Long-term Efficacy and Safety of Fluticasone Propionate Powder Administered Once or Twice Daily via Inhaler to Patients With Moderate Asthma^*

Materials and Methods

Patients

Male and female patients (≥ 12 years old) were enrolled in the double-blind phase of the study if they had chronic asthma diagnosed according to the American Thoracic Society criteria,¹⁶ and required daily pharmacotherapy over the 6 months immediately prior to the study. Other eligibility criteria included an FEV₁ of 50 to 80% of predicted values (Polgar and Promadhat¹⁷) for ages 12 to 17, and predicted values (Crapo et al¹⁸) for ages ≥ 18 years, and a ≥ 15% increase in FEV₁ within 15 min after inhaling two puffs of albuterol aerosol at screening, or a documented ≥ 15% variation in FEV₁ within 6 months prior to the study. Patients who completed the double-blind phase, or were withdrawn due to lack of efficacy, were eligible to participate in the open-label extension.

Patients were excluded from the study if they (1) had a history of life-threatening asthma or other severe chronic disease; (2) used oral, intranasal, or parenteral corticosteroids, or inhaled nedocromil or cromolyn sodium within 1 month prior to the study; (3) used methotrexate or gold salts, or any prescription or over-the-counter medication that might have affected the course of asthma or its treatment; or (4) had participated in any previous trial involving the use of the Diskus device.

Study Design

The study (Protocol No. FLTA2005) was conducted in two phases: a 12-week, double-blind, parallel-group, placebo-controlled phase, and a 54-week, open-label extension. There was provision for patients who were withdrawn due to lack of efficacy in the first phase to continue in the open-label extension. Informed patient consent and Institutional Review Board approval were obtained prior to the start of the study at 16 clinical centers in the United States.

Patients were stratified according to baseline therapy of maintenance inhaled corticosteroids vs β₂-agonists alone. During a 2-week single-blind screening period, patients received placebo via Diskus and were instructed on the proper technique for using this device. During this period, compliance was measured by the patient’s ability to withhold antiasthma medications prior to clinic visits, use ≥ 70% of the placebo, and complete diary cards. Patients previously receiving inhaled corticosteroids, salmeterol, or theophylline continued these medications provided there was no change in dose. All patients continued albuterol as needed for relief of asthma symptoms.

Acceptable asthma stability criteria established during the last 7 days of the screening period included no day in which ≥ 12 puffs of albuterol were used, no more than four mornings during which the peak expiratory flow (PEF) had decreased > 20% below the PEF of the previous evening, and no more than two nighttime awakenings resulting from asthma requiring albuterol.

Treatments

During the double-blind period, eligible patients were randomly assigned by stratum (baseline therapy of inhaled corticosteroids vs β₂-agonists alone) to one of the following treatments administered via the Diskus multidose powder inhaler for 12 weeks: fluticasone propionate, 250 μg bid; fluticasone propionate, 500 μg qd; or placebo bid. In order to maintain the blind, patients in the once-daily group received active treatment in the morning and placebo in the evening. Patients previously receiving inhaled corticosteroids had to discontinue these drugs for the remainder of the study, and all patients had to withhold albuterol for ≥ 6 h, salmeterol for 12 h, and theophylline for 12 to 36 h prior to clinic visits. Patients were evaluated weekly for the first 4 weeks and every other week up to 12 weeks.

In order to ensure that the 12-week efficacy trial continued to be double blind and to ensure balance across double-blind groups, patients were re-randomized during the open-label extension to receive fluticasone propionate, 250 μg bid or 500 μg qd, via Diskus for up to 54 weeks. There was no control group during the open-label phase. Oral prednisone, intranasal corticosteroids, and other antiasthma medications except for other inhaled corticosteroids were permitted as needed. Patients were evaluated every 2 weeks for the first 4 weeks and every 4 weeks thereafter for the remaining 54 weeks.

