Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma

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Pulmonary Pharmacology & Therapeutics 21 (2008) 264–275 www.elsevier.com/locate/ypupt

Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma E.D. Batemana,, A.E. Linnhofb, L. Homikc, U. Freudensprungd, L. Smaud, R. Engelsta¨tterd a

Division of Pulmonology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, P.O. Box 34560, Groote Schuur 7937, Cape Town, South Africa b Private Practice, Berlin, Germany c Concordia Hospital, Winnipeg, Manitoba, Canada d ALTANA Pharma AG, Konstanz, Germany Received 28 November 2006; received in revised form 30 April 2007; accepted 6 May 2007

Abstract Objective: To investigate the relative efficacy of ciclesonide and fluticasone propionate (FP) administered at comparable microgram doses in maintaining asthma control in patients with moderate-to-severe persistent asthma. Methods: This randomized, open-label, parallel-group study enrolled patients aged 12–75 years with a X6-month history of bronchial asthma. To enter a 2-week run-in period, patients had to have received FP 500–1000 mg/day or equivalent at a stable dose for X4 weeks and have a forced expiratory volume in 1 s (FEV1) X80% of predicted. To enter the treatment period, patients had to have the following during run-in: FEV1 X80% of predicted; reversibility of DFEV1 X12% after 200–400 mg salbutamol; and X1 day without asthma symptoms during the last 7 days. Patients were randomized to twice-daily ciclesonide 320 mg (ex-actuator) or twice-daily FP 330 mg (exactuator) for 6 months. Efficacy was assessed by lung function, asthma exacerbations, asthma symptoms and rescue medication use. Patients completed the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Adverse events (AEs), including local oropharyngeal AEs, were recorded. Results: 528 patients were randomized (ciclesonide, n ¼ 255; FP, n ¼ 273). In both groups, FEV1 was maintained from baseline to study end (mean increase: ciclesonide 11 mL, FP 24 mL; intention-to-treat [ITT] analysis). The least squares mean7standard error of the mean for the treatment difference was 13729 (95% confidence interval [CI]: 70, 44) in the ITT analysis and 27734 (95% CI: 93, 40) in the per-protocol (PP) analysis, demonstrating non-inferiority of ciclesonide to FP. Morning, evening and site-measured PEF improved significantly with both treatments (ITT and PP analyses: po0.05). Six patients receiving ciclesonide and seven receiving FP (ITT analysis) experienced an asthma exacerbation requiring treatment with oral corticosteroids. Both treatments significantly decreased asthma symptom score sum (ITT and PP analyses: pp0.0001) and rescue medication use (ITT and PP analyses: po0.05), with no significant difference between treatments. Both treatments significantly improved overall AQLQ(S) score (ITT and PP analyses: po0.05). Significantly more patients experienced candidiasis and dysphonia with FP compared with ciclesonide (p ¼ 0.0023). Conclusion: Ciclesonide 320 mg and FP 330 mg administered twice daily over 6 months provided similar efficacy in patients with moderate or severe persistent asthma previously well-controlled by high doses of ICS at baseline. Ciclesonide was associated with fewer local AEs than FP. r 2007 Elsevier Ltd. All rights reserved. Keywords: Ciclesonide; Fluticasone propionate; Persistent asthma; Lung function; Quality of life; Oral candidiasis

1. Introduction

Corresponding author. Tel.: +27 021 406 6901; fax: +27 021 406 6902.

E-mail address: [email protected] (E.D. Bateman). 1094-5539/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2007.05.002

Inhaled corticosteroids (ICS) are first-line therapy for all severities of persistent asthma [1,2]. Some of the early molecules in this class, although still in use, have been superseded by molecules with greater efficacy, longer

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duration of action, more convenient formulations and more advantageous safety profiles. The ideal ICS is characterized by high local anti-inflammatory efficacy combined with a fast metabolic inactivation to avoid systemic effects. Although at low doses there may appear to be little to choose between the ICS in terms of therapeutic index, a large proportion of patients require moderate or high doses to gain control of their asthma, and in these patients the safety profile of the ICS assumes greater relevance [3–8]. Fluticasone propionate is an ICS considered to have excellent local efficacy in the lower airway, and has been shown to be highly effective when given both alone and in combination with long-acting b2-agonists (LABAs). Other favourable features are a high first-pass metabolism, which ensures that the majority of absorbed corticosteroid is inactivated by the liver. In spite of this, it has been associated with adrenocortical suppression, especially when given in high and excessive doses [5], and rare examples of adrenocortical crisis in children resulting from its use have been described. In addition, twice-daily dosing with fluticasone propionate has been shown to provide better clinical results than a once-daily regimen [9,10], and it is not approved for once-daily dosing. Ciclesonide, a new class of ICS that is currently available in a number of countries, has several favourable features. These include high potency and prolonged duration of action, making it suitable for once-daily administration in the majority of patients [11–13], and a very favourable therapeutic index. Ciclesonide is a prodrug and is converted to the active metabolite, desisobutyryl-ciclesonide, in the lungs by airway-specific esterases [14]; the active metabolite has high affinity for the glucocorticoid receptor (an approximate 100-fold increase compared with the parent compound) [15]. This reduces the potential for local side effects in the oropharynx and for absorption of corticosteroid from the intestinal tract. Other features that contribute to its high-level therapeutic ratio are low oral deposition (the result of its delivery as a solution propelled by hydrofluoroalkane [HFA] in a mist of smaller particle size than the usual chlorofluorocarbon pressurized metered-dose inhalers [MDIs]), as well as high protein binding [16] and first-pass metabolism by the liver [17], both of which reduce the systemic bioavailability of any drug that is absorbed. Results of an in vivo animal study suggest that the duration of action of ciclesonide may be attributable to its lipophilicity and the formation of lipid conjugates in the lung [18]. The efficacy of ciclesonide has been compared with that of fluticasone propionate in a number of studies and over a range of doses [19–21]. For example, ciclesonide 160 mg once daily has been shown to provide comparable results to fluticasone propionate 88 mg twice daily at improving lung function and asthma symptoms, and in reducing rescue medication use in patients with mild-to-moderate persistent asthma [19]. A dose of 320 mg once daily also showed similar efficacy to that of fluticasone propionate 176 mg

