Efficacy and safety of ciclesonide in patients with severe asthma: a 12-week, double-blind, randomized, parallel-group study with long-term (1-year) follow-up.

OBJECTIVE: To investigate the efficacy and safety of ciclesonide in patients with severe asthma over a 1-year period. RESEARCH DESIGN AND METHODS: Patients aged 18 - 75 years with persistent asthma were enrolled in a 12-week, double-blind, randomized study and treated with ciclesonide 320 or 640 µg twice daily (b.i.d.) with the option of continuing in a 40-week extension phase (EP). MAIN OUTCOMES MEASURES: Change in morning peak expiratory flow (PEF) from baseline to 12 weeks and safety over 1 year. RESULTS: 365 patients were randomized and 275 continued into the EP. During 12 weeks' treatment, morning peak expiratory flow significantly increased by 16 l/min (p < 0.001) and 14 l/min (p = 0.001) in the 320 and 640 µg b.i.d. groups, respectively. Both doses significantly reduced total asthma symptom scores by 0.29 (p < 0.0001). In both groups, the incidence of adverse effects (AEs) was low and mean cortisol levels in serum and urine were not suppressed during the EP. CONCLUSIONS: Ciclesonide 320 µg b.i.d. sustained lung function and asthma symptoms in patients with severe asthma over 12 weeks' treatment, and maintained lung function during a 40-week EP; ciclesonide 640 µg b.i.d. did not provide additional benefits. Long-term use of ciclesonide was not associated with increased local AEs or negative effects on cortisol levels.

Efficacy and safety of three ciclesonide doses vs placebo in children with asthma: the RAINBOW study.

OBJECTIVE: To evaluate the efficacy and safety of three doses of ciclesonide (with or without spacer) in children with persistent asthma. PATIENTS AND METHODS: This was a multicentre, double-blind, placebo-controlled, 12-week study of ciclesonide 40, 80 or 160 µg (once daily pm). Children (6-11 years) were randomised 1:1 to treatment via a metered dose inhaler (MDI) or MDI plus spacer. The primary variable was change from baseline in mean morning peak expiratory flow (PEF). Secondary variables included: time to first lack of efficacy (LOE), asthma control, forced expiratory volume in 1 s (FEV(1)), asthma symptom score and quality of life (QoL). Safety assessments included: adverse events (AEs), urinary cortisol excretion and body height. RESULTS: In total, 1073 children received treatment. At endpoint, mean morning PEF significantly improved with all doses of ciclesonide vs. placebo. There was no difference over placebo in time to first LOE, but ciclesonide was superior to placebo on asthma control, symptom score, FEV(1) and QoL. There were no differences between the spacer or non-spacer subgroups. The incidences of AEs were comparable between treatment groups (approximately 35%) and there were no between-group differences in body height or urinary cortisol. CONCLUSIONS: Ciclesonide 40-160 µg once daily is effective and well tolerated in children with persistent asthma; its efficacy and safety are unaffected by the use of a spacer. clinicaltrials.gov registration number: NCT00384189.

A 24-week comparison of low-dose ciclesonide and fluticasone propionate in mild to moderate asthma.

OBJECTIVE: To compare the efficacy of ciclesonide (80 microg/day) with fluticasone propionate (200 microg/day) in mild to moderate persistent asthma. METHODS: Patients aged 12-75 years and previously treated with low doses of inhaled corticosteroid (fluticasone propionate 250 microg/day or equivalent) entered a 2-4 week run-in period during which only rescue medication was permitted. For inclusion into the double-blind, 24-week treatment period, patients had to show a forced expiratory volume in 1s (FEV(1)) of 61-90% predicted and a decrease in FEV(1) during run-in of >or=10%. Patients (n = 480) were randomized to ciclesonide 80 microg (ex-actuator) once daily in the evening or fluticasone propionate 100 microg (ex-valve) twice daily. The primary efficacy variable was the change from baseline in FEV(1). Secondary efficacy variables included asthma control and asthma-specific quality of life. RESULTS: Both treatments significantly increased FEV(1) and other lung function variables from baseline (p < 0.0001, both groups, all variables). The least squares mean increases in FEV(1) were 0.46L (ciclesonide) and 0.52L (fluticasone propionate); non-inferiority of ciclesonide to fluticasone propionate was demonstrated (p = 0.0002, per-protocol analysis). Five patients in each group experienced asthma exacerbations. Improvements in the percent of days with asthma control (days with no asthma symptoms and no use of rescue medication) and asthma-specific quality of life were comparable between treatments. CONCLUSIONS: The study confirmed similar efficacy of ciclesonide 80 microg once daily and fluticasone propionate 100 microg twice daily in mild to moderate persistent asthma. The low dose of ciclesonide was efficacious during long-term treatment. EudraCT number: 2004-001072-39.