Assessments

Baseline pulmonary function tests were performed prior to study drug administration, and stability limits were established for FEV₁ (a 20% decrease in the best FEV₁ obtained at baseline) and PEF (a 20% decrease in mean morning PEF obtained during the last 7 days of the run-in period). At each clinic visit, FEV₁ values had to be greater than or equal to the FEV₁ stability limit. Additionally, during the 7 days immediately preceding each visit during the double-blind phase, patients should have had ≤ 2 days of ≥ 12 puffs of albuterol, ≤ 2 nighttime awakenings resulting from asthma requiring albuterol, and ≤ 3 days during which a morning or evening PEF was below the PEF stability limit. Patients who failed to meet these criteria, and those who had a clinical asthma exacerbation (symptoms requiring hospitalization or asthma medication excluded by study protocol), were discontinued from the study for lack of efficacy. The Diskus dose counter was used to monitor drug compliance throughout the study.

The primary efficacy variable was morning predose FEV₁ obtained at each clinic visit. Other efficacy variables included duration of study participation; patient-measured morning and evening PEF; patient-rated asthma symptom scores (double-blind phase) or number of days without asthma symptoms (open-label phase); albuterol use (double-blind phase only); and nighttime awakenings per night (double-blind phase) or nighttime awakenings per week (open-label phase) requiring albuterol use.

During both phases, safety assessments included adverse event monitoring, routine clinical laboratory tests, physical examinations (including oropharyngeal examination and vital signs), 12-lead ECGs, and assessment of hypothalamic-pituitary-adrenal (HPA) axis integrity as measured by morning unstimulated plasma cortisol concentrations (normal, ≥ 5 μg/dL). At the end of the open-label phase, patients underwent a short cosyntropin stimulation test. Blood samples for plasma cortisol concentrations were collected 30 to 60 min after an IV or IM injection of 250 μg of the synthetic adrenocorticotrophic hormone cosyntropin; a peak plasma cortisol concentration < 18 μg/dL was considered an abnormal response.

Statistical Analysis

Data from all patients exposed to the study drug (intent-to-treat population) were used for safety analyses. The population used for all efficacy analyses was the intent-to-treat population minus a total of 17 patients from one site who were excluded because data did not meet study standards (the efficacy population). Statistical tests were two sided, with treatment differences ≤ 0.05 considered significant. End-point data, defined as the last measurement taken prior to withdrawal regardless of whether the patient completed the study, were also analyzed. Testing was performed on combined data from all investigators.

Seventy evaluable patients per treatment group were required to detect a mean difference of 0.25 L in FEV₁ with a power of 80%. In the double-blind treatment phase, FEV₁ and PEF values were tested for treatment differences using an analysis of variance F test with a model using treatment and investigator. For the open-label phase, the population was classified into six groups for analysis of efficacy data based on whether patients were switched from placebo to either of the two fluticasone propionate groups, continued to receive one of the two fluticasone propionate treatments as before, or were switched between the two fluticasone propionate regimens. However, these data were not statistically analyzed due to the small number of patients per group. For analysis of safety data, the patients were classified only into the two groups receiving fluticasone propionate, 250 μg bid or 500 μg qd.

Determination of the probability of remaining in the study over time (double-blind phase) was based on the Kaplan-Meier estimates of survival. Patient-rated asthma symptom scores (0 = none, 1 = mild, 2 = moderate, 3 = severe), albuterol use, and nighttime awakenings were averaged over 7 days; since these data are discrete, all testing was based on the nonparametric test (van Elteren¹⁹), controlling for investigator.

Results

A total of 253 patients (age range, 12 to 69 years) were randomized to double-blind treatment at 16 clinical sites. Data from 17 patients at one site were not included in the efficacy analyses because they did not meet study standards. As a result, data from 236 patients (efficacy population) were used in the efficacy analyses. Baseline demography, disposition, and pulmonary function are presented in Table 1 . No significant differences were observed between the treatment groups in demographic and pulmonary function characteristics at baseline. Lack of efficacy based on predetermined criteria largely accounted for withdrawal from the study, and was highest in the placebo group (p < 0.001). Other withdrawals were primarily due to noncompliance with study procedures and medications.

A similar proportion of patients received prior inhaled corticosteroids (49%) and β₂-agonists alone (51%). Salmeterol was used by 24, 21, and 34%, while theophylline was used by 23, 19, and 11% of patients in the placebo; fluticasone propionate, 250 μg bid; and fluticasone propionate, 500 μg qd groups, respectively. The mean study drug compliance rates during the double-blind period, as judged by counting the number of doses taken from the Diskus devices, were ≥ 93% across the three treatment groups.