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twice daily in patients with moderate persistent asthma [20]. However, to date, no studies at higher, comparable doses in patients with moderate-to-severe persistent asthma have been reported. For some ICS, increased dosing frequency (twice or even four-times daily) is associated with improved efficacy and, therefore, many physicians prefer to use twice-daily dosing in patients with more severe asthma (at least at the beginning of treatment). To accommodate this tendency, the current study, which set out to compare the safety and efficacy data of ciclesonide and fluticasone propionate at similar nominal daily dosing, employed twice-daily doses for both treatments. The study compared cicleonide 640 mg/day ex-actuator and fluticasone propionate 660 mg/day ex-actuator in terms of maintaining asthma control in patients with moderate-to-severe persistent asthma. 2. Methods 2.1. Subjects Study subjects were outpatients aged 12–75 years with a X6-month history of bronchial asthma as defined by the American Thoracic Society criteria. To enter the 2-week run-in period, patients had to have been receiving fluticasone propionate 500–1000 mg/day or equivalent at a stable dose for X4 weeks and had to have a forced expiratory volume in 1 s (FEV1) X80% of predicted, measured at least 4 h after short-acting b2-agonists and at least 24 h after other asthma controllers. For entry into the treatment period (at baseline), patients had to have an FEV1 X80% of predicted, measured X4 h after the last use of rescue medication and X24 h after the last use of asthma controllers. In addition, a reversibility of DFEV1 X12% (and X0.200 L) after inhalation of 200–400 mg salbutamol during the run-in period, or a diurnal peak expiratory flow (PEF) fluctuation X15% during 3 or more days within the last 7 days of run-in, was required. Patients also had to have experienced at least 1 day without any asthma symptoms during the last 7 days prior to baseline. Exclusion criteria included: concomitant severe diseases; chronic obstructive pulmonary disease and/or other relevant lung diseases other than asthma; clinically relevant abnormal laboratory values; the use of systemic steroids within 4 weeks (for injectable depot steroids, 6 weeks) prior to entry into the run-in period or more than three times during the last 6 months; and the use of non-allowed drugs, including corticosteroids other than specified in the inclusion criteria, ketotifen, inhaled anticholinergics, disodium cromoglycate and nedocromil, and bronchoconstrictive agents, including b-blockers. Patients with X10 cigarette pack-years (ex-smokers or current smokers), pregnant or lactating females, and women of child-bearing potential not using safe contraception were also excluded. Written informed consent was obtained from patients and their parent(s) or legal guardian(s) in the case of

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minors before the start of the study, and the protocol was reviewed and approved by the appropriate regional Institutional Review Boards or Independent Ethics Committees. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and with the rules of the International Conference on Harmonization Good Clinical Practice consolidated guideline. 2.2. Study design This randomized, open-label, parallel-group study was performed in a total of 100 centres in Belgium, Canada, France, Germany, Ireland, the Netherlands, South Africa, Switzerland and the United Kingdom. During a 2-week run-in period, patients continued treatment with their current ICS (500–1000 mg/day fluticasone propionate or equivalent). Additionally, patients using LABAs, oral b2-agonists, theophylline, leukotriene antagonists or lipoxygenase inhibitors could continue treatment provided the dosage was kept constant throughout the trial. Eligible patients were randomized 1:1 using a centralized, automated facsimile system (Fisher Automated Clinical Trial Service [FACTS]), provided by Fisher Clinical Services AG (Allschwil, Swizerland), to either twice-daily ciclesonide 320 mg (two puffs of 160 mg exactuator [200 mg ex-valve]; total daily dose 640 mg) or twicedaily fluticasone propionate 330 mg (three puffs of 110 mg ex-actuator [125 ex-valve]; total daily dose 660 mg), administered in the morning and evening, for 6 months. In order to allow efficient drug management at each participating site, the investigators interacted with FACTS each time new study medication was dispensed at all further visits after randomization. Study medication was provided as MDIs with HFA as the propellant. Each canister contained at least 120 puffs and patients were instructed to replace inhalers after 2 weeks of use. During the study, salbutamol (100 mg/puff) was used as rescue medication. 2.2.1. Efficacy measures FEV1, forced vital capacity (FVC) and PEF were measured at the clinic at baseline and at Weeks 4, 8, 12, 16, 20 and 24 (or study end). Rescue medication was withheld for X4 h and oral b2-agonists and LABAs, theophyllines, leukotriene antagonists and lipoxygenase inhibitors were withheld for X24 h prior to lung function testing. Patients recorded PEF, asthma symptoms and use of rescue medication daily on diary cards. Nighttime and daytime asthma symptoms were assessed using 5-point scales (nighttime: 0 ¼ no asthma symptoms, slept through the night to 4 ¼ bad night, awake most of the night because of asthma; daytime: 0 ¼ very well, no asthma symptoms to 4 ¼ asthma very bad, unable to carry out daily activities as usual). Therefore, for asthma symptom sum score, the maximum value achievable in any 24-h value was eight. Asthma exacerbations were defined as worsening asthma symptoms or a reduction in lung

