budesonide (Pulmicort Turbuhaler)

budesonide (Pulmicort Turbuhaler)

ARTICLE IN PRESS Respiratory Medicine (2007) 101, 610–615 Potency ratio fluticasone propionate (Flixotide Diskus)/budesonide (Pulmicort Turbuhaler) Bj...

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ARTICLE IN PRESS Respiratory Medicine (2007) 101, 610–615

Potency ratio fluticasone propionate (Flixotide Diskus)/budesonide (Pulmicort Turbuhaler) Bjo ¨rn Sta ¨llberga, Eva Pilmanb, Bengt-Eric Skooghc,, Bengt Arne Hermanssond a

Department of Public Health and Caring Sciences, Uppsala and Trosa Primary Health Care Centre Trosa, Uppsala University, Sweden b Primary Health Care Centre Stattena, Helsingborg, Sweden c Department of Respiratory Medicine and Allergology, Go ¨teborg University, Sweden d GlaxoSmithKline, Sweden Received 12 March 2006; accepted 9 June 2006

KEYWORDS Inhaled steroids; Asthma; Randomized clinical trial; Potency ratio; Fluticasone propionate; Budesonide

Summary 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-naı¨ve patients, the potency difference was evident only at low daily doses, below 200 mcg. & 2006 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +46 3134 231 75; fax: +46 3182 4904.

E-mail address: [email protected] (B.-E. Skoogh). 0954-6111/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2006.06.008

ARTICLE IN PRESS Potency ratio fluticasone propionate

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Introduction

dose was then reduced in a stepwise fashion every 8 weeks (Fig. 1) until an exacerbation was registered according to predetermined criteria, at which point the patient was withdrawn from the study. The first 4 weeks during step 1 were assigned to establish the treatment effect and no patient was excluded because of an exacerbation during this period.

Inhaled corticosteroids (ICS) are recommended as a first-line maintenance treatment of persistent asthma. In the choice of, or switch between, various 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.1,2 Therefore, clinical efficacy comparisons must encompass the drug–inhaler combinations. The study design of the comparison is also of decisive importance. In a recent editorial, Beasley et al.3 argued against the value of comparative efficacy studies based on single high-dose comparisons. Instead they recommended dose response comparisons including doses below the top of the dose response curves and suggested three different study designs4 for such comparisons, one of which was a dose down-titration technique. The aim of this study was to estimate 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 with loss of asthma control, denoted ‘‘exacerbation’’, as the primary, dose defining end point.

Study population Asthma patients of at least 16 years of age were eligible for the study if they had not used any steroids for the last 3 months, if forced expiratory volume (FEV1) was 470% predicted normal after salbutamol inhalation, and if they at least once a week for the last 2 months had had asthmarelated symptoms such as disturbing cough without infection and/or episodes of wheezing and/or episodes of chest tightness and/or awakening with chest symptoms. Further, within 2 months before randomization they should show improvement on salbutamol inhalation of FEV1 (X15%) or of peak expiratory flow (PEF) (X60 L/min) or show a PEF variability of X20% and during run-in have a cumulative symptom score X7 during (see below) last 10 days and/or need rescue medication X3 days/week. Patients were not eligible if they had another significant disease or were pregnant, or if they needed oral steroids or used cromoglycate, long-acting beta-agonists, antileukotriens, beta blockers or ACE-inhibitors. All patients gave written informed consent and the study was approved for each centre by the ethics committee.

