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

doi:10.1378/chest.118.2.303

Chest

Volume 118, Issue 2, August 2000, Pages 303-312

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Objective

To evaluate the efficacy and safety of fluticasone propionate administered as a once-daily or twice-daily regimen over a period of 1 year to patients with moderate asthma.

Design

Double-blind, randomized, parallel group, and placebo-controlled phase (12 weeks) and an open-label phase (54 weeks).

Setting

Multicenter study in an outpatient setting.

Participants

Patients (n = 253; age,≥ 12 years) with a mean FEV₁ of 67% predicted normal were stratified according to baseline therapy of maintenance inhaled corticosteroids vs β₂-agonists alone.

Measurements and interventions

Fluticasone propionate (250μ g bid or 500 μg qd) or placebo (bid) was administered via the Diskus multidose powder inhaler (Glaxo Wellcome; Research Triangle Park, NC) for 12 weeks. During open-label treatment, patients were re-randomized to once-daily or twice-daily fluticasone propionate.

Results

Compared to placebo, fluticasone propionate administered qd or bid significantly improved FEV₁ (p < 0.001), morning (p < 0.001) and evening peak expiratory flow (PEF; p < 0.001), asthma symptom scores (p ≤ 0.001), and albuterol use (p ≤ 0.001), and decreased nighttime awakenings. By the end of 12 weeks, withdrawal due to lack of efficacy was significantly higher in the placebo group than in the once-daily (p = 0.001) or twice-daily (p < 0.001) groups. When comparing the two active dosing regimens, significant differences in favor of twice-daily dosing were noted in FEV₁, albuterol use, and withdrawal due to lack of efficacy. During 54 weeks of open-label treatment, FEV₁ and PEF continued to improve with both regimens, and improvements seen in the first 12 weeks were maintained in patients who switched from twice-daily to once-daily dosing. Fluticasone propionate treatment over a 54-week period was well tolerated, with few drug-related adverse events, which were primarily topical effects of inhaled corticosteroids.

Conclusions

Fluticasone propionate powder improved lung function when administered either qd or bid over a 1-year period to patients with moderate asthma, with twice-daily dosing demonstrating significantly greater improvement in some efficacy parameters than once-daily dosing over the first 12 weeks of treatment. Fluticasone propionate treatment was not associated with significant systemic effects.

Section snippets

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

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

Discussion

Fluticasone propionate improved or maintained lung function in patients with moderate asthma regardless of whether they had been previously treated with inhaled corticosteroids orβ ₂-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

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

ACKNOWLEDGMENTS

We thank the following for their contributions to this study: Thomas D. Bell, MD; Jim Christensen, MD; Gerald S. Davis, MD; Margaret Drehobl, MD; Thomas B. Edwards, MD; Patrick A. Flume, MD; Frank Hampel, MD; Benjamin Interiano, MD; Peter LoGalbo, MD; Anjuli S. Nayak, MD; William F. Schoenwetter, MD; Paul A. Shapero, MD; and D. Robert Webb, MD. We would also like to thank Abbas G. Hamedani, Lori Witham, and J. Ellen Payne for statistical analyses and Shehnaz Gangjee for assistance in writing