function requiring treatment with oral steroids. Patients experiencing an asthma exacerbation during the study were withdrawn and the exacerbation was recorded as an adverse event (AE). The standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]) was self-administered by patients at baseline and Weeks 8, 16 and 24 (or study end) before other investigations were performed. The AQLQ(S) [22,23] comprises 32 questions divided into four domains (activity limitations, symptoms, emotional function and exposure to environmental stimuli). Patients responded to each question on a 7-point scale (1 ¼ maximal impairment to 7 ¼ no impairment), with the period of recall being the last 2 weeks. 2.2.2. Safety evaluation Safety was assessed by AE reporting using open questioning at each study visit, vital sign (blood pressure and heart rate) monitoring, physical examination and clinical laboratory tests. When an oropharyngeal AE was reported, the oropharynx was inspected and a pharyngeal swab was obtained for fungal culture. Confirmation from culture was required for a diagnosis of oral candidiasis. The number of patients with treatment-emergent local oropharyngeal AEs was a secondary variable. 2.3. Statistical analyses The primary efficacy variable was change in FEV1 from baseline to Week 24 (or study end) and the co-primary variable was drop-out rate due to asthma exacerbation. Secondary spirometry variables were change in FVC, FEV1% predicted and PEF from baseline to study end. Secondary variables from diaries included morning and evening PEF; asthma symptom scores (sum scores were the combination of daytime and nighttime scores); use of rescue medication; percentage of days free from asthma symptoms, rescue medication and nocturnal awakenings; and percentage of days with asthma control (defined as days without asthma symptoms and without rescue medication use). Secondary variables also included the AQLQ(S). The ITT analysis was based on patients who had a baseline value and at least one post-baseline value. The sample size calculation required that for differences in FEV1, a per-protocol (PP) sample size of 382 patients (each treatment, n ¼ 191) was sufficient to ensure a power of 90% for correctly concluding non-inferiority of ciclesonide to fluticasone propionate (a ¼ 0.025, one-sided). Allowing for approximately 20% of patients not qualifying for the PP analysis, at least 240 patients were required to be randomized in each treatment group. Non-inferiority limits, based on the lower limit of the 95% CIs for the between-treatment differences, were pre-set a priori and were 0.2 L for FEV1 and FVC, 25 L/min for PEF (spirometry) and morning and evening PEF (from diary), +5% for the drop-out rate due to an asthma exacerbation

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and 0.5 scores for the AQLQ(S). For the primary endpoint FEV1, the 0.2 L limit was chosen because the mean difference of daily doses between 200 and 1000 mg versus placebo ranged from 280 to 740 mL for the active comparator fluticasone propionate when administered by MDI, with a median above 400 mL. The non-inferiority margin of 0.2 L corresponds to half of that fluticasone propionate difference versus placebo. The analysis plan required that demonstration of noninferiority of ciclesonide 320 mg twice daily compared with fluticasone propionate 330 mg twice daily for change in FEV1 would be followed by assessment of non-inferiority of ciclesonide to fluticasone propionate for drop-out rate due to an asthma exacerbation. If this was demonstrated, superiority of ciclesonide to fluticasone propionate for number of patients with treatment-emergent local oropharyngeal AEs would be tested. If superiority was demonstrated for local AEs, non-inferiority of ciclesonide to fluticasone propionate with respect to the difference in FVC was to be tested. This hierarchy was defined a priori, thus, no a-adjustment for multiple testing was required. Primary and (key-) secondary lung function variables, and AQLQ(S), were evaluated using an analysis of covariance, including the factors and covariates value at baseline, age, sex and country (besides the treatment). Drop-out rate due to asthma exacerbation was analyzed by means of the Newcombe—Wilson score method. Diurnal PEF fluctuation; asthma symptom scores; daily use of rescue medication; percentage of rescue medication-free days, asthma symptom-free days and nocturnal awakening-free days; and percentage of days with asthma control (defined as days without asthma symptoms and without use of rescue medication) were performed using the Mann—Whitney U test. Non-parametric within-group comparisons were done using Pratt’s-modified Wilcoxon’s signed-rank test. Fisher’s exact test was used in the analysis of number of patients with treatment-emergent local oropharyngeal AEs. The significance level was a ¼ 0.05 (two-sided), tests for non-inferiority or superiority were one-sided (a ¼ 0.025). 3. Results Overall, 658 patients were enrolled and a total of 528 patients were randomized and entered the treatment period (ciclesonide 320 mg twice daily, n ¼ 255; fluticasone propionate 330 mg twice daily, n ¼ 273) (Fig. 1). All randomized patients took at least one dose of study medication and were included in the ITT and safety analyses. A total of 81 patients (ciclesonide, n ¼ 43; fluticasone propionate, n ¼ 38) terminated the study prematurely, mainly due to AEs and ‘other reasons’. In the ciclesonide and fluticasone propionate groups, 212 and 235 patients, respectively, completed the study, while 209 and 237 patients, respectively, were included in the PP analysis. The majority of protocol violations occurred in the randomization and inclusion criteria.