Methods Study design At 24 Swedish Primary Health Care Centres, steroid-naive asthmatics were randomized centrally to double-blind, double-dummy ICS treatment. During a run-in period of 2 weeks the diagnosis was confirmed by reversibility testing and recordings of symptom scores and rescue medication. The only treatment allowed during the run-in was rescue medication with salbutamol inhalation. After run-in the patients were allocated to treatment according to a centralised randomization schedule choosing the lowest available pack number. The ICS treatment was initiated with either 250 (metered dose) mcg BID of FP or 400 (metered dose) mcg BID of BUD for 12 weeks. These initial doses were chosen according to available data in the literature.5–7 The Step 1

Assessments and outcome measures The primary outcome was the lowest effective dose defined as the dose just above that at which asthma control was lost. The number of patients who could quit inhaled steroids, FEV1, PEF, day-time and night-time symptoms scores and use of rescue medication were assessed as descriptive measures or to diagnose loss of asthma control, in this paper denoted as exacerbation. Clinic visits were scheduled at weeks 2, 0, 4, 8, 12 and then every 8 weeks up to week 44 or until the patient was withdrawn from the study. At each visit during the

Step 2

Step 3

Step 4

Step 5

Dose of Inhaled corticosteroid

FP 250 BD or BUD 400 BD

FP 100 BD or BUD 200 BD FP 50 BD or BUD 100 BD FP 50 OD or BUD 100 OD FP 0 or BUD 0 -2

0

12

20 week

28

36

44

Figure 1 Schematic depiction of the study design with dose reduction schedule.

ARTICLE IN PRESS 612 treatment period dynamic spirometry and PEF (mini-Wright peak flow meter) was performed in triplicate. The occurrence of any adverse event was also recorded. The patients completed daily record cards on intake of study medication, morning and evening PEF, use of rescue medication, and day-time and night-time asthma symptom scores. Night-time symptoms were scored from 0 (no symptoms) to 4 (symptoms so severe I did not sleep at all), and daytime symptoms from 0 (no symptoms) to 5 (symptoms so severe that I could not go to work or perform normal daily activities). Base-line values were calculated from recordings during week 4 as follows: PEF—mean of the three best morning recordings before any possible rescue medication; rescue medication—the second highest use during night-time and day-time, respectively; symptom score—the second highest score for night-time and daytime scores, respectively. If these values improved further until week 12 (the last week during step 1), the corresponding values from this week were used as base-line values for the following dose steps. The second highest value was used to reduce the influence from single out-lying values. An exacerbation was diagnosed if one or more of the following criteria were fulfilled: 1. Decrease of PEF—one episode with a critical low value as judged by a physician or morning PEF o85% for 3 days in a row and/or morning PEF o85% for 4 out of 7 days. 2. Increase of rescue medication—X3 doses/day for 3 days in a row or X3 doses/day on four out of 7 days, or X1 dose/night for two nights in a row. 3. Increase of symptom score—by 2 units/day for three days in a row, or by 2 units/day on four out of 7 days, or by 1 unit/night for two nights in a row. If the exacerbation criteria were associated with symptoms of infection, two exacerbations within 6 weeks were necessary to define the lowest efficient maintenance dose. It was allowed to treat infectious exacerbations with oral prednisolone, 30 mg daily, until recovery of PEF (X90% baseline), rescue medication and symptoms. Antibiotics were allowed at the discretion of the physician.

B. Sta ¨llberg et al. be acceptable. To get 220 evaluable patients we decided to include 280 patients. The improvement of lung function, symptom scores and use of rescue medication between end of step 1 and run-in was analyzed by the Wilcoxon signed rank. To describe these improvements mean and standard deviation of the difference between end of step 1 and run-in was used. Dose dependency was tested by repeated measurement analysis using generalized estimating equations (GEE) logistic regression.

Results Patient characteristics during run-in and base line In total, 282 patients were recruited to the run-in phase. Of these 50 did not fulfill the run-in criteria and 3 were randomized in spite of not fulfilling all criteria. Thus, 229 patients entered the double-blind treatment phase per protocol. Only minor differences were seen between the two treatment groups (Table 1). In total, 28 patients were later withdrawn from the study because of protocol violations (n ¼ 6), withdrawn consent (n ¼ 5), lost at Table 1

Patient characteristics during run-in.