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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.
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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.
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Protection by budesonide and fluticasone on allergen-induced airway responses after discontinuation of therapy
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Citation Excerpt :
These studies have generally been in patients with milder disease whose symptoms are controlled with lower doses of inhaled corticosteroids. Other studies have suggested an improvement in asthma stability with twice-daily dosing compared with once-daily therapy in more difficult-to-control asthma.34,35 In conclusion, this study, the first randomized controlled trial to evaluate the duration of the protective effects of different inhaled steroids after cessation of treatment, shows that the protection afforded by both fluticasone and budesonide against allergen-induced airway responses and airway inflammation is partially lost 12 hours after stopping treatment.
Treatment with inhaled steroids is an effective method of reducing bronchoconstriction and airway inflammation after allergen challenge. However, the durationof the protective effects of inhaled steroids after discontinuation of therapy has not been established.
We sought to evaluate the protective effect of 1 week of inhaled steroid therapy against inhaled allergen challenge 12 hours after discontinuation of therapy.
In this randomized, double-blind, placebo-controlled crossover trial, 26 asthmatic subjects (>18 years old) not using inhaled steroids were administered 200 μg of budesonide twice daily, 200 μg of fluticasone twice daily, or placebo twice daily for 1 week. Twelve hours after discontinuation of therapy, subjects were administered an inhaled allergen challenge. Each treatment period was separated by a 3-week washout period.
When compared with placebo (26% ± 14%), there was a slight but significant protection against the allergen-induced early response after fluticasone treatment (19% ± 10%, P = .001) but not after budesonide treatment (23% ± 13%, P = .08). However, when the area under the curve for the early airway response was examined, there was no difference between the 2 drugs in the amount of protection (P = .62). Partial protection was demonstrated against the late-response allergen-induced sputum eosinophilia with both treatments (P = .001). By contrast, no protection was observed against allergen-induced airway hyperresponsiveness for either treatment.
The protective effects of inhaled steroids against allergen-induced early responses, airway eosinophilia, and allergen-induced airway hyperresponsiveness are partially or completely lost as early as 12 hours after discontinuation of therapy.
Asthma and gastroesophageal reflux disease in children: Exploring the relationship
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Asthma is a well-recognized disease and one of the most common illnesses in childhood. More recently, gastroesophageal reflux disease has increasingly been appreciated as a common daily occurrence in children and adolescents. These two diagnoses often present in tandem, with their coexistence being more frequent than would be expected for a chance occurrence. The mainstay of asthma management is the regulation and control of chronic airway hyperreactivity and inflammation. Children who do not respond to standard asthma regimens should be evaluated for other sources of their pulmonary symptoms, most notably gastroesophageal reflux. Baseline assessment of pulmonary function tests followed by an empiric trial of proton pump inhibitor therapy, using double the standard doses commonly used in acid-related disorders and administered for 3 months, is a cost-effective, noninvasive diagnostic strategy. Children who fail to exhibit pulmonary symptom improvement should be evaluated for both medication compliance and proper administration. Twenty-four-hour esophageal pH monitoring with concurrent dairy recordings of their symptoms is recommended to ascertain adequacy of acid suppression and confirm the diagnosis in those who continue to have symptoms. Children with acid-related causes of their pulmonary symptoms often require long-term treatment. Studies have confirmed the efficacy, safety, and tolerability of proton pump inhibitors in the treatment of children and adolescents. Surgery should be reserved for those with severe disease and those who are unable to comply with pharmacologic treatment.
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It is generally believed that there is a direct correlation between asthma control and a patient's health-related quality of life (HRQL). Objective and subjective measures of asthma control are used interchangeably. A retrospective analysis from 8994 patients from 27 randomized, controlled clinical trials with persistent asthma was conducted to determine the degree of association which exists between objective (lung function) and subjective (symptoms, quality of life) measures. Assessments were made via forced expiratory volume in 1-second (FEV₁), self-reported symptoms and the Asthma Quality of Life Questionnaire (AQLQ) overall scores. Baseline percent predicted FEV₁ was weakly correlated with baseline symptom-free days (SFD) and baseline overall AQLQ scores (r=0.11 and 0.09, respectively; P <0.001). Changes in percent predicted FEV₁ correlated weakly with changes in SFD but was more strongly correlated with changes in overall AQLQ scores (r=0.26 and 0.38, respectively; P <0.001). Additionally, SFD at both baseline and endpoint were moderately correlated with overall AQLQ scores at baseline and endpoint (r=0.36 and 0.44; P <0.001). This study suggests that the impact of asthma on a patients’ HRQL is not fully accounted for by objective measures such as lung function. Thus, HRQL data complements rather than duplicates results from traditional, objective assessments of asthma control.
Safety of SABA Monotherapy in Asthma Management: a Systematic Review and Meta-analysis
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This study was supported by a grant from Glaxo Wellcome Inc.

Dr. ZuWallack is a member of the Glaxo Speakers’ Bureau. Ms. Duke, and Drs. Wire, Faris, and Harding are employees of Glaxo Wellcome, Inc.

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Chest

Clinical Investigations: AsthmaLong-term Efficacy and Safety of Fluticasone Propionate Powder Administered Once or Twice Daily via Inhaler to Patients With Moderate Asthma

Objective

Design

Setting

Participants

Measurements and interventions

Results

Conclusions

Section snippets

Patients

Results

Discussion

Conclusion

ACKNOWLEDGMENTS

Respir Med

Steroids

J Allergy Clin Immunol

Eur J Pharm Sci

J Allergy Clin Immunol

Respir Med

Chest

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

Structure-activity relationships of topically active steroids: the selection of fluticasone propionate

Respir Med

Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo

Eur Respir J

A comparison of the effects of bid and qid dosing on compliance with inhaled flunisolide

Chest

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