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Fig. 1. Flow diagram of patient deposition (CONSORT diagram). ITT ¼ intention to treat.

The treatment groups were comparable in terms of their demographic and baseline characteristics (Table 1). The majority of patients in both groups had severe persistent asthma according to the Global Initiative for Asthma 2003 classification (ciclesonide, 71%; fluticasone propionate, 66%; ITT population). Mean values of FEV1 and FEV1% predicted at randomization were comparably high, suggesting satisfactory or good control of patients’ asthma on previous ICS treatment. Demographic data and baseline characteristics in the PP and ITT sets were comparable. Median doses of pre-treatment ICS (expressed as chlorofluorocarbon–beclomethasone dipropionate equivalents) were X1000 mg/day in both analysis sets for both treatment groups. Concomitant treatment was balanced between the two treatment groups prior to study entry, during run-in and during the treatment phase. During the treatment phase, approximately 50% of patients in each treatment groups used LABAs (Table 2). Patients on combination inhalers of ICS plus LABAs during run-in were switched to monocomponent inhalers to permit substitution of the ICS during the treatment period. 3.1. Lung function For both the ITT and PP analyses, FEV1 was maintained in both treatment groups with no significant changes seen from baseline to study end (Table 3). The least squares (LS) mean7standard error of the mean (SEM) for the treatment difference was 13729 (95% CI: 70, 44) in the ITT analysis and 27734 (95% CI: 93, 40) in the PP analysis. In the ITT population, the FVC remained stable, with no significant changes from baseline in either treatment group (Table 3). A small increase was

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Table 1 Demographic and baseline disease characteristics of the intention-to-treat and per-protocol populations Variable

ITT

PP

Ciclesonide 320 mg bid

Age (years) Sex Female Smoking Non-smokers Ex-/current smokers Use of ACC Prior ICS dosesa (mg/day ex-valve) FEV1 (L) at randomization FEV1 (% predicted) at randomization Reversibilityb

n ¼ 255

Fluticasone propionate 330 mg bid n ¼ 273

Ciclesonide 320 mg bid n ¼ 209

Fluticasone propionate 330 mg bid n ¼ 237

Median (range)

43 (13–74)

44 (12–75)

42 (16–74)

44 (12–75)

n (%)

158 (62)

164 (60)

123 (59)

142 (60)

n (%) n (%) n (%) Mean7SD Mean7SD Mean7SD

173 (68) 82 (32) 151 (59) 11257378 2.93970.764 93.5711.6

179 (66) 94 (34) 164 (60) 11467408 2.87970.750 93.0710.7

141 (67) 68 (33) 132 (63) 11497362 2.97570.785 93.1711.3

157 (66) 80 (34) 143 (60) 11787392 2.89070.751 93.2710.8

%

16.678.0

17.678.3

16.977.8

18.277.7

a

Beclomethasone dipropionate–chlorofluorocarbon equivalent values. Improvement in FEV1 after inhalation of 200–400 mg of salbutamol administered by pressurized metered-dose inhaler; % of pretreatment FEV1; ITT: intention to treat; PP: per protocol; bid: twice daily; ACC: additional asthma controller; ICS: inhaled corticosteroids; FEV1: forced expiratory volume in 1 second; SD: standard deviation. b

Table 2 Respiratory and related medications used by at least 2% of patients Treatment

Number (%) of patients Before study

b2-agonists and anticholinergics Inhaled SABAs Inhaled LABAs Combination inhaled b2-agonists and short-acting anticholinergics Combination of inhaled anti-allergics and b2-agonists Other Antihistamines LTRAs Xanthines

Treatment

n ¼ 255

Fluticasone propionate 330 mg bid n ¼ 273

n ¼ 255

Fluticasone propionate 330 mg bid n ¼ 273

187 (68.5) 101 (37.0) 46 (16.8) 20 (7.3)

246 (96.5) 10 (3.9) 38 (14.9) 10 (3.9)

267 (97.8) 6 (2.2) 47 (17.2) 12 (4.4)

2 (0.8) 0 (0.0) 48 (18.8) 25 (9.8)

0 (0.0) 1 (0.4) 58 (21.2) 23 (8.4)

220 (86.3) 62 (24.3) 9 (3.5)

245 (89.7) 60 (22) 8 (2.9)

251 (98.4) 132 (51.8) 2 (0.8)

273 (100) 146 (53.5) 0 (0.0)

252 (98.8) 135 (52.9) 0 (0.0)

273 (100) 144 (52.7) 0 (0.0)

5 (2.0)

9 (3.3)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

23 (9.0) 7 (2.7) 12 (4.7)

40 (14.7) 6 (2.2) 14 (5.1)

25 (9.8) 4 (1.6) 6 (2.4)

38 (13.9) 3 (1.1) 10 (3.7)

41 (16.1) 3 (1.2) 8 (3.1)

68 (24.9) 2 (0.7) 7 (2.6)

Ciclesonide 320 mg bid

Corticosteroids ICS Combination ICS and inhaled LABAs INS Corticosteroids excl. ICS and INS

Baseline Ciclesonide 320 mg bid

n ¼ 255

Fluticasone propionate 330 mg bid n ¼ 273

175 (68.6) 101 (39.6) 40 (15.7) 12 (4.7)

Ciclesonide 320 mg bid

Bid: twice daily; ICS: inhaled corticosteroid; LABAs: long-acting b2-agonists; INS: intranasal corticosteroid; SABAs: short-acting b2-agonists; LTRAs: leukotriene receptor antagonists.

seen in the fluticasone propionate group in the PP analysis (p ¼ 0.0493). The LS mean7SEM for the treatment difference was 0.04570.033 (95% CI: 0.109, 0.019) in the ITT analysis and similar findings were seen in the PP analysis. Non-inferiority was achieved with respect to

FEV1 and FVC as the lower limit of the CI for the treatment differences was above the predefined noninferiority limits of 200 mL for FEV1 and FVC. The time course of change in FEV1% predicted for the ITT population is shown in Fig. 2.

