A Dose-Ranging Study of Fluticasone Propionate Administered Once Daily via Multidose Powder Inhaler to Patients With Moderate Asthma

doi:10.1378/chest.118.2.296

Chest

Volume 118, Issue 2, August 2000, Pages 296-302

https://doi.org/10.1378/chest.118.2.296 Get rights and content

Study objective

This dose-ranging study evaluated the clinical efficacy and safety of inhaled fluticasone propionate administered once daily via a multidose powder inhaler in patients with moderate asthma (FEV₁, 45 to 75% predicted).

Materials and methods

In this multicenter trial, 330 patients (≥ 12 years old) previously receiving inhaled corticosteroids or β₂-agonists alone were randomized in a double-blind manner to receive fluticasone propionate at 100, 200, or 500 μg once daily or matching placebo for 12 weeks.

Results

Once-daily treatment with fluticasone propionate resulted in an improvement in efficacy variables, such as FEV₁, morning and evening peak expiratory flow (PEF), asthma symptom scores, nighttime awakenings, albuterol use, and duration of study participation. A dose-related trend was observed for improvements in morning and evening PEF and albuterol use. Statistical significance for pairwise comparisons was achieved for 200 μg and 500μ g fluticasone propionate vs placebo for all efficacy variables, and for 100 μg fluticasone propionate vs placebo for morning and evening PEF at most or all time points. Drug-related adverse events were few (≤ 5%) and mostly related to the topical effects of inhaled corticosteroids. No dose-response effect or clinically relevant differences were observed in morning plasma cortisol concentrations or after cosyntropin stimulation.

Conclusion

Once-daily treatment with fluticasone propionate was well tolerated and demonstrated some dose-related trends in improvements in lung function and asthma control in patients with moderate asthma.

Section snippets

Patients

Male and female patients (≥ 12 years old) were enrolled in the study if they had at least a 6-month history of chronic asthma, as defined by the American Thoracic Society,¹³ which required daily pharmacotherapy over the 6 months immediately prior to the study. Patients were required to have a baseline FEV₁ of 45 to 75% of the values predicted by Polgar and Promadhat¹⁴ (patient ages 12 to 17 years) and Crapo et al¹⁵ (patient age, ≥ 18 years) with an adjustment for a 12% reduction in predicted

Results

A total of 330 patients who met entry criteria were enrolled in the study at 21 clinical sites. A slightly higher percentage of patients received inhaled corticosteroid therapy (55%) thanβ ₂-agonists alone (45%). Across treatment groups, concurrent salmeterol use ranged from 27 to 33% of patients, while theophylline use ranged from 19 to 29% of patients. Demography, asthma history, and baseline pulmonary function test results were not significantly different between treatment groups (Table 1).

Discussion

This study demonstrated that once-daily treatment with fluticasone propionate, 100, 200, or 500 μg, via a multidose powder inhaler was effective in patients with moderate asthma, and resulted in improvements in measures of clinical efficacy such as FEV₁, morning and evening PEF, duration of study participation, asthma symptoms, nighttime awakenings, and albuterol use. Fluticasone propionate was well tolerated, with no dose-related increases in drug-related adverse events or HPA-axis suppression.

ACKNOWLEDGMENTS

We would like to thank the following for their contributions to this study: D. Chardon, MD; R. Cohen, MD; W.T. Ellison, MD; C.F. LaForce, MD; S.P. Galant, MD; G. Greenwald, MD; W. Howland, MD; H.B. Kaiser, MD; J.P. Karpel, MD; J. Kemp, MD; E.M. Kerwin, MD; W. Lumry, MD; M.J. Noonan, MD; E.J. Schenkel, MD; W.E. Stricker, MD, J.H. VanBavel, MD; and S.A. Wool, MD. We would also like to thank Shehnaz Gangjee, PhD, for assistance in writing this manuscript.

