Randomized comparison of ciclesonide 160 and 640 μg/day in severe asthma

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Abstract

Objective

Demonstrating clinical benefit of higher doses of inhaled corticosteroids in asthma is frequently problematic owing to their relatively flat dose–response curve in this condition. In this study we compared the efficacy and safety of a fourfold difference in the dose of ciclesonide—ciclesonide 320 μg twice daily (CIC640) versus ciclesonide 160 μg once daily (CIC160)—in patients with severe persistent asthma.

Methods

Patients with bronchial asthma (⩾6 months) were included in this randomized, double-blind study. After receiving fluticasone propionate 250 μg twice daily during run-in, patients were randomized to CIC160 (n=339) or CIC640 (n=341) for 12 weeks. Primary endpoints were time to first asthma exacerbation and forced expiratory volume in 1 s (FEV1). Secondary endpoints included other lung function variables, asthma symptom scores and rescue medication use (RMU).

Results

Asthma exacerbations occurred in 12.7% of patients receiving CIC160 and 6.7% receiving CIC640. CIC640 was superior for time to first exacerbation (p=0.0050, one-sided). FEV1 increased significantly with CIC160 and CIC640 (least squares mean±SE of mean: 269±31 and 332±31 mL, respectively; p<0.0001), with no significant difference between groups. Change in % predicted FEV1 and morning peak expiratory flow (PEF) were significantly higher with CIC640 (p<0.05). Asthma symptom score sums and RMU decreased in both groups; CIC640 was statistically superior (p=0.0108 and 0.0005, respectively). No unexpected adverse events were reported in either group and the majority of the events reported were mild or moderate in intensity. No significant changes in serum cortisol were observed from the baseline to the study end. Small decreases in creatinine-adjusted 24 h urine cortisol levels from baseline were seen in both the treatment groups, which, due to the large patient numbers, were statistically significant (p<0.05); however, no dose–response effect was seen and the difference between groups was not significant (p=0.7892).

Conclusion

CIC640 was superior to CIC160 for time to first exacerbation, % predicted FEV1, morning PEF, asthma symptom score sum and RMU in patients with severe asthma; both doses had similar tolerability profiles and no significant changes in serum cortisol were seen in either treatment group.

Introduction

Asthma is a chronic inflammatory disorder of the airways [1], and the aim of treatment is to achieve and maintain long-term asthma control, including normal or near-normal lung function [1], [2]. Inhaled corticosteroids (ICS) are the recommended treatment of choice for patients of all ages with persistent asthma of all severities [1], [2]. Taken regularly, ICS are effective at improving lung function, reducing asthma symptoms and reducing long-term sequelae. Sub-optimal long-term control of asthma is generally the result of poor adherence and an under-use of ICS rather than the lack of efficacy of ICS [3], [4].

A majority of patients with asthma respond readily to low-dose ICS with improvements in lung function and asthma symptoms [5], [6]. Although the dose–response curve is relatively flat for this class of treatment, in patients who demonstrate relative refractoriness to lower doses, this can be overcome by increasing the dose [7]. The benefits of higher doses are also more obvious during periods of instability or asthma exacerbations [5], [8]. By contrast, the dose–response curve for side effects is relatively steep [6], with reduced therapeutic ratios at higher doses. For this reason, guidelines recommend the use of the lowest dose of ICS that maintains control and in order to avoid potential systemic adverse effects, such as adrenal suppression and osteopenia [9], [10], and local effects, such as oral candidiasis [11], avoidance of the prolonged use of high doses, especially in children [1]. At any dose, but especially when high doses of ICS are required, there is an obvious advantage in using an ICS with a high therapeutic ratio.