Table 3 Lung function after 24 weeks of treatment with either ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily Variable

ITT Ciclesonide 320 mg bid

249 2915 2926 11722

249 3.82 3.82 0.00170.025

PEF (L/min) n Baseline Study end Change from baseline

249 428.2 436.7 8.674.4

Diary Diary AM PEF (L/min) n 241 Baseline 444.0 Study end 470.2 Change from 26.274.9 baseline

Fluticasone propionate 330 mg bid

0.6367

269 2915 2939 24721

0.9704

269 3.82 3.87 0.04470.024

0.0495

269 428.2 436.6 8.474.1

o0.0001

263 444.0 465.0 21.074.6

p value

0.2679

0.0691

0.0434

o0.0001

Treatment difference (95% Cl)

13729 (70, 44)

0.04570.033 (0.109, 0.019)

0.275.7

5.376.3 (7.1, 17.6)

Ciclesonide 320 mg bid

171 2932 2943 11726

171 3.85 3.86 0.01370.028

171 430.4 446.0 15.674.9

177 449.2 485.1 35.975.8

p value

p value

Treatment difference (95% CI)

0.6786

200 2932 2969 38724

0.1189

27734 (0.093, 0.040)

0.6373

200 3.85 3.90 0.05270.026

0.0493

0.03970.037 (0.111, 0.033)

0.0016

200 430.4 446.9 16.574.5

0.0003

0.9076.3 (13.3, 11.5)

o0.0001

208 449.2 471.0 21.775.3

o0.0001

14.177.4 (0.4, 28.7)

Fluticasone propionate 330 mg bid

All data are least squares mean7standard error of the mean. ITT ¼ intention to treat; PP ¼ per protocol; bid ¼ twice daily; CI ¼ confidence interval; FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; PEF ¼ peak expiratory flow; AM ¼ morning; PM ¼ evening.  Two-sided p-value for within-treatment differences, significance level 5% (study end versus baseline).

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FVC (L) n Baseline Study end Change from baseline

p value

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Spirometry FEV1 (mL) n Baseline Study end Change from baseline

PP

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Morning and evening PEF recorded by patients, as well as clinic PEF, improved significantly (all po0.05) in both the ciclesonide and fluticasone propionate groups (ITT and PP analyses) (Table 3; Fig. 3). Between-treatment analyses confirmed non-inferiority of ciclesonide versus fluticasone propionate for morning, evening and spirometric PEF. Non-inferiority was achieved with respect to PEF as the lower limit of the CI for the treatment differences was above the predefined non-inferiority limit of 25 L/min (Table 3). 3.2. Asthma exacerbations, asthma symptoms and rescue medication use Six patients in the ciclesonide group and seven in the fluticasone propionate group in the ITT analysis experienced an asthma exacerbation that required treatment with

oral corticosteroids. Similar findings were seen in the PP data set. The upper limits of the 95% CI in both the ITT (0.031, 0.028) and PP (0.016, 0.043) populations were below the stipulated non-inferiority acceptance limit of 5%. Both treatments significantly decreased asthma symptom score sum (ITT and PP analyses: all pp0.0001) and rescue medication use (ITT and PP analyses: all po0.05) (Table 4). The treatment differences between ciclesonide and fluticasone propionate were not statistically significant for any of the asthma symptom scores or rescue medication use (Table 4). Median values for percentages of symptom-free days, rescue-medication-free days and nocturnal-awakening-free days were high and did not differ significantly between the two treatment groups (Fig. 4). The percentage of days with asthma control was 74.1% in the ciclesonide group and 73.2% in the fluticasone propionate group. There were no significant differences between treatment groups. 3.3. Quality of life There were significant improvements in health-related quality of life (HRQoL) in the two treatment groups for the overall AQLQ(S) score, as well as for all domain scores (ITT and PP analyses, all po0.05). For overall AQLQ(S) scores, the LS mean7SEM for the treatment difference was 0.0370.07 (95% CI: –0.10, 0.16) in the ITT analysis and 0.0670.07 (–0.09, 0.20) in the PP analysis. Similar findings were seen for the individual domain scores (Table 4). 3.4. Safety

Fig. 2. Mean time course over 6 months of forced expiratory volume in 1 s (expressed as % of predicted value) in patients receiving either ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily (intentionto-treat population). FEV1 ¼ forced expiratory volume in 1 s; CIC ¼ ciclesonide; BID ¼ twice daily; FP ¼ fluticasone propionate.