Once-daily ciclesonide via metered-dose inhaler: Similar efficacy and safety with or without a spacer.

BACKGROUND: Inhaled corticosteroids (ICS) are recommended as first-line treatment for adults and children with persistent asthma. The Global Initiative for Asthma recommends that patients taking medium- or high-dose ICS delivered by metered-dose inhalers (MDIs) should use a spacer device. METHODS: This randomized, open-label, 12-week, non-inferiority study compared the efficacy and safety of ciclesonide 160microg once daily delivered via hydrofluoroalkane-MDI alone (CIC160) or with a spacer (either an AeroChamber Plus [CIC160P] or an AeroChamber MAX [CIC160M]) in patients with persistent asthma. The primary efficacy variable was change in forced expiratory volume in 1s (FEV(1)) from baseline to study end. RESULTS: Significant improvements in FEV(1) were observed from baseline to study end in each treatment group; least squares mean change from baseline ranged between 0.32 and 0.34L in the per-protocol (PP) analysis and similar results were observed for the intention-to-treat (ITT) analysis (p<0.0001 for all). Non-inferiority of CIC160P and CIC160M to CIC160 was observed for both PP and ITT populations (p<0.0001 [one-sided]). In all groups, daily asthma symptom scores were reduced to 0 and significant reductions were observed in rescue medication use at study end (p<0.0001 versus baseline for all). Ciclesonide was well tolerated in all groups and no cases of oral candidiasis were reported. Morning serum cortisol levels significantly increased in all groups from baseline to study end (p< or =0.0389), with no significant between-treatment differences. CONCLUSION: In patients with persistent asthma, ciclesonide was shown to have similar efficacy and tolerability when administered via MDI alone or with a spacer.

Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma.

BACKGROUND: Ciclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning. OBJECTIVE: This 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared the efficacy and safety of ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma. METHODS: Seven hundred and forty-four patients (aged 6-11 years) were randomized to ciclesonide (80 or 160 microg once daily) or fluticasone propionate (88 microg twice daily), following a 2-4-week run-in. Efficacy measurements included forced expiratory flow in 1s (FEV(1)), morning peak expiratory flow (PEF), asthma symptom scores, rescue medication use and quality of life. Systemic effect was assessed by 24-hour urine free cortisol adjusted for creatinine. RESULTS: FEV(1) and morning PEF increased from baseline in all groups (p<0.0001). Ciclesonide 160 microg was not inferior to fluticasone propionate 176 microg for FEV(1) (p=0.0030, one-sided). In all groups, asthma symptom score sums and rescue medication use significantly improved (p<0.0001). The percentages of asthma symptom-, rescue medication- and nocturnal awakening-free days were high, with no significant differences between treatments. Quality of life scores improved with all treatments (p<0.0001). A significant dose-response occurred between low and higher doses of ciclesonide for exacerbations and asthma control definitions. The incidences of adverse events were comparable across treatments. Urine free cortisol levels decreased significantly with fluticasone propionate (p=0.0103), but not with ciclesonide. CONCLUSION: Once-daily ciclesonide has a clinical effect similar to that of fluticasone propionate, but does not suppress cortisol excretion, in children with moderate and severe asthma.

Rapid effect of inhaled ciclesonide in asthma: a randomized, placebo-controlled study.