Of the 253 patients who received double-blind treatment, 185 patients chose to participate in the open-label extension phase and 131 patients completed 54 weeks of treatment. At open-label baseline, pulmonary function of patients who had previously been treated with once-daily or twice-daily fluticasone propionate was improved compared with those previously treated with placebo (Table 2 ). During open-label treatment, the use of prednisone ranged from 15 to 31%, salmeterol from 6 to 9%, and theophylline from 0 to 12% across treatment groups. Withdrawal due to lack of efficacy (based on investigator discretion rather than predefined criteria) was similar among treatment groups. Mean study drug compliance rates were ≥ 87% across treatment groups.

Efficacy

Pulmonary Function (Double-Blind Phase):

During the double-blind phase, mean change from baseline FEV₁ was significantly improved (p < 0.001) at end point with both once-daily and twice-daily fluticasone propionate compared with placebo, and with twice-daily dosing compared with once-daily dosing. The percentage of patients with a ≥ 0.25-L improvement in FEV₁ was 45% and 64% in the once-daily and twice-daily fluticasone propionate groups, respectively, compared to 15% in the placebo group (Table 3 ). Fluticasone propionate significantly improved FEV₁ at all time points (Fig 2 ) in the 250 μg twice-daily group (p ≤ 0.001) and at weeks 2, 4, 6, 10, and at end point in the 500 μg once-daily group (p ≤ 0.044). Significant differences (p ≤ 0.033) were observed in favor of the twice-daily dosing regimen compared with once-daily dosing at all time points except week 10.

Analysis of FEV₁ data by strata showed that patients previously treated with inhaled corticosteroids had slightly lower FEV₁ at baseline (2.24 to 2.37 L), compared with patients previously receiving β₂-agonists alone (2.55 to 2.76 L). After double-blind treatment, they also showed a slightly smaller improvement in FEV₁ (0.05 to 0.37 L) compared with those previously receiving β₂-agonists (0.18 to 0.46 L). In the placebo group, patients in the inhaled corticosteroids stratum showed a greater deterioration in FEV₁ (− 0.24 L) than those in the β₂-agonists stratum (− 0.08 L).

Compared with placebo, diary morning and evening PEF were significantly improved (p < 0.001) at end point with both once-daily and twice-daily fluticasone propionate, but did not differ significantly between the two dosing regimens (Table 3). Fluticasone propionate significantly improved diary morning PEF at all time points (Fig 3 ), both with twice-daily dosing (p ≤ 0.001) and with once-daily dosing (p ≤ 0.003).

Pulmonary Function (Open-Label Phase):

Patients in all groups either maintained or continued to show an improvement in FEV₁, compared to their new baseline during open-label treatment with fluticasone propionate (Table 4 ). Those previously treated with placebo during the double-blind phase, when switched to either once-daily or twice-daily fluticasone propionate, showed large increases in FEV₁ (0.43 to 0.83 L) beginning as early as week 2 and continuing throughout the open-label phase. Those previously treated bid with fluticasone propionate, when switched to either once-daily or twice-daily fluticasone propionate, generally maintained their improvement in lung function throughout the 54-week open-label period. At the end of the double-blind phase, patients treated once daily with fluticasone propionate showed a smaller improvement in FEV₁ when compared with those treated twice daily. However, FEV₁ continued to improve whether patients remained on once-daily dosing or were switched to twice-daily dosing during the open-label phase, with greater improvements observed in the latter group.

Morning PEF showed similar improvement in patients previously treated with placebo when switched to once-daily or twice-daily fluticasone propionate during the open-label phase (Table 4). Patients previously treated twice daily with fluticasone propionate maintained the improvement in morning PEF, whether they remained on twice-daily treatment or were switched to once-daily dosing. Morning PEF continued to improve in patients previously treated once daily with fluticasone propionate, whether they remained on once-daily treatment or were switched to twice-daily dosing, with greater improvement seen in the latter group.