In total, 328 patients experienced 774 treatment-emergent AEs (TEAEs). The frequency of TEAEs was comparable in both treatment groups (ciclesonide, n ¼ 373; fluticasone

Fig. 3. Time-course over 6 months of morning peak expiratory flow recorded in patient diaries of patients with moderate-to-severe asthma receiving ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily (intention-to-treat population). PEF ¼ peak expiratory flow; CIC ¼ ciclesonide; BID ¼ twice daily; FP ¼ fluticasone propionate.

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Table 4 Improvement in asthma symptom score, rescue medication use and quality of life score after 24 weeks of treatment with either ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily Variable

ITT Ciclesonide 320 mg bid

Asthma symptom sum scores n Baseline (median) Study end (median) Change from baselinea

238 0.43 0.00 –0.14

Rescue medication use (puffs/day) n 241 Baseline (median) 0.29 Study end (median) 0.00 Change from baselinea –0.07

PP p value

Fluticasone propionate 330 mg bid

o0.0001

257 0.43 0.00 –0.14

0.0005

263 0.43 0.00 –0.14

0.0004

5.79 5.94 0.1570.05

0.0071

5.91 6.01 0.1070.05

0.0004

5.71 5.88 0.1770.06

0.0029

5.94 6.09 0.1570.06

0.0001

5.53 5.72 0.1970.06

p value

Ciclesonide 320 mg bid

0.0001

174 0.30 0.00 –0.14

o0.0001

176 0.29 0.00 –0.14

0.0026

5.84 6.06 0.2270.06

0.0378

5.96 6.13 0.1770.06

0.0029

5.76 6.04 0.2870.06

0.0068

5.99 6.17 0.1870.07

0.0015

5.55 5.84 0.2870.07

p value

Fluticasone propionate 330 mg bid

p value

o0.0001

201 0.29 0.00 –0.14

o0.0001

0.0003

208 0.33 0.00 –0.14

o0.0001

0.0001

5.84 6.00 0.1670.05

0.0020

0.0033

5.96 6.07 0.1170.05

0.0378

o0.0001

5.76 5.99 0.2370.06

0.0001

0.0080

5.99 6.13 0.1470.06

0.0260

0.0001

5.55 5.71 0.1670.07

0.0212

b,c

Quality of life Overall Baseline Study end Change from baseline

5.79 5.97 0.1870.05

Activities Baseline Study end Change from baseline

5.91 6.05 0.1470.05

Symptoms Baseline Study end Change from baseline

5.71 5.92 0.2170.06

Emotions Baseline Study end Change from baseline

5.94 6.11 0.1770.06

Environment Baseline Study end Change from baseline

5.53 5.77 0.2570.06

a

Data presented as Hodges–Lehman point estimate. Data presented as least squares mean7standard error of the mean. c ITT population: ciclesonide n ¼ 242, fluticasone propionate n ¼ 258, and PP population: ciclesonide ¼ 178, fluticasone propionate ¼ 200; ITT ¼ intention to treat; PP ¼ per protocol; bid ¼ twice daily.  Two-sided p-value for within-treatment differences, significance level 5% (study end versus baseline). b

propionate, n ¼ 401). Nasopharyngitis and upper respiratory tract infection were the most frequent TEAEs in both treatment groups (Table 5). Most AEs were mild-to-moderate in intensity and were considered to be ‘not related’ or ‘unlikely related’ to the study medication in both groups. No deaths occurred and a small number of serious AEs were reported; all were assessed as being ‘not related’ or ‘unlikely related’ to the study medication. Significantly more patients treated with fluticasone propionate experienced local oropharyngeal AEs (confirmed candidiasis and dysphonia) compared with those treated with ciclesonide (p ¼ 0.0023; two-sided value for superiority) (Fig. 5). There were no clinically relevant

changes in chemistry or hematology variables, blood pressure and heart rate, and physical examination findings after the 24-week treatment period. 4. Discussion The current study was designed to compare equal doses (based on mg per day) of ciclesonide and fluticasone propionate, under a similar dosing regimen. As patients entering this study were previously relatively well controlled on ICS, with normal or near-normal spirometry and at least one symptom-free day per week, initial lung function values at baseline were high, and asthma symptom scores and rescue medication use were low. However, at

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Fig. 4. Symptom-free days and rescue-medication-free days of patients with moderate-to-severe asthma receiving ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily (intention-to-treat analysis). CIC ¼ ciclesonide; BID ¼ twice daily; FP ¼ fluticasone propionate.

Table 5 Treatment-emergent adverse events reported by 43% of patients receiving ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily (safety set) Adverse event

Total Nasopharyngitis Upper respiratory tract infection Pharyngolaryngeal pain Asthma Bronchitis Sinusitis Influenza Rhinitis Dysphonia Back pain Headache Oral candidiasis

Frequency of events (% of patients) Ciclesonide 320 mg bid (n ¼ 255)

Fluticasone propionate 330 mg bid (n ¼ 273)

61.2 11.8 8.2

63.0 8.8 7.3

4.3

4.4

3.9 3.5 3.5 3.1 3.1 3.1 3.1 2.4 2.0

5.5 4.0 3.3 4.4 2.9 9.2 1.1 4.4 4.8

bid ¼ twice daily.

this level of control there was room for both improvement and the possibility of worsening with the treatments under study. The results confirmed that both ciclesonide 320 mg (exactuator) and fluticasone propionate 330 mg (ex-actuator) twice daily effectively maintained lung function over a 6-month period in patients with moderate-to-severe persistent asthma controlled on high doses of ICS (500– 1000 mg/day of fluticasone propionate or equivalent). The treatments maintained lung function to a similar degree, as measured by FEV1 and FVC, and resulted in similar and low exacerbation rates over the 6-month treatment period.