BACKGROUND: Ciclesonide is a novel inhaled corticosteroid for the treatment of asthma, and it is important to measure the onset of effect of this therapy on airway hyperresponsiveness (AHR), exhaled nitric oxide (NO), and levels of eosinophils in induced sputum. METHODS: In a randomized, double-blind, crossover study, 21 patients with mild asthma inhaled ciclesonide 320 microg (ex-actuator) qd, ciclesonide 640 microg (ex-actuator) bid, and placebo for 7 days. Exhaled NO and AHR to adenosine monophosphate (AMP), measured as the provocative concentration of AMP producing a 20% reduction in FEV1 (PC20FEV1), were assessed after inhalation on days 1, 3 and 7. Eosinophil levels in induced sputum were also measured. RESULTS: Ciclesonide 320 microg qd and 640 microg bid produced significantly greater improvements in PC20FEV1 compared with placebo on day 1 (within 2.5 h), and on days 3 and 7 (all p < 0.0001). On day 3, both ciclesonide doses significantly reduced exhaled NO levels by - 17.7 parts per billion (p < 0.0001) and - 15.4 parts per billion (p < 0.003) vs placebo, respectively. Significant reductions were maintained during the study with both ciclesonide doses (p < 0.01). A nonsignificant trend towards a decrease in eosinophil cell numbers was observed after 7 days of ciclesonide treatment, especially in patients receiving the higher dose. CONCLUSIONS: A single dose of ciclesonide decreased AHR to AMP and exhaled NO within 3 h, while FEV, improved at 3 days and 7 days.

Similar efficacy of ciclesonide once daily versus fluticasone propionate twice daily in patients with persistent asthma.

This 12-week, double-blind, parallel-group study compared the efficacy and safety of once daily ciclesonide and twice daily fluticasone propionate in patients aged 12-75 years with persistent asthma. Patients were randomized to once-daily ciclesonide 80 micro g (n = 278) or 160 micro g (n = 271), or twice daily fluticasone propionate 88 micro g (n = 259) (all ex-actuator). Significant improvements from baseline were seen in all three treatment groups for forced expiratory volume in 1 second, asthma symptom scores and rescue medication use (all p < 0.0001). Asthma exacerbation rates were low (each ciclesonide group, n = 2; fluticasone group, n = 1). Adverse event reporting indicated good tolerability. Once daily ciclesonide 80 micro g or 160 micro g showed comparable efficacy and tolerability to twice daily fluticasone propionate 88 micro g in persistent asthma.

Comparison of the efficacy and safety of ciclesonide 160 microg once daily vs. budesonide 400 microg once daily in children with asthma.

Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = 0.0009, one-sided non-inferiority, per-protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one-sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk.

A randomized study comparing ciclesonide and fluticasone propionate in patients with moderate persistent asthma.

OBJECTIVE: To compare the effects of once-daily ciclesonide and twice-daily fluticasone propionate in patients with moderate persistent asthma. METHODS: Patients aged 12-75 years with moderate bronchial asthma entered a 1-4 week run-in period. For inclusion into the 12-week, randomized, open-label treatment period, patients had to have a forced expiratory volume in 1s (FEV1) of either 60-80% of predicted or 80% of predicted and a defined use of rescue medication and asthma symptoms, depending on previous treatment. Patients received ciclesonide 320 microg once daily (ex-actuator) or fluticasone propionate 200 microg twice daily. Primary efficacy endpoint was change from baseline in FEV1. RESULTS: In total, 474 patients were randomized. FEV1 increased significantly from baseline with ciclesonide and fluticasone propionate in the intention-to-treat (ITT) and per-protocol (PP) analyses (all p < 0.0001). Treatment difference was -31 mL (95% confidence interval [CI]: -121, 59) in the PP analysis, demonstrating non-inferiority of ciclesonide. Similar findings were seen for other measures of lung function. In the ITT population, asthma symptom scores and rescue medication use decreased with both treatments (all p < 0.0001). Improvement in health-related quality of life (HRQoL) from baseline was significantly greater with ciclesonide than fluticasone (p = 0.005; one-sided). There were no cases of oral candidiasis in patients receiving ciclesonide and nine cases (3.8%) in those receiving fluticasone propionate (p = 0.002; one-sided). CONCLUSIONS: Treatment with once-daily ciclesonide and twice-daily fluticasone propionate resulted in similar improvements in lung function in patients with moderate persistent asthma. Ciclesonide showed significant improvements in oral candidiasis and HRQoL over fluticasone.

A multinational, 12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma.