Age, years (mean7SD) Female, n (%) Male, n (%) Clinic FEV1, L (mean7SD) Clinic FEV1, % pred (mean7SD) Morning PEF, L/min (mean7SD) Total symptom score/24 h (mean7SD) Rescue inhalations/24 h (mean7SD)

FP (n ¼ 116)

BUD (n ¼ 113)

40714 65 (56) 51 (44) 3.170.87 91717

38714 64 (57) 49 (43) 3.070.78 88717

4337105

4297100

2.1371.3

1.971.2

2.672.2

2.472.1

 Reported values are before inhalation of beta-2-agonists.

Statistical analysis The primary analysis is the potency ratio between least efficient dose for BUD and FP. To be able to estimate the confidence interval for the median of the potency ratio the following calculations were used: Assuming that X is least efficient dose (40) for BUD and Y is the corresponding stochastic variable for FP, the potency ratio between BUD and FP, X=Y can be expressed as exp (log Xlog Y). If the distributions of X and Y are lognormal distributed then an estimation and 95% confidence interval for mean and median of log Xlog Y can easily be calculated using normal theory. The median and 95% confidence interval for the potency ratio BUD/FP ðX=YÞ was calculated by taking the antilogarithm of the above estimates.8 Assuming potency ratios of 1.5; 2.0; 2.5 we calculated that 2  110 patients would yield a 95% CIs of 1.17–1.93; 1.55–2.57; 1.94–3.22, respectively ,which we considered to

Table 2 Effect of treatment by inhaled steroids as reflected by change in group mean values from run-in to end of step 1. Mean7SD

Clinic FEV1, L Morning PEF, L/min Total symptom score/ 24 h Rescue inhalations/24 h

Change FP (n ¼ 113)

BUD (n ¼ 105)

0.2270.44 40.6749.1 1.2971.38

0.1370.46 39.4745.9 1.1571.48

1.7872.03

1.6771.99

 Reported values are before inhalation of beta-2-agonists.

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followup (n ¼ 6), suspected adverse advents (n ¼ 2) and other causes (n ¼ 9) with similar distribution between the two treatment arms. Accordingly, 103 patients in the FP group and 98 patients in the BUD group completed the study per protocol. By the observations during run-in 6/116 in the FP group and 3/113 in the BUD-group were classified as having mild asthma, and the rest of them as having moderate asthma, according to GINA guidelines.9 Initiation of the therapy was both in the FP group and in the BUD-group followed by significant improvements (Po0.001, Wilcoxon signed rank test) in mean values for lung function, symptom scores and use of rescue medication (Table 2).

significantly at the end of step 1 also for these patients although the improvement was less marked compared to those still remaining in the study. At the following dose steps the frequency of exacerbations then increased in a dose dependent fashion (Pp0.0001 for FP and P ¼ 0.0156 for BUD) as the dose was reduced (Fig. 2). In the FP-group 23/103, and in the BUD group 19/98, patients could quit inhaled steroids and not get an exacerbation during the following 8 weeks (Table 3). Most of the dose defining exacerbations were diagnosed according to symptom scores or to symptom scores in combination with PEF and/or rescue medication criteria (Table 3). Only 15 exacerbations in each treatment group were diagnosed on PEF or rescue medication criteria only.

Exacerbations During the study period 147 (FP 76, BUD 72) non-infectious, and 117 (FP 53, BUD 64) infectious, exacerbations were diagnosed. Only 4 infectious exacerbations in the FP- and 7 in the BUD-group were followed by a second one within 6 weeks thus causing a dose defining withdrawal. In the FPgroup 5 and in the BUD-group 4 prednisolone courses were given among patients still remaining in the trial after an infectious exacerbation. Thus, most infectious exacerbations were mild, not needing oral steroid treatment. At the end of step one 16% of the patients in the FP group and 21% in the BUD group left the study because they never reached stable asthma control as they experienced a dose defining exacerbation already during weeks 5–12. However, a post hoc analysis showed that the mean values for PEF, symptom score and rescue medication had improved

30

15 Bud: 113 FP:

78 116

64 92

48 32 63 51 36

% exacerbations

BUD

0 800

600

400 200 Metered daily dose, µg

0

Figure 2 The frequency of exacerbations at the various dose steps. The frequency is expressed as % among those at risk. Numbers at risk at each dos step is indicated by figures in italics.