Furthermore, both agents improved PEF and asthma symptoms, and reduced the use of rescue medication. These objective measures also translated into improvements in patients’ HRQoL with both ICS. Analysis showed that ciclesonide was non-inferior to fluticasone propionate with respect to all efficacy and HRQoL variables, with a defined non-inferiority margin. Both ciclesonide and fluticasone propionate were generally well tolerated over the 6-month treatment period, and the AE pattern was typical for the population under investigation. The efficacy of ciclesonide in maintaining asthma control and improving symptoms in this study is consistent with the results of previous double-blind, placebo-controlled studies with ciclesonide [11–13,24]. The comparison of ciclesonide with fluticasone propionate has been examined in previous 12-week studies involving lower doses of each ICS in patients with different severities of asthma. These, like the current study, have confirmed similar efficacy [19–21]. For example, in a randomized, double-blind study comparing ciclesonide 160 mg once daily and fluticasone propionate 88 mg twice daily, both treatments had similar beneficial effects on lung function, asthma symptoms and rescue medication use [19]. FEV1 increased by 506732 mL and 536732 mL in the ciclesonide and fluticasone propionate groups, respectively (both po0.0001 versus baseline; PP population) and ciclesonide was shown to be noninferior to fluticasone [19]. In another randomized, doubleblind study, ciclesonide 80 and 160 mg once daily administered in the evening, showed similar efficacy to fluticasone propionate 88 mg twice daily [21], as did an open-label, parallel-group study comparing ciclesonide 320 mg once daily and fluticasone propionate 200 mg twice daily (administered by Diskuss/Accuhaler) [20]. In the latter study, FEV1 increased by 171 mL in the ciclesonide group and by 186 mL in the fluticasone group (both po0.0001 versus baseline) and the percentage of asthma

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Fig. 5. Composite local adverse events: oral candidiasis and hoarseness in patients with moderate-to-severe asthma receiving ciclesonide 320 mg twice daily or fluticasone propionate 330 mg twice daily for 6 months (intention-to-treat population). *po0.01 between-treatment difference (two-sided for superiority); CIC ¼ ciclesonide; BID ¼ twice daily; FP ¼ fluticasone propionate.

symptom-free days was similar (88% in both groups), but ciclesonide resulted in greater improvements in HRQoL and was better tolerated [20]. The current study adds to these reports by examining patients with severe asthma over a 6-month period and employing a twice-daily higher dose of ciclesonide. The current findings also support those from previous small comparative studies between ciclesonide and fluticasone propionate, which found that both agents decreased hyper-responsiveness to adenosine 5’monophosphate and methacholine challenge in patients with persistent asthma [25–27]. Two of these studies also indicated a lack of effect of ciclesonide on HPA-axis function, while fluticasone suppressed plasma cortisol levels [26,27]. A further study suggested that ciclesonide produced a faster and greater decrease in exhaled nitric oxide in patients with mild allergic asthma. No statistically significant differences were seen between the treatments in terms of pulmonary function [28]. Furthermore, in the current study, both ciclesonide and fluticasone propionate led to further small, but statistically significant, improvements in HRQoL, as assessed using the disease-specific, standardized AQLQ(S) [22,23]; ciclesonide was non-inferior to fluticasone propionate with respect to this parameter. The HRQoL improvements were seen in spite of the high baseline level of asthma control in these patients, as reflected in the high baseline AQLQ(S) values. Fluticasone propionate was chosen as the comparator to ciclesonide in this study as it is a highly potent ICS that is widely used in adults with moderate-to-severe persistent asthma and commonly used, as in this study, in doses above 500 mg/day. A Cochrane review of 56 previous studies (12,119 participants) comparing fluticasone with beclomethasone and budesonide for the treatment of chronic asthma, concluded that, based upon efficacy, fluticasone was equivalent to twice the microgram dose of

the other two ICS, but was associated with a higher rate of pharyngitis and no difference in the likelihood of oral candidiasis. At a dose ratio of 1:1, fluticasone propionate produced statistically significant greater improvements in morning PEF (9.58 L/min; 95% CI: 5.20, 13.97), evening PEF (7.41 L/min; 95% CI: 2.61, 12.22) and FEV1 (0.09 L; 0.02, 0.17), but with an increase in the incidence of hoarseness [29]. Two studies have also compared the efficacy of ciclesonide with budesonide [30,31]. One randomized study comparing double-blind ciclesonide 160 mg once daily and open-label budesonide 200 mg twice daily confirmed that both treatments were able to maintain pulmonary function and other features of asthma control (asthma symptoms and rescue medication use) in patients previously successfully treated with a constant dose of beclomethasone dipropionate (up to 500 mg/day), fluticasone propionate (200–250 mg/day) or budesonide (400 mg/day or equivalent) [30]. In a separate study, ciclesonide 320 mg once daily was non-inferior and numerically superior to budesonide 320 mg once daily at improving FEV1 and statistically superior to budesonide in improving FVC (p ¼ 0.010) in patients previously receiving budesonide 320–640 mg or equivalent and other controller medications [31]. A significant decrease in rescue medication use was only seen in the ciclesonide group (p ¼ 0.009). In terms of safety in the current study, local oropharyngeal AEs were of particular interest, since they represent the known side effects of ICS [32]. Ciclesonide was superior to fluticasone propionate with respect to the occurrence of local oropharyngeal AEs, despite being administered at equivalent doses. Oropharyngeal AEs were rigorously monitored in this study; any report had to be followed by an inspection of the oropharynx by the investigator and confirmation by a fungal culture before a diagnosis of oral candidiasis could be given.