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The safety of long-term use of inhaled corticosteroids in patients with asthma: A systematic review and meta-analysis
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Citation Excerpt :
The P value of Begg's rank correlation test (STATA 12.0) was used to assess the presence of publication bias in included articles for each outcome. Of 17,234 trials recognized by the initial search, 331 were retrieved for more detailed assessment, and 86 trials [8–91,105–107] were included in the meta-analysis (Fig. 1). Baseline characteristics of trials included in the meta-analysis are shown in Table 1.
This systematic review and meta-analysis was performed to determine the safety of long-term use of ICS in patients with asthma.
A systematic search was made of PubMed, Embase, Web of Science, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of asthma with ICS, compared with non-ICS treatment (placebo or other active drugs), were reviewed.
Eighty-six RCTs (enrolling 51,538 participants) met the inclusion criteria. Oral or oropharyngeal candidiasis (RR 2.58, 95% CI 2.00 to 3.33), and dysphonia/hoarseness (RR 1.56, 95% CI 1.31 to 1.85) were less frequent in the control group. There was no statistically significant difference in the risk of upper respiratory tract infection, lower respiratory tract infection, influenza, decline in bone mineral density, and fractures between the two groups.
In addition to the mild local adverse events, the long-term use of ICS was safe in patients with asthma.
Efficacy and safety of fluticasone propionate/salmeterol 250/50 mcg Diskus administered once daily
2008, Respiratory Medicine
The twice daily administration of an inhaled corticosteroid (ICS) and long-acting beta₂-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients.
To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo.
A 12-week, randomized, double-blind multicenter study conducted in 844 patients ⩾12 years of age who were symptomatic while using a short-acting beta₂-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskus^® device.
All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24 h compared with twice daily dosing. All treatments were well tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups.
In patients symptomatic on a short-acting beta₂-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients.
Registered at http://ctr.gsk.co.uk/welcome.asp (SAS30022)
Potency ratio fluticasone propionate (Flixotide Diskus)/budesonide (Pulmicort Turbuhaler)
2007, Respiratory Medicine
Citation Excerpt :
However, it must be pointed out that the present results were obtained in steroid-naive patients with mild to moderate asthma using loss of asthma control as the dose-defining end-point. The dose response relationship is probably different in severe asthma5,19,20 and may also be different using other end-points as oral steroid sparing effect21–23 or tests of bronchial hyperresponsiveness.12 The need for a balanced individualized approach to dose selection of inhaled steroids in asthma was illustrated in the recently published GOAL-study.24
In the choice of, or switch between, various inhaled corticosteroids (ICS) it is important to know equipotent doses for clinical treatment effects of the alternatives. Various ICS do have different inherent potency. Further, the ICS are delivered from inhalers that may differ markedly in output characteristics and drug delivery to intrapulmonary airways. Therefore, clinical efficacy comparisons must include drug–inhaler comparisons.
We estimated the therapeutic potency ratio of the Flixotide Diskus (fluticasone propionate, FP) and the Pulmicort Turbuhaler (budesonide, BUD) in steroid-naive asthma patients, using a dose-reduction technique (FP 500-0 mcg/day, BUD 800-0 mcg/day). The dose defining end point was loss of asthma control in this paper denoted as exacerbation. In total, 282 patients with proven asthma were enrolled in the study, and 103 in the FP group and 98 in the BUD group completed the study per protocol.
In total, 80 patients in the FP-group and 79 in the BUD-group experienced a dose defining exacerbation. The exacerbation frequency increased in a dose-dependent way as the dose was titrated down. From these data the potency difference between the present drug inhaler combinations, Flixotide Diskus and Pulmicort Turbuhaler, was calculated to be between 1.50:1 (95% CI 1.10:1–2.05:1) and 1.75:1 (CI 1.26:1–2.43:1) depending on if patients with insufficient steroid-response were excluded from the calculations or not. In these steroid-naïve patients, the potency difference was evident only at low daily doses, below 200 mcg.
Impact of inhaled corticosteroid-induced oropharyngeal adverse events: Results from a meta-analysis
2007, Annals of Allergy, Asthma and Immunology
Oropharyngeal adverse events associated with inhaled corticosteroid (ICS) use can affect adherence; however, these effects have been studied less extensively than those that occur systemically.
To calculate the risk of ICS-induced oral candidiasis, dysphonia, and pharyngitis among currently available therapies and to determine related effects of dose and device.
