasone, formoterol, and placebo, in adolescents and adults with mild-to-moderate asthma. EudraCT number: 2007-002866-36; US NCT number: NCT00393991.

Figure 1

Study design. *Albuterol/salbutamol pro re nata (as needed) as rescue medication. b.i.d. = twice daily; ICS = inhaled corticosteroid; pMDI = pressurised metered dose inhaler.

Figure 2

Patient flow diagram.

Figure 3

A – Mean change in FEV₁(L): mean change from baseline to pre-dose at weeks 2, 4, 8, and 12, Full Analysis Set (LOCF). * P-value ≤ 0.05 versus fluticasone/formoterol 100/10 μg b.i.d. combination therapy treatment group. Baseline means were 2.416 L, 2.425 L, 2.459 L, and 2.352 L for the fluticasone/formoterol, fluticasone, formoterol, and placebo treatment groups, respectively, for all patients in the Full Analysis Set. b.i.d. = twice daily; FEV₁ = forced expiratory volume in the first second; LOCF = last observation carried forward. Figure 3 B – Mean change in FEV₁(L): mean change from baseline to 2 hours post-dose at weeks 2, 4, 8, and 12, Full Analysis Set (LOCF). * P-value ≤ 0.05 versus fluticasone/formoterol 100/10 μg b.i.d. combination therapy treatment group. Baseline means were 2.416 L, 2.425 L, 2.459 L, and 2.352 L for the fluticasone/formoterol, fluticasone, formoterol, and placebo treatment groups, respectively, for all patients in the Full Analysis Set. b.i.d. = twice daily; FEV₁ = forced expiratory volume in the first second; LOCF = last observation carried forward.

Figure 4

Morning and evening PEFR (L/min): mean change from baseline to week 12, Full Analysis Set. * P-value < 0.01 versus fluticasone/formoterol 100/10 μg b.i.d. combination therapy treatment group. † P-value < 0.001 versus fluticasone/formoterol 100/10 μg b.i.d. combination therapy treatment group. b.i.d. = twice daily; PEFR = peak expiratory flow rate; SE = standard error. Changes from baseline are shown as least-squares mean ± SE for the full analysis set.