Table 3

The primary end point, lowest efficient maintenance dose, could not be determined for 18 patients in the FP group and for 24 patients in the BUD group as they did not reach the predetermined criteria for asthma control during step 1 (Table 4). However, these patients still showed significant improvements in their asthma status although not reaching full control. Assuming that a doubling of the dose would have resulted in full control in these patients will yield a potency ratio between Flixotide Diskus and Pulmicort Turbuhaler of 1.75:1 (95% CI 1.26:1–2.43:1). Alternatively, excluding these patients from the calculations gives a potency ratio of 1.50:1 (95% CI 1.10:1–2.05:1).

Adverse events

45 FP

The potency ratio between FP (Flixotide Diskus) and BUD (Pulmicort Turbuhaler)

The pattern of adverse events was similar in the two treatment groups. The most frequently reported possibly related adverse event was hoarseness (FP 3%, BUD 3%) and oral candidiasis (FP o1%, BUD 2%).

Discussion Using loss of asthma control (exacerbation) as the dose defining end-point we in this study found the therapeutic potency ratio between FP (Flixotide Diskus) and BUD (Pulmicort Turbuhaler) to be between 1.50:1 and 1.75:1 depending on if patients with insufficient steroid-response were excluded from the calculations or not. The first

Dose defining exacerbations as diagnosed by PEF-recordings, rescue medication or symptom score.

Exacerbation criteria All possible combinations

PEF Rescue medication Symptom score

Criterion as single determinant

PEF+

Rescue+

FP

BUD

FP

BUD

FP BUD FP

12 38 60

18 42 60

7 8 28

9 6 21

— — 0 0 2 3

0 — 27

PEF+rescue+

BUD

FP

BUD

0 — 30

— — 3

— — 6

Note 1: data are missing for 4 patients in the FP and 2 in the BUD group with exacerbations diagnosed at unscheduled visits. Note 2: one exacerbation in the FP and 2 in the BUD group were diagnosed by the physician in spite of not fulfilling any of the diary card criteria.

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B. Sta ¨llberg et al.

Table 4 Number of patients according to lowest efficient maintenance dose (mcg/day). FP (n ¼ 103)

BUD (n ¼ 98)

Dose

n

Dose

n

4500 500 200 100 50 0

18 25 11 13 13 23

4800 800 400 200 100 0

24 13 14 15 13 19

alternative assumed all excluded patients to be resistant to the treatment, which clearly was not true as they did improve on treatment although not reaching full control. However, we cannot exclude that these patients had some steroid resistant components in their disease. Therefore, it might not be correct to assume that all these patients had reached full asthma control after doubling the dose in step 1, a fact that would move the calculated potency ratio from 1.75 towards somewhat lower values. The second point (200 mcg) in the dose–response curve for FP clearly deviated from the rest of the curve (Fig. 2) in a direction that shifts the calculated potency ratio from about 2 to lower values. We believe the high exacerbation rate found at the dose step 200 mcg for FP to be a by chance finding. We feel that this conclusion is supported by the fact that at this dose step 18/25 exacerbations in the FP group were defined according to a single criterion only, compared to 28/80 at all dose steps together. There are few other studies published comparing the therapeutic efficacy of FP and BUD based on dose–response data. Two earlier studies, one in children10 and one in adults,11 used a dose reduction design similar to the present and did not find any significant potency difference between FP and BUD. However, these studies differed from our study in a number of aspects. They included only subjects with proven asthma control on inhaled steroids, whereas our study included steroid-naive asthmatics only. They used 5 weeks treatment periods compared to 8 weeks in our study. Compared to our study the earlier study in children10 did not include the lower daily FP dose (50 mcg/day) and the earlier study in adults11 did not include the two lower daily FP doses (100 and 50 mcg/day) as well as the lower BUD dose (100 mcg/day). To the best of our knowledge our study is the first dose–response comparison including daily metered doses down to FP 50 and BUD 100 mg. The separation between the dose response curves is most evident at the lower daily doses (Fig. 2). In a dose step up study in asthma patients formerly on treatment with moderate to high doses of inhaled steroids the relative efficacy of FP and BUD on bronchial metacholine PD20 reactivity was found to be 2.5.12 However, the short treatment periods, 2 weeks, make the results difficult to interpret, although it could be argued that too short treatment periods should have similar consequences in the two treatment arms.