Probability of Remaining in the Study:

Kaplan Meier survival analysis of double-blind treatment data (Fig 4 ) showed a significant overall treatment effect on duration of study participation (p < 0.001). Patients in each fluticasone propionate group had a significantly lower probability of discontinuing the study due to lack of efficacy than those in the placebo group. At double-blind treatment end point, 51% of placebo patients had discontinued the study due to lack of efficacy compared with 7% (p < 0.001) and 26% (p = 0.001) in the fluticasone propionate 250 μg bid and 500 μg qd groups, respectively, with the difference between the two dosing regimens also being statistically significant (p < 0.001).

Asthma Symptoms, Albuterol Use, Nighttime Awakenings:

At double-blind treatment end point, both regimens of fluticasone propionate significantly reduced (p ≤ 0.001) asthma symptom scores, with decreases of approximately 30% in the once-daily and twice-daily dosing groups, compared with an increase of 16% in the placebo group. Albuterol use decreased significantly (p ≤ 0.001) by approximately 37% and 24% in the 250 μg bid and 500 μg qd groups, respectively, compared with a 30% increase in the placebo group. Nighttime awakenings per week decreased in both fluticasone propionate groups at end point, compared with placebo. Only albuterol use differed significantly (p = 0.045) between the two fluticasone propionate dosing regimens at end point (Table 3).

Compared with values at double-blind end point, nighttime awakenings per week at open-label end point decreased in all treatment groups except patients maintained on twice-daily fluticasone propionate, with the greatest decrease observed in placebo subjects re-randomized to once-daily or twice-daily fluticasone propionate. Compared with values at double-blind end point, the number of days per week without asthma symptoms at open-label end point was lowest in patients treated with once-daily fluticasone propionate in both phases of the study (Table 4).

Safety

Adverse Events:

Fluticasone propionate was well tolerated, with most drug-related adverse events being pharmacologic effects of inhaled corticosteroids, including hoarseness, candidiasis of the mouth/throat, and throat irritation. Drug-related adverse events occurred with a low incidence during the double-blind phase (placebo, 1%; fluticasone propionate 250 μg bid and 500 μg qd, 8% and 5%, respectively). During open-label treatment, drug-related events occurred with a higher incidence in the 250 μg bid group (16%) than in the 500 μg qd group (7%). Of the patients withdrawn due to adverse events, one was considered related to study drug (anxiety, nervous tic, hypersalivation, and jaw aches) and one possibly related to study drug (moderate thrush and hoarseness, and a mild sore throat), both in the 250 μg bid group.

HPA Axis Evaluation:

Abnormalities in morning plasma cortisol concentrations during both phases of the study and cosyntropin stimulation data during open-label treatment are presented in Table 5 . In general, a higher frequency of abnormalities was observed in patients treated bid when compared with those treated once daily with fluticasone propionate. Cosyntropin stimulation data showed that one patient receiving fluticasone propionate 500 μg qd had both a poststimulation plasma cortisol concentration of < 18 μg/dL and an abnormally low morning plasma cortisol on the day of the stimulation test, but achieved an adequate poststimulation rise of 15 μg/dL. This patient had received oral prednisone approximately 6 weeks prior to the stimulation test.

Other Laboratory and Clinical Tests:

No treatment-related changes were observed in laboratory evaluations, vital signs, physical examinations, or ECGs during both treatment phases of the study.

Discussion

Fluticasone propionate improved or maintained lung function in patients with moderate asthma regardless of whether they had been previously treated with inhaled corticosteroids or β₂-agonists. During the 12-week double-blind phase, this was evidenced by significant improvements in FEV₁, patient-measured PEF, asthma symptoms, rescue albuterol use, and nighttime awakenings in fluticasone propionate-treated patients compared with placebo. Patients treated twice daily with fluticasone propionate showed significantly greater improvements in FEV₁, albuterol use, and withdrawal due to lack of efficacy, when compared to those treated once daily for 12 weeks. Improvements in PEF showed no significant differences between the two dosing regimens. During the 1-year extension period, improvements in lung function observed during the 12 weeks of double-blind treatment were maintained or further enhanced with both dosing regimens. Although patient numbers during this phase were too small to permit statistical analyses, they were sufficient to assess clinically relevant trends.