A computerized search in MEDLINE (January 1966 to June 2004) and EMBASE (January 1974 to June 2004) was conducted using indexed MedDRA terms for oropharyngeal adverse events. Odds ratios (ORs) were used to determine the rate of ICS-induced adverse events based on dose and device.
A total of 23 studies (59 drug arms) were evaluated. Incidence of oral candidiasis (P ≤ .001), dysphonia (P ≤ .001), and pharyngitis (P ≤ .023) increased significantly with dose vs placebo at all dose levels and combined, regardless of device. Overall, the ICS metered-dose inhaler (MDI) device (hydrofluoroalkane formulation, 4 arms; chlorofluorocarbon formulation, 26 arms) was associated with a 5-fold greater risk of oral candidiasis vs MDI placebo (OR, 5.40). In contrast, the ICS dry-powder inhaler (DPI) device had a 3-fold greater risk for oral candidiasis vs DPI placebo (OR, 3.24). A similar trend was observed with regard to dysphonia (ICS MDI: OR, 5.68; ICS DPI: OR, 3.74; both vs placebo). Both ICS MDI and DPI were associated with an approximately 2-fold greater risk of pharyngitis compared with placebo.
Currently available inhaled corticosteroids can be associated with oropharyngeal adverse events. Such events may be reduced by postdose mouth rinsing or use of a spacer.
The dose-response characteristics of inhaled corticosteroids when used to treat asthma: An overview of Cochrane systematic reviews
2006, Respiratory Medicine
Inhaled corticosteroids form the cornerstone of treatment for most patients with asthma. A range of compounds are available with a wide range of prescribable doses. In this overview, we summarize the findings from a number of Cochrane systematic reviews that have examined the relative benefits of different doses of beclometasone dipropionate, budesonide and fluticasone propionate when used to treat children and adults. The key findings are that all inhaled corticosteroids demonstrate a dose–response relationship for efficacy measures, but most of the benefit in mild-to-moderate severity disease is gained in the low-to-moderate dose range of each drug. In this group, high doses of fluticasone lead to small improvements in measures of control at the expense of a steep increase in the incidence of oral side-effects. In patients with severe disease who are dependent on oral steroids, there may be appreciable benefit in reducing oral steroids from very high compared with high doses of fluticasone.
Efficacy and safety of roflumilast in the treatment of asthma
2006, Annals of Allergy, Asthma and Immunology
The central role of chronic inflammation of the airways in asthma pathogenesis is supported by the efficacy of corticosteroids in controlling clinical symptoms. However, the search continues for potentially safer anti-inflammatory alternatives. Roflumilast is an oral, once-daily phosphodiesterase type 4 inhibitor with anti-inflammatory activity in preclinical models of asthma and chronic obstructive pulmonary disease.
To investigate the dose-ranging efficacy and safety of roflumilast in patients with mild-to-moderate asthma.
Patients (N = 693) were randomized in a double-blind, parallel-group, phase 2/3 study. After a 1- to 3-week placebo run-in period, patients (mean forced expiratory volume in 1 second [FEV₁], 73% of predicted) were randomized to receive 100, 250, or 500 μg of roflumilast once daily for 12 weeks. The primary end point was change from baseline in FEV₁; secondary end points included change from baseline in morning and evening peak expiratory flow.
Roflumilast use significantly increased FEV₁ (P < .001 vs baseline). Improvements from baseline in FEV₁ at the last visit were 260, 320, and 400 mL for the 100-, 250-, and 500-μg dose groups, respectively. Roflumilast, 500 μg, was superior to roflumilast, 100 μg, by 140 mL in improving FEV₁ (P = .002). There were also significant improvements from baseline in morning and evening peak expiratory flow in all the dose groups (P ≤ .006). Roflumilast was well tolerated at all doses tested. Most adverse events were mild to moderate in intensity and transient.
These results support the emerging role of roflumilast, 500 μg/d, in the treatment of asthma.

View all citing articles on Scopus

This study was supported by a grant from Glaxo Wellcome Inc.

Portions of this manuscript were presented in May 1997 at the Annual Meeting of the American Thoracic Society in San Francisco, CA.

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Chest

Clinical Investigations: AsthmaA Dose-Ranging Study of Fluticasone Propionate Administered Once Daily via Multidose Powder Inhaler to Patients With Moderate Asthma

Study objective

Materials and methods

Results

Conclusion

Section snippets

Patients

Results

Discussion

ACKNOWLEDGMENTS

Chest

Lancet

J Allergy Clin Immunol

Clin Ther

Ann Allergy Asthma Immunol

Chest

J Allergy Clin Immunol

Chest

Lancet

Nonadherence in asthmatic patients: is there a solution to the problems?

Ann Allergy Asthma Immunol

Fluticasone propionate aerosol reduces oral prednisone requirements while it improves control of asthma and quality of life

Am J Respir Crit Care Med

A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma

J Allergy Clin Immunol

A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma

J Asthma

Clinical Investigations: Asthma
A Dose-Ranging Study of Fluticasone Propionate Administered Once Daily via Multidose Powder Inhaler to Patients With Moderate Asthma