There are several published comparisons between FP and BUD of clinical efficacy using fixed doses throughout the study. Almost all of them have used doses (reviewed in)4,13 that are, at least in mild and moderate asthma, near or above the top of the dose response curves, see Fig. 2.14,15 This fact will seriously impede potency comparisons between the drugs based on meta-analyses of pooled data from such studies. The results will in this respect be largely dependent on the doses chosen for the comparisons.4 The time-course for the onset of improvement in PEF and symptom score was nearly identical for the two treatment groups (data not shown) and similar to earlier published data for FP16 and for BUD.17 The present study used a dosereduction technique and to the best of our knowledge there is no detailed information available about the time-course for the wearing off therapeutic effect upon cessation of inhaled steroids, although significant impairments have been shown to occur within 2 weeks.18 We therefore used relatively long, 8 weeks, treatment periods. Further, the identical onset course for FP and BUD to our minds makes it unlikely that the time-course for tapering off should differ between the two drugs, thus hampering the potency comparison. This study did not include measures of systemic activity because this has been extensively compared for FP and BUD in several studies.4 Although the highest daily doses used in this study have been demonstrated to affect various biomarkers of systemic activity, there is no evidence that these doses in adults may induce clinically relevant side-effects like adrenal insufficiency, osteoporosis, skin bruising or cataract.4 Thus, in the clinical situation it is relevant to focus on the equipotent doses for therapeutic effects. The maximal therapeutic effect seems to have been achieved already at a daily dose of 100–200 mg for FP and 200–400 mg for BUD (Fig. 2). This is in accordance with two recent meta-analyses14,15 and supports the notion that mild to moderate asthma should preferably be treated by low to moderate daily doses of inhaled steroid. 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 endpoints 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 GOALstudy.24 In this study, 70% of earlier steroid-naı¨ve patients obtained well-controlled asthma on a 1-year treatment course with inhaled FP in increasing daily doses up to 1000 mg including a final course with oral steroids. However, among those who obtained well-controlled asthma, 82% did this on an inhaled daily dose of 500 mg or lower. Symptom score defined the majority the exacerbations both as single criterion and in combination with recordings of rescue medication and/or PEF (Table 3). Only about 10% of the exacerbations were defined by PEF criteria only. The agreement within the three criteria was clearly best between symptom score and rescue medication, whereas no exacerbation was defined by a combination of rescue medication and PEF (Table 3). These data cast some doubt

ARTICLE IN PRESS Potency ratio fluticasone propionate on the value of PEF recordings compared to a careful symptom history to monitor the asthma disease state. In conclusion, in steroid-naı¨ve patients with mild to moderate asthma we found the therapeutic potency ratio between FP (Flixotide Diskus) and BUD (Pulmicort Turbuhaler) to be between 1.50:1 and 1.75:1 using loss of asthma control as the dose defining end-point. The potency difference was evident only at low daily doses, below 200 mcg. It should be pointed out that the present data might not be valid for other drug–inhaler combinations.

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