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* From Asthma and Allergy Associates, PC (Dr. Nathan), Colorado Springs, CO; Allergic Diseases and Internal Medicine (Dr. Li), Mayo Clinic and Foundation, Rochester, MN; Allergy and Asthma Centers of Charleston, PA (Dr. Finn), Charleston, SC; Allergy and Asthma Research Group (Dr. Jones), Eugene, OR; Glaxo Wellcome Inc. (Mss. Payne and Wolford, and Dr. Harding), Research Triangle Park, NC.
Correspondence to: Robert A. Nathan, MD, FCCP, Asthma and Allergy Associates, PC, 2709 North Tejon St, Colorado Springs, CO 80907
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and methods: In this multicenter trial, 330
patients (
12 years old) previously receiving inhaled
corticosteroids or ß2-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 500
µg 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.
Key Words: asthma • dose ranging • fluticasone propionate • multidose powder inhaler
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Since clinically relevant dose-response relationships with inhaled corticosteroids have not been clearly demonstrated in patients with asthma, this study was also designed to explore a potential dose-response relationship. Previous dose-ranging studies have shown both increased efficacy at higher doses,2 3 4 as well as flat dose-response curves.5 6 7 8 9 Factors likely to influence the relationship between degree of efficacy and dose include disease severity, differences in inhaler technique and compliance, the dose interval studied, and the efficacy parameter measured. For example, a dose-response relationship has been demonstrated using the methacholine challenge test as an end point, instead of the more traditional efficacy variables in patients with mild asthma.10 11 Increased efficacy at higher doses for end points such as FEV1 and asthma symptoms was shown in a recent meta-analysis of eight fluticasone propionate studies encompassing a range of severity of asthma.12
In order to demonstrate a dose response, patients with more severe asthma were enrolled in the present study, since higher doses of inhaled corticosteroids are less likely to provide incremental benefits to patients with mild asthma. Although 100 µg once daily was selected as the lowest dose, limited efficacy was expected at this dose, since the recommended starting dosage of fluticasone propionate is 200 µg/d (100 µg bid).
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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 normal values for African Americans. To
confirm the diagnosis of asthma, patients had to demonstrate a 15%
increase in FEV1 within 30 min after two puffs of
albuterol aerosol at screening, or have a documented 15%
variability in FEV1 within 6 months prior to the
study. Measures of asthma instability (daily asthma symptoms, nighttime
awakenings due to asthma, and frequent rescue
ß2-agonist use) were not required for inclusion
in this study. Patients were excluded from the study if they had life-threatening asthma, severe chronic disease, or a history of glaucoma and/or posterior subcapsular cataracts; used oral, intranasal, or parenteral corticosteroids, or nedocromil/sodium cromolyn within 1 month prior to the study; used methotrexate or gold salts, or any prescription or over-the-counter medication that might have affected the course of asthma or its treatment; were steroid naive with plasma cortisol abnormalities (morning levels, < 5 µg/dL; poststimulation peak, < 18 µg/dL); had participated in any previous trial involving the use of the Diskus device; or were pregnant or lactating women.
Study Design
This randomized, double-blind, parallel-group,
placebo-controlled study (protocol number FLTA2016) was conducted at 22
clinical centers in the United States. Institutional Review Board
approval and a consent form signed by each patient were obtained prior
to the start of the study.
During a 2-week, single-blind, placebo run-in period, patients previously receiving inhaled corticosteroids (beclomethasone dipropionate, triamcinolone acetonide, or flunisolide) or theophylline were allowed to continue these medications with no change in the dose or treatment regimen. Patients on oral or inhaled bronchodilators (except salmeterol) discontinued this therapy and, instead, received inhaled albuterol as needed. All patients received placebo via the inhaler and were instructed on the proper technique for using this device.
Criteria for acceptable asthma stability during the last 7 days
of the run-in period included no day with 12 puffs of albuterol
aerosol per day, 4 mornings during which the peak expiratory flow
(PEF) had decreased > 20% below the PEF of the previous evening, and
2 nighttime awakenings resulting from asthma requiring albuterol.
Patients not meeting these criteria were excluded from randomization.
Compliance was measured by the patient’s ability to withhold
antiasthma medications prior to clinic visits, use of 70% of the
placebo during the run-in period, and complete diary cards.