Ciclesonide is a novel ICS for the treatment of persistent asthma that may have beneficial pharmacokinetic and pharmacodynamic characteristics. Delivered via a hydrofluoroalkane-134a metered-dose inhaler (MDI), ciclesonide has a high lung deposition (>50%) due to a high fraction of fine particles [12]. It is converted in the lung by airway-specific esterases to the active metabolite desisobutyryl-ciclesonide [13], which has a 100-fold higher affinity for glucocorticoid receptors than ciclesonide [13]. In addition, ciclesonide and its active metabolite have low oral bioavailability (<1%) [14], combined with a high systemic clearance rate [13], [15], accounting for a low potential for systemic and local side effects. Local adverse events (AEs) associated with ciclesonide use occur at a similar rate to that in placebo-treated patients [16], [17], and at a much lower rate than with the other ICS [18]. Similarly, clinically relevant systemic effects, such as hypothalamic–pituitary–adrenal (HPA)-axis suppression, have not been reported with ciclesonide, even at high doses [16], [18], [19].

Furthermore, ciclesonide is suitable for once-daily dosing in the range of 80–640 μg/day [16], [17], [20]. However, a dose–response effect with ciclesonide for efficacy has not been demonstrated so far. A study with a ‘step-down’ design performed in patients with primarily mild-to-moderate persistent asthma, previously controlled with medium doses of ICS, failed to show a significant difference between 160 and 640 μg ciclesonide given once daily [16]. In a study of moderate-to-severe persistent asthma, twice-daily doses of ciclesonide (640 and 1280 μg/day) significantly increased peak expiratory flow (PEF; p=0.0002 and 0.001, respectively) and decreased mean daily symptom scores (p<0.0001). No superiority was shown for the higher dose [21]. However, in a study in patients with severe asthma, ciclesonide 320 and 640 μg/day demonstrated significant dose-related improvements in the forced expiratory volume in 1 s (FEV1; p=0.0374 and 0.0008, respectively) versus placebo [22].

The aim of the current dose–response study was to establish whether ciclesonide at a high dose (320 μg twice daily) provides greater therapeutic benefit than the low dose of 160 μg once daily in patients with severe persistent asthma. In addition, the effects of ciclesonide on the frequency of oral candidiasis and measures of serum and urinary cortisol were assessed in the subset of patients to determine any dose–response effect on safety.

Section snippets

Subjects

Male and female patients aged 12–75 years were included if they had a history of bronchial asthma as defined by the American Thoracic Society (ATS) criteria for at least 6 months [23], but were otherwise in good health. Patients previously receiving fluticasone propionate 500 μg/day (or equivalent) were required to have a FEV1 ⩽70% of predicted normal, and those receiving fluticasone propionate >500–1000 μg/day (or equivalent) a FEV1 ⩽90% of predicted normal. Patients received 250 μg fluticasone

Subjects

Of 896 patients recruited, 680 (76%) were randomized in the ITT population (ciclesonide 160 μg/day, n=339; ciclesonide 640 μg/day, n=341). Of the 680 patients randomized, 85 discontinued treatment before the end of the 12-week treatment period (55 receiving ciclesonide 160 μg/day and 30 receiving ciclesonide 640 μg/day) (Fig. 1). Most withdrawals were due to asthma exacerbations (43 in the 160 μg/day group and 23 in the 640 μg/day group). Baseline and patient characteristics were similar in the two

Discussion

The results of this study confirm a dose–response relationship for efficacy endpoints for ciclesonide in severe asthma at the doses tested. Ciclesonide 320 μg twice daily provided greater therapeutic benefit than ciclesonide 160 μg once daily in preventing asthma exacerbations, improving morning PEF, reducing use of rescue medication, improving daytime, nighttime and asthma symptom score sum and asthma control, and increasing the percentage of days that patients were free from nocturnal

Acknowledgments

This study was funded and sponsored by ALTANA Pharma. The authors would like to thank Lesley Brewer, BSc (Hons), Medicus International, and Armella Escher, PhD, ALTANA Pharma for their editorial assistance. Editorial support was funded by the ALTANA Pharma.

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