Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: A randomized, double-blind, placebo-controlled, 12-week study

Objective: This study compared the efficacy and tolerability of the combination of fluticasone proplonate (FP) and salmeterol (SAL) delivered via a single hydrofluoroalkane (HFA) 134a metered-dose inhaler (MDI) with those of its 2 components alone delivered via a chlorofluorocarbon (CFC) MDI and placebo (PLA) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses (equivalent to FP 440-660 mu g/d) of inhaled corticosteroids (ICSs). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study consisting of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period. Participants had to be >= 12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study. Patients had to have used ICS therapy for >= 3 months before the study and at a consistent dose for the previous month. Lack of asthma control was defined as a forced expiratory volume in I second (FEV1) that was 40% to 85% of the predicted value. Patients could not enter the double-blind treatment period if they had 3 days when they required > 12 puffs of rescue albuterol per day or > 3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the randomization visit. Patients were randomized to receive one of the following treatments delivered via MD1 twice daily for 12 weeks: FSC 220/42 mu g HFA (2 inhalations of FSC 110/21 mu g; 125 mu g/21 mu g ex-valve); FP 220 mu g CFC (2 inhalations of FP 110 mu g); SAL 42 mu g CFC (2 inhalations of 21 mu g); or 2 inhalations of PLA HFA. The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV1 curve relative to the prerandomization baseline (FEV1 AUC(bl)). The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV1 at end point and the probability of not being withdrawn from the study due to worsening asthma. Tolerability assessments included electrocardiograms, routine clinical laboratory tests, vital signs, oropharyngeal examinations, and physical examinations. Adverse events were assessed at each clinic visit. Results: Thirty-two adolescent and 333 adult patients were randomly assigned to receive double-blind treatment. The treatment groups were comparable at baseline with respect to demographic characteristics (mean age, 38-41 years; white race, 78%-88%) and pulmonary function (mean percent predicted FEV1, 68%-69%; mean asthma symptom score, 1.6 [scale 0-5]; and mean daily albuterol use, 3.1 puffs). After 12 weeks of treatment, the mean FEV1 AUCbl was significantly greater in patients who received FSC compared with those who received FP, SAL, or PLA (7.0, 3.6, 5.3, and 1.4 L-h, respectively; all comparisons, P <= 0.020). At end point, the mean change from baseline in morning predose FEV1 for FSC was significantly greater than that for FP, SAL, and PLA (0.41, 0.19, 0.15, and -0.12 L; all comparisons, P <= 0.001). During 12 weeks of treatment, 7% of patients receiving FSC were withdrawn due to worsening asthma, compared with 24% of patients receiving SAL and 54% of patients receiving PLA (P < 0.001); 11% of patients receiving FP were withdrawn due to worsening asthma. Treatment with FSC resulted in significant improvements in morning and evening peak expiratory flow compared with FP, SAL, and PLA (both, P < 0.001); need for rescue albuterol compared with FP and PLA (P <= 0.005); and asthma symptom scores compared with PLA (P < 0.001). The tolerability of FSC was similar to that of FP or SAL alone. The incidence of possibly drug-related adverse events was generally similar across treatment groups, and the most common (occurring in >= 2% of patients) were headache (1%-4%), throat irritation (1%-2%), candidiasis of the mouth/throat (0%-2%), unspecified oropharyngeal plaques (0%-2%), and palpitations (0%-2%). Conclusions: In these adolescent and adult patients whose asthma was not controlled by medium doses of an ICS, FSC delivered via HFA 134a MDI (2 inhalations of 110/21-mu g strength administered BID) was more effective in improving lung function than FP or SAL monotherapy or PLA. All treatments were well tolerated.