Treatments
During the double-blind period, eligible patients were randomly
assigned by stratum (baseline therapy of inhaled corticosteroids or
ß2-agonists alone) to one of the following
treatments administered once daily via the multidose powder inhaler for
12 weeks: fluticasone propionate, 100, 200, or 500 µg, or
placebo. Patients previously receiving inhaled corticosteroids were
required to discontinue these drugs for the remainder of the study, and
all patients were required to withhold salmeterol for 12 h,
theophylline for 12 to 36 h, and albuterol for 6 h prior to
clinic visits.
Measurements
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). Patients returned to the clinic weekly for the first
month, and at weeks 6, 8, 10, and 12. At each clinic visit,
FEV1 values had to be greater than the stability
limit. Additionally, during the 7 days immediately preceding each
visit, patients should have had 2 days of 12 puffs of albuterol
aerosol per day, 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 an asthma exacerbation (symptoms
requiring hospitalization or asthma medication excluded by the study
protocol), were discontinued from the study for lack of efficacy.
The primary efficacy variable was morning predose FEV1 obtained at each clinic visit. Other efficacy variables included the following: patient-measured morning and evening PEF; patient-rated asthma symptom scores; nighttime awakenings requiring albuterol use; albuterol use; and duration of study participation. Study drug compliance was monitored via the dose counter (Diskus; Glaxo Wellcome).
Safety assessments included adverse event monitoring, routine clinical laboratory tests, physical examinations (including oropharyngeal examination and vital signs), and 12-lead ECGs. Hypothalamic-pituitary-adrenal (HPA) axis function was monitored by measuring morning plasma cortisol concentrations both before and after performing a short cosyntropin stimulation test at baseline, and at week 12 or early termination. IM or IV injections of 0.25 mg of the synthetic adrenocorticotrophic hormone, cosyntropin, were administered and blood samples collected after 30 min for determination of plasma cortisol concentrations. Peak plasma cortisol concentrations < 18 µg/dL were considered abnormal.
Statistical Analysis
The intent-to-treat population (all patients exposed to
study drug) was used for all safety and efficacy analyses. Testing was
performed on combined data from all investigators, controlling for
investigator effect. All statistical tests were two sided, with
treatment differences 0.05 level of significance being considered
statistically significant. Pairwise comparisons were performed without
adjusting p values for the number of comparisons made.
Change from baseline in FEV1 values was calculated for each time point during the study, and also at end point (final evaluable measurement regardless of whether the patient completed the study). In order to avoid a possible bias toward the placebo group during later time points, an FEV1 value, termed last observation carried forward, was calculated using the last FEV1 value for each patient as a best estimate of the patient’s FEV1 value at these later time points. Change from baseline was compared across treatment groups using analysis of variance F test.
Mean morning and evening PEF rates measured by subjects daily (the best of three measurements at each determination) were averaged weekly (minimum of three diary card records). The end point measurement was the average PEF from the last complete week (7 days) of diary data recorded. Again, in order to avoid a potential bias in favor of the placebo group at later time points, a last observation carried forward PEF value was calculated using the last weekly PEF value for each patient as a best estimate of the patient’s weekly PEF value at these later time points. Change from baseline values in morning and evening PEF was compared across treatment groups using analysis of variance F test.
Determination of the probability of remaining in the study over time was based on the Kaplan-Meier estimates of survival. Patient-rated symptom scores (0 = none, 1 = mild, 2 = moderate, 3 = severe), albuterol use (number of puffs), and nighttime awakenings were averaged weekly; since these values are discrete, all testing was performed using the nonparametric van Elteren test.16
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.05), at weeks 4, 6 10, 12, and end point in the 200-µg
group (p 0.045), and only showed significance at week 6 in the
100-µg group (p = 0.049). Except for a significant increase in mean
change from baseline FEV1 in the 500-µg group
compared with the 100-µg group at week 3 (p = 0.042), no
significant differences were observed between the fluticasone
propionate treatment groups at any time point. Analysis by strata
revealed that patients previously receiving
ß2-agonists alone showed greater improvement in
FEV1 when receiving fluticasone propionate at end
point (0.4 to 0.45 L) than those previously receiving inhaled
corticosteroid therapy (0.05 to 0.2 L). A dose-related trend was
seen in mean change from baseline morning PEF, with increases at end
point being 1, 11, and 28 L/min in the 100-, 200-, and 500-µg groups,
respectively, compared with - 15 L/min in the placebo group (Table 2)
. Compared with placebo, increases in morning PEF (Fig 2
) were significant at all time points in the 500-µg group
(p < 0.001), at all time points except week 1 in the 200-µg group
(p 0.016), and at all time points except weeks 1, 8, 10, and 12 in
the 100-µg group (p < 0.041). In addition, the 500-µg group
showed significant increases in morning PEF compared with the 100-µg
group (p 0.020) and the 200-µg group (p 0.038) from week 2
onwards. Changes in morning PEF were generally similar in the 100- and
200-µg groups, being significantly different only at weeks 8 and 12
(p 0.041).