BACKGROUND: Ciclesonide is a new lung-activated inhaled corticosteroid (ICS) that has shown efficacy in previous placebo-controlled and comparative studies in patients with persistent asthma. It is important to compare new treatments with existing ICSs to obtain relative data concerning their efficacy and tolerability. OBJECTIVE: This study compared the efficacy and tolerability of ciclesonide QD with budesonide BID in patients with asthma. METHODS: This 12-week, randomized study was conducted at 62 study sites across Europe. Male and female patients aged 12 to 75 years with primarily mild to moderate asthma were enrolled. This study was double blind with respect to the ciclesonide dose and open label for budesonide, as placebofor budesonide was not available. Patients were randomly assigned to receive inhaled ciclesonide 80 or 320 microg QD (morning) or budesonide 200 microg BID for 12 weeks. Efficacy and tolerability assessments were performed at weeks 0 (baseline), 4, 8, and 12. The primary end point was the change from baseline in forced expiratory volume in 1 second (FEV1) at 12 weeks. Secondary end points were changes from baseline in morning peak expiratory flow (PEF), asthma symptom scores, and rescue medication use. Tolerability was assessed throughout the study by monitoring of standard laboratory variables (hematology and biochemistry); physical examination, including vital signs; reporting of adverse events (AEs); and 24-hour urinary cortisol as a measure of hypothalamic-pituitary-adrenal-axis function. RESULTS: Five hundred fifty-four patients were randomized (301 men, 253 women; mean age, 41.3 years; ciclesonide 80 microg QD, 182 patients; ciclesonide 320 microg QD, 195; budesonide 200 microg BID, 177). Demographic and baseline clinical characteristics, including age, sex, weight, and (FEV1) were similar between the 3 groups. Compared with baseline values, week-12 FEV1 (least squares mean [LSM] [SEM] A, +0.267 [0.035], +0.256 [0.033], and +0.355 [0.034] L, respectively; all, P<0.001) and morning PEF (LSM [SEM] Delta, +12 [5], +17 [4], and +21 [4] L/min, respectively; all, P

Comparable efficacy of ciclesonide once daily versus fluticasone propionate twice daily in asthma.

BACKGROUND: Inhaled corticosteroids are the mainstay of therapy in asthma, but local and systemic side effects and adherence remain a concern. Ciclesonide is an inhaled corticosteroid with on-site lung activation that provides potent anti-inflammatory activity and has been shown to have a good safety profile, even at high doses. OBJECTIVE: The aim of this study was to compare the efficacy and safety of once-daily ciclesonide versus twice-daily fluticasone propionate at comparable daily doses in patients with asthma. METHODS: In this multicenter, randomized, double-blind, double-dummy, parallel group study, 529 patients were randomized to ciclesonide 160 microg once daily or fluticasone propionate 88 microg twice daily for 12 weeks. The primary endpoint was change in lung function. RESULTS: Both ciclesonide and fluticasone propionate significantly improved forced expiratory volume in 1s, forced vital capacity, and morning peak expiratory flow compared with baseline (p<0.0001 for all variables). Both medications reduced asthma symptoms and rescue medication use within the first 24 h. At the tested dose, both medications were equally safe and well tolerated. CONCLUSION: Ciclesonide 160 microg once daily was as effective as fluticasone propionate 88 microg twice daily in improving lung function and asthma symptoms, and in reducing rescue medication use in patients with asthma.

Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5'monophosphate in asthmatic patients.

The efficacy and systemic effects of ciclesonide, a novel glucocorticosteroid, inhaled via pressurized metered-dose inhaler (pMDI) were compared with fluticasone propionate pMDI in 26 patients with asthma, using a randomized, double blind, placebo-controlled, double dummy, 6-period crossover study design. Treatments were placebo, ciclesonide 320 microg (ex-actuator dose) once daily (o.d.), ciclesonide 640 microg o.d., ciclesonide 640 microg twice daily (b.i.d.), fluticasone propionate 440 microg (ex-actuator dose) b.i.d., and fluticasone propionate 880 microg b.i.d. The primary variable was area under the plasma cortisol concentration-time curve over 24 h (plasma cortisol AUC(0-24), relative to placebo) derived from samples taken every 2 h, on the 9th day of treatment. Secondary variables were 24-h urinary cortisol excretion and PC20 for adenosine 5'-monophosphate (AMP) (relative to placebo and expressed in doubling concentrations). Ciclesonide did not affect 24-h cortisol secretion. Fluticasone propionate suppressed cortisol secretion as demonstrated by a decrease in plasma cortisol AUC(0-24), relative to placebo, by 29% (95% CI 15-41) and 59% (95% CI 51-66) with 440 and 880 microg b.i.d., respectively. PC20 more than doubled with each active treatment, but no statistically significant dose-response effect could be established. It was concluded that moderate to high doses of fluticasone propionate suppressed cortisol secretion, that ciclesonide did not suppress cortisol secretion, and that all active treatments decreased hyperresponsiveness to AMP.