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The current findings support the favourable safety and tolerability profiles of ciclesonide reported from previous studies [11–13]. The reduction in local AEs versus fluticasone has also been reported in the open-label, parallel-group study comparing ciclesonide 320 mg once daily and fluticasone propionate 200 mg twice daily (oropharyngeal candidiasis: 0 and 9 events, respectively; p ¼ 0.002) [20]. This difference may be due to the low oropharyngeal deposition of ciclesonide compared with fluticasone propionate, as measured by alcoholic extraction of orally deposited ICS and analysis by liquid chromatography with tandem mass-spectrometric detection. Approximately 50% less ciclesonide and 90% less active metabolite compared with fluticasone was present in the oropharynx [33]. Less than 20% of the residual ciclesonide in the oropharynx was metabolized to active metabolite in this study [33], which may be due to the airway-specific conversion of ciclesonide to the active metabolite [14]. The available data from clinical studies also confirm the good systemic safety of ciclesonide, with no clinically relevant effect on cortisol excretion or growth impairment in children reported [34–37]. In this maintenance of control study, an open-label design was employed as a double-blind, double-dummy design would have required the patients to inhale 10 puffs/ day for 6 months, increasing the burden on patients and potentially affecting compliance. However, a centralized and automated randomization method was used in order to minimize any potential selection bias. The patients in this study were classified as having moderate-to-severe asthma (according to the Global Initiative for Asthma 2003 classifications available at the time of the study), based on their clinical features of asthma (frequency of symptoms and beta2-agonist use) despite use of moderate-to-high doses of ICS. However, no attempt was made to establish the lowest controlling dose of ICS at study entry, and it cannot be ruled out (or excluded) that some patients were receiving higher doses than were necessary. However, the fact that improvements in features of asthma control were observed in both treatment groups after a reduction in the nominal dose of treatment with the study drugs compared with that of the baseline treatment, suggests that this was not the case in the majority of patients. A possible explanation for this improvement is that the two study treatments had greater efficacy than those treatments being previously used by the patients prior to study entry. The study was well-powered for the non-inferiority analysis, indicating the robustness of the findings. In addition, the efficacy and safety endpoints were assessed over a 6-month period, rather than the usual 12-week treatment period, enabling longer-term effects to be determined. No wearing-off of effect occurred over the treatment period with either ICS, while low local AE rates were seen with ciclesonide despite the length of the study period and the high dose used. This finding is of importance as a recent survey demonstrated that side

effects are one of the main reasons for poor compliance in patients taking ICS [38]. In summary, the current 6-month study demonstrates that ciclesonide 320 mg and fluticasone propionate 330 mg, both administered twice daily, provide similar efficacy in patients with moderate or severe persistent asthma wellcontrolled by high doses of ICS at baseline and that, in this setting, ciclesonide is associated with fewer local AEs compared with fluticasone propionate. Acknowledgments This study was funded and sponsored by ALTANA Pharma. The authors would like to appreciate the data management performed by Mario Lozina (ALTANA Pharma) and thank Lesley Brewer, BSc (Hons), Medicus International, for her editorial assistance. Editorial support was funded by ALTANA Pharma. References [1] NIH. National Institutes of Health National Heart Lung and Blood Institute. 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 2002; 110: S141–S219. [2] GINA. Global Initiative for Asthma. National Institutes of Health, National Heart, Lung and 338 Blood Institute. /www.ginasthma. comS. 2005. [3] Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ. Inhaled corticosteroids: past lessons and future issues. J Allergy Clin Immunol 2003;112(3 Suppl):S1–S40. [4] Cave A, Arlett P, Lee E. Inhaled and nasal corticosteroids: factors affecting the risks of systemic adverse effects. Pharmacol Ther 1999;83(3):153–79. [5] Lipworth B. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159(9):941–55. [6] Roland N, Bhalla R, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest 2004;126:213–9. [7] Dubus JC, Marguet C, Deschildre A, Mely L, Le Roux P, Brouard J, et al. Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age, and device. Allergy 2001;56(10):944–8. [8] Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can guideline-defined asthma control be achieved? Am J Resp Crit Care Med 2004;170:836–44. [9] Masoli M, Weatherall M, Beasley R. Fluticasone given once versus twice a day: meta-analysis. Respirology 2005;10(2):183–8. [10] Purucker ME, Rosebraugh CJ, Zhou F, Meyer RJ. 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 2003;124(4):1584–93. [11] Postma DS, Sevette C, Martinat Y, Schlosser N, Aumann J, Kafe H. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Respir J 2001;17(6):1083–8. [12] Chapman KR, Patel P, D’Urzo AD, Alexander M, Mehra S, Oedekoven C, et al. Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma. Allergy 2005;60(3):330–7. [13] Langdon CG, Adler M, Mehra S, Alexander M, Drollmann A. Oncedaily ciclesonide 80 or 320 mg for 12 weeks is safe and effective in patients with persistent asthma. Respir Med 2005;99:1275–85.

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