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0.030), 200-µg (p 0.023), and 500-µg
(p 0.004) groups at all time points. Changes in evening PEF were
significantly different between the 100- and 200-µg groups at week 3
(p = 0.048), and between the 500-µg and 100-µg (p 0.035) or
200-µg (p 0.041) groups at several time points during the
study.
Probability of Remaining in the Study:
At the end of the study, 44% of the patients in the placebo group had
discontinued from the study due to lack of efficacy
compared with 29%, 25%, and 14% in the fluticasone propionate 100-,
200-, and 500-µg groups, respectively. Kaplan-Meier survival
analysis of dropouts over time (Fig 3
) showed that 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 (p 0.030). In
addition, the probability of remaining in the study was significantly
greater in the fluticasone propionate 500-µg group (p 0.040)
than in either the 100- or 200-µg groups.
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0.003). At end point, albuterol use decreased from
baseline by approximately 15%, 7%, and 28% in the 100-, 200-, and
500-µg groups, respectively, compared with a 28% increase in the
placebo group. Mean reduction from baseline in albuterol use was
significantly different in all fluticasone propionate groups compared
with placebo (p < 0.001), and in the 500-µg group compared with
the 200-µg group (p = 0.035). Compared with placebo, the mean
change from baseline in the number of nighttime awakenings requiring
albuterol decreased significantly (p 0.009) in the 200-µg and
500-µg groups at end point (Table 2)
.
Safety
Adverse Events:
Fluticasone propionate, at dosages of 100, 200, or 500 µg once
daily, was well tolerated during the 12-week study, with a low
incidence of drug-related adverse events (placebo, 1%; fluticasone
propionate 500 µg, 5%). In the placebo group, these included one
patient with sore throat and sinus drainage. In the fluticasone
propionate 500-µg group, drug-related adverse events reported by four
patients, included hoarseness and bad breath, hoarseness, headache, and
shakiness.
HPA Axis Evaluation:
No relevant differences were observed in the frequencies of basal or
postcosyntropin stimulation plasma cortisol abnormalities in the
inhaled corticosteroid or ß2-agonist stratum
(Table 3 ). Fluticasone propionate treatment did not show a dose-related effect
on the frequencies of prestimulation or poststimulation plasma cortisol
abnormalities in either stratum. In the inhaled corticosteroid stratum,
the number of patients with poststimulation cortisol concentrations
< 18 µg/dL at screening ranged from 5 to 7%. However, at end
point, these frequencies were lower in the fluticasone propionate
groups (2 to 7%) when compared with placebo (11%). In the
ß2-agonist stratum, no patients had
poststimulation plasma cortisol concentrations < 18 µg/dL at
screening. At end point, a few such abnormalities were observed, with
the highest number (3 of 35 patients; 9%) in the fluticasone
propionate 500-µg group. Of these three patients, one received
prednisone a week prior to discontinuing from the study due to lack of
efficacy, while another received a tapering dose of prednisolone 4
months prior to starting the study. At screening and at end
point, mean plasma cortisol concentrations before and after cosyntropin
stimulation, as well as the mean increase after stimulation, were
similar across treatment groups and strata (Table 4
). No dose-related effects were observed.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Improvements in some efficacy parameters showed a dose-related trend, with morning and evening PEF, and albuterol use being the most sensitive parameters for detecting differences in dose response. Similar levels of statistical significance for between-dose comparisons were not achieved with FEV1. Previous dose-ranging studies with fluticasone propionate6 8 as well as with other inhaled corticosteroids17 18 have demonstrated similar results. The lack of significance for FEV1 may have been due to the fact that differences in FEV1 were attenuated because these measurements were performed in the clinic after patients had been mobilized in the morning, whereas PEF and albuterol use were recorded by patients in their home environment.
