Randomized comparison of ciclesonide 160 and 640 μg/day in severe asthma
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.
References (32)
Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients
Chest
(1998)Managing a variable disease
Pulm Pharmacol Ther
(2002)- et al.
Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group
Chest
(2000) Benefits and risks of inhaled glucocorticoids in children with persistent asthma
J Allergy Clin Immunol
(1998)- et al.
High lung deposition of (99m)Tc labeled ciclesonide administered via HFA-MDI to patients with asthma
Respir Med
(2006) - et al.
Once-daily ciclesonide 80 or 320 microg for 12 weeks is safe and effective in patients with persistent asthma
Respir Med
(2005) - et al.
Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal axis function in adults with mild-to-moderate persistent asthma
Ann Allergy Asthma Immunol
(2005) - et al.
Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5' monophosphate in asthmatic patients
Pulm Pharmacol Ther
(2005) - et al.
Validation of a standardized version of the Asthma Quality of Life Questionnaire
Chest
(1999) - et al.
Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma
Chest
(2006)
Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler
Respir Med
National asthma education and prevention program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics
J Allergy Clin Immunol
Inadequate therapy for asthma among children in the United States
Pediatrics
Inhaled corticosteroid doses in asthma: an evidence-based approach
Med J Aust
Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study
Am J Respir Crit Care Med
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2016, Journal of Pharmaceutical SciencesCitation Excerpt :Hansel et al.61 in a multinational randomized study suggest that ciclesonide (80 and 320 μg QD) is as efficacious as budesonide (200 μg BID) in controlling asthma attack and improving lung functions. Bateman et al.62 evaluated higher daily dose of ciclesonide (640 μg) in severe asthma patients and found to be efficacious in improving forced expiratory volume 1, morning PEF and improving asthma symptoms when tested against its lower dose of 160 μg. Pauwels et al.28 suggested that ciclesonide administration at dose levels of 1000 μg and 2000 μg did not cause any suppression in the plasma cortisol levels (systemic side effect) in comparison to fluticasone treatment, where significant cortisol suppression was observed.
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2015, Paediatric Respiratory ReviewsCitation Excerpt :In studies focused on severe asthma in patients aged 12-75 years, 320 μg b.i.d. CIC had lower side effects than 500 μg b.i.d. FLUT in a 24-week trial [24]. In the same age group, 320 μg b.i.d. for 12 weeks was superior to 160 μg q.d. for time-to-first-exacerbation, % predicted FEV1, morning PEF, asthma-symptom score and rescue-medication use [25]. A second approach would be to add a second drug in order to overcome cortico-resistance and to reduce doses.
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2015, Archivos de BronconeumologiaCitation Excerpt :Although some studies support the greater therapeutic efficacy of fine particle IC (related with their effect on the peripheral airways), there is no evidence of their superiority in SUCA34 (evidence C-R2). Among the new glucocorticoids, ciclesonide has fewer local and systemic side effects since it is a prodrug converted to its active form in the lung parenchyma35 (evidence B-R2). New steroids, known as “dissociated” compounds (mapracorat), that aim to separate the anti-inflammatory mechanisms from the side effects, are currently under development36 (evidence D-R2).
Experimental Design
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