Studies evaluating the effects of reducing dose frequency of inhaled corticosteroids have reported both poorer asthma control with once-daily dosing,²⁰²¹ as well as effective control.^22232425 All these studies included patients with mild asthma, and the treatment periods were relatively short (4 to 12 weeks), with only one study²⁵ including a 12-week maintenance period. In two double-blind crossover trials, deteriorating PEF and asthma symptom scores were reported in patients treated for 4 weeks with beclomethasone propionate, 400 μg qd vs a bid regimen,²⁰ or beclomethasone dipropionate, 250 μg qd vs a tid regimen.²¹ However, another study showed that beclomethasone dipropionate at a higher dose of 1,000 μg/d administered either in the afternoon or at night for 4 weeks was equivalent to a twice-daily 500 μg dose.²² More recently, studies using a double-blind, parallel group design showed that patients maintained effective asthma control when switched from flunisolide, 500 μg bid, to flunisolide, 1,000 μg administered once daily either in the morning or in the evening for 12 weeks,²³ or when treated with once-daily doses of budesonide, 200 to 400 μg, over periods ranging from 8 to 18 weeks.²⁴²⁵

The average baseline FEV₁ in the present study was 67% of predicted values, indicating that patients with moderately severe asthma were included. The efficacy of reducing dose frequency was evaluated during an initial treatment period of 12 weeks, but unlike most previous studies, this study also assessed the effects of either switching between the two regimens or maintaining the same dosing regimen over a period of 1 year. This study demonstrated that reducing the frequency of dosing over a long-term period of 1 year did not result in deterioration in lung function. Patients who switched from twice-daily to once-daily dosing during the open-label period maintained the improvements in FEV₁ and PEF. Those who switched from once-daily to twice-daily dosing, or from placebo to once-daily or twice-daily dosing, showed further improvements in FEV₁ and PEF within 2 weeks and maintained these improvements over the 1-year period. In another long-term study, the clinical efficacy of budesonide, 800 μg, administered as a once-daily dose at night vs twice-daily doses was evaluated over a period of 1 year in patients with moderate asthma.²⁶ No significant differences were observed in the provocative concentration of methacholine causing a 20% fall in FEV₁, and PEF between the two regimens, but rescue albuterol use, asthma symptoms, and PEF variability were increased in the once-daily group, compared to the twice-daily group.

In clinical practice, not all patients may be able to be treated with once-daily doses of inhaled corticosteroids, and the amount as well the frequency of dosing may differ depending on whether it is required for improving lung function, controlling asthma symptoms, or reducing albuterol use or nighttime awakenings. The severity of asthma may also be a factor to be considered, as patients with more severe asthma may require more frequent dosing. Since the improvement in FEV₁ in the present study was greater in the twice-daily group compared with the once-daily group, an objective assessment of pulmonary function should be considered in the latter group. Additionally, if once-daily dosing is considered a viable treatment option, patients should be followed clinically after they are switched to such a regimen to ensure that disease control is maintained.

Safety monitoring showed that long-term therapy with fluticasone propionate was well tolerated, with a low incidence of both drug-related adverse events and abnormalities in HPA-axis function. There was only one abnormal response to cosyntropin stimulation (peak < 18 μg/dL) after a year of treatment; however, the rise in plasma cortisol concentration on stimulation was adequate (15 μg/dL), and the patient had taken oral prednisone 6 weeks previously. The clinical significance of this result is uncertain.

Conclusion

This study, which provides data on reduction of dosing frequency over a long-term period, demonstrated that twice-daily dosing with fluticasone propionate showed significantly greater improvements in some efficacy parameters, compared with once-daily dosing over a 12-week period, but once-daily dosing was effective in maintaining improvements in pulmonary function over a period of 1 year in patients with moderate asthma. This suggests that once-daily dosing with fluticasone propionate may be an option for patients with mild to moderate asthma. The reduced frequency of dosing, combined with the ease of use of the Diskus inhaler, should facilitate adherence to treatment. At the daily dose of fluticasone propionate used, 500 μg, there were few topical side effects and negligible evidence of systemic activity.