In the present study, improvements in efficacy parameters were observed at earlier time points in patients treated with 200 µg and 500 µg of fluticasone propionate. As expected, the 100-µg/d dosage, which is below the recommended dose, showed the smallest improvements. Patients in the ß2-agonist stratum showed a greater improvement in FEV1 than those in the inhaled corticosteroids stratum, suggesting that a once-daily dosing option may be more appropriate for patients with less severe asthma or those not previously treated with inhaled corticosteroids or other anti-inflammatory agents. Consistently, other clinical trials evaluating once-daily dosing with 200 µg,19 or 500 µg20 of fluticasone propionate have demonstrated efficacy in patients with mild to moderate asthma.
Dose-related efficacy was also seen in duration of study participation, with 49% patients receiving placebo completing the 12 weeks of study treatment compared with 57 to 77% of patients receiving active treatment. Previous dose-ranging studies with fluticasone propionate have shown similar results, with 36% of patients receiving placebo treatment completing 8 weeks of treatment, compared with 77 to 96% of patients receiving fluticasone propionate,6 and 28% of patients receiving placebo treatment completing 12 weeks of treatment, compared with 84 to 87% of patients receiving fluticasone propionate patients.8
Inhaled therapy for asthma involving administration three or four times daily has been associated with low levels of compliance,21 22 and a reduction in dosing frequency has been reported to increase compliance.23 24 A very high level of compliance (94 to 96%) was reported in this once-daily dosing study, although this was likely to have been influenced by the maintenance of a patient diary record.
In the present study, all doses of fluticasone propionate were well tolerated, with a low incidence of adverse events, which were typical of the topical effects of inhaled corticosteroids. These results are consistent with the finding that reducing dosing frequency of beclomethasone dipropionate or budesonide from four times daily to twice daily resulted in a reduction in topical effects such as oropharyngeal candidiasis.25 26 Additionally, systemic effects of inhaled corticosteroids are more apparent at higher doses. The steep part of the curve for systemic effects, including adrenal suppression, reportedly occurs at dosages > 800 µg/d.27 In the present study, no apparent dose relationship was evident in plasma cortisol abnormalities, and there was no evidence of clinical adrenal insufficiency as measured by cosyntropin stimulation. Previous dose-response studies with fluticasone propionate utilizing cosyntropin stimulation have similarly demonstrated minimal or no effects on the HPA axis in patients with mild to moderate asthma.4 7 9
Results of this study, in which fluticasone propionate powder administered once daily to patients with moderate, chronic asthma improved asthma control and showed dose-related improvements in some efficacy parameters but no dose-related systemic effects, confirm the high therapeutic potential of fluticasone propionate. Once-daily dosing with fluticasone propionate would facilitate compliance to treatment by improving convenience and provide a viable treatment option for patients with moderate asthma.
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Acknowledgements |
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Footnotes |
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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.
Received for publication October 28, 1999. Accepted for publication March 2, 2000.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This article has been cited by other articles:
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  M. Masoli, M. Weatherall, S. Holt, P. Shirtcliffe, and R. Beasley Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis Eur. Respir. J., November 1, 2006; 28(5): 960 - 967. [Abstract] [Full Text] [PDF]
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 D. D. Sin, J. Man, H. Sharpe, W. Q. Gan, and S. F. P. Man Pharmacological Management to Reduce Exacerbations in Adults With Asthma: A Systematic Review and Meta-analysis JAMA, July 21, 2004; 292(3): 367 - 376. [Abstract] [Full Text] [PDF]
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M. E. Purucker, C. J. Rosebraugh, F. Zhou, and R. J. Meyer Inhaled Fluticasone Propionate by Diskus in the Treatment of Asthma: A Comparison of the Efficacy of the Same Nominal Dose Given Either Once or Twice a Day Chest, October 1, 2003; 124(4): 1584 - 1593. [Abstract] [Full Text] [PDF]
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 R H Green, C E Brightling, I D Pavord, and A J Wardlaw Management of asthma in adults: current therapy and future directions Postgrad. Med. J., May 1, 2003; 79(931): 259 - 267. [Abstract] [Full Text] [PDF]
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B. J. Lipworth, R. A. Nathan, and R. ZuWallack Fluticasone and Cortisol Measurements Chest, March 1, 2001; 119(3): 984 - 985. [Full Text] [PDF]
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