Efficacy and safety of ciclesonidein patients with severe asthma:a 12-week, double-blind,randomized, parallel-group studywith long-term (1-year) follow-upBrian J O’Connor†, Stephen Kilfeather, David Cheung, Henri Kafe,Mark D Blagden, Noel Schl€osser, Jon G Ayres, Hans-Jochen Weber &Renate Engelstatter†King’s College London, School of Medicine, The London Chest Clinic, 20A Pennant Mews,
London, UK
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 main-
tained 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.
Keywords: asthma, ciclesonide, cortisol, lung function
Inhaled corticosteroids (ICSs) are the mainstay of therapy for patients with persis-tent asthma because of their potent anti-inflammatory effects [1-3]. Regular treat-ment with ICSs reduces airway inflammation, improves lung function, andreduces frequency and severity of asthma exacerbations [2]. This consensus isreflected in current asthma guidelines, which recommend early intervention withICSs for long-term control of chronic asthma [3-5]. ICSs are generally consideredsafer than oral corticosteroids because systemic side effects are markedly reducedwith this route of administration [6,7]. However, there is still concern that
long-term treatment with ICSs can cause clinically relevantsystemic and local adverse effects (AEs). Systemic AEs associ-ated with ICSs include adrenal suppression, osteoporosis andimpairment of growth in children; local AEs include oralcandidiasis and dysphonia [8,9].Ciclesonide is an ICS with advanced pharmacokinetic and
pharmacodynamic properties [10,11]. It is formulated as a solu-tion and inhaled with a hydrofluoroalkane (HFA)-propelledmetered-dose inhaler (MDI), resulting in a high proportionof fine particles that ensure high lung deposition [12,13]. Thepotential for oropharyngeal and systemic AEs is reduced bythe low oral deposition, low oral bioavailability, high proteinbinding and in particular the rapid clearance from the sys-temic circulation [10,11,14,15]. In addition, a rapid clearancelimits the amount of free drug available for binding to sys-temic glucocorticoid receptors and, therefore, systemic sideeffects [10,11].The efficacy and safety of ciclesonide in patients with
asthma of different severities have been demonstrated at dosesof 80 -- 640 µg/day in several clinical studies [16-19]. In partic-ular, one study investigated the effects of ciclesonide 160 µgonce daily and 320 µg twice daily in patients with severeasthma [19], as defined by American Thoracic Society (ATS)criteria [20]. Superiority of the higher dose was indicated fora number of end points, including time to first exacerbation,lung function measures, asthma symptom scores and rescuemedication use [19]. The current study aimed to investigatethe efficacy and safety of two doses of ciclesonide (640 and1280 µg/day) in patients with severe asthma in a 12-week,randomized, double-blind treatment period, followed by a40-week open-label extension phase to assess the long-termsafety of ciclesonide.
2. Patients and methods
2.1 SubjectsMale and female subjects aged 18 -- 75 years with a diagnosisof persistent asthma, as defined by ATS criteria (increasedresponsiveness to a variety of stimuli, symptoms like dyspnea,wheezing and cough of varying degree, spontaneous fluctua-tions in the severity of obstruction with substantial improve-ments following bronchodilators or corticosteroids) [21], wereeligible for inclusion in the study. Subjects also had to havebeen treated for ‡ 4 weeks with a constant dose of800 -- 2000 µg/day beclomethasone dipropionate (BDP) orequivalent prior to a 2-week run-in period. Patients wereexcluded if they had used systemic corticosteroids within4 weeks of enrollment in the study or more than three timesduring the 6 months prior to enrollment. Other relevantlung diseases, such as chronic obstructive pulmonary diseaseor diseases that contraindicated the use of ICS, were also cri-teria for exclusion, as was a smoking history of ‡ 10 pack-years. Patients were excluded if they had an asthmaexacerbation or a lower airway infection or were admitted toa hospital for asthma during the 4 weeks prior to enrollment.
Female subjects who were pregnant or breast-feeding, or whowere not using effective contraception, were also excluded.
At randomization, patients were required to have a meanmorning peak expiratory flow (PEF) £ 80% of predicted dur-ing the last 7 days of the run-in period and either reversibilityof airway obstruction, measured as an increase in forced expi-ratory volume in 1 sec (FEV1) of ‡ 15% after administrationof salbutamol MDI 200 -- 400 µg, or a diurnal PEF variationof ‡ 15% [22] for ‡ 4 days during the last 7 days of the run-in period. Other requirements included an asthma symptomscore of ‡ 4, or ‡ 14 puffs of rescue medication during thelast 7 days of the run-in period.
All study-related procedures were conducted in accordancewith the International Conference on Harmonization guide-lines on Good Clinical Practice and the Declaration ofHelsinki, taking into account regional and national regula-tions. The study protocol was approved by the ethics com-mittee of each site and all subjects provided writteninformed consent.
2.2 Study designThe study was conducted in two consecutive phases: i) a dou-ble-blind, randomized, parallel-group phase (12 weeks), pre-ceded by a 2-week, open-label run-in period; and ii) anopen-label 40-week extension phase. Patients were enrolledfrom 51 sites in Belgium, France, The Netherlands and theUnited Kingdom.
In the run-in period, patients received BDP 1600 µg/day(ex-valve; four puffs of 200 µg twice daily via a chlorofluoro-carbon (CFC)--MDI). Patients discontinued use of previousICSs and other asthma medications except for rescue medica-tions. However, continued use of sustained-release theophyl-line (xanthines), oral b2-agonists or inhaled long-actingb2-agonists was permitted during the study by patients whohad been using these medications consistently for ‡ 4 weeksprior to the start of the run-in period.
At the start of the treatment period (baseline), patientswere randomized to receive ciclesonide 320 µg (ex-actuator,equivalent to 400 µg ex-valve) or ciclesonide 640 µg(ex-actuator, equivalent to 800 µg ex-valve) twice daily.Patients inhaled four puffs (80 µg/puff in the 320 µg dosegroup or 160 µg/puff in the 640 µg dose group) in the morn-ing and four puffs in the evening using HFA--MDIs for12 weeks. Both MDIs were identical in appearance. Toachieve homogeneity between the two treatment groups, ran-domization was stratified so that each group would have asimilar number of patients with a morning PEF of £ 65%of predicted and a morning PEF over 65 to £ 80%of predicted.
Patients who completed the double-blind phase accordingto protocol could continue treatment in the open-label,40-week extension phase. During the first 4 weeks of theextension phase, all patients received ciclesonide 640 µg twicedaily to maintain blinding from the 12-week double-blindphase. Thereafter, the dose could be adjusted at the discretion
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of the investigator based on the patient’s individual needs.Ciclesonide was administered twice daily except during exac-erbations, when it could be administered up to four timesdaily at the physician’s discretion.
2.3 Efficacy measuresAfter the baseline visit at the start of the 12-week randomizedphase, patients returned for scheduled visits after 4, 8 and12 weeks. At each visit, lung function measures (FEV1, forcedvital capacity [FVC] and PEF) were performed ‡ 4 h after thelast use of rescue medication and at the same time of day(± 1.5 h). Morning (measured on arising) and evening (mea-sured between 06.00 and 08.00 h) PEF, asthma symptomsand rescue medication use were recorded in patient diaries.Diary PEF determinations (Pulmotest AS, Roland Arzneimit-tel GmbH, Germany) were performed with the patient seated,before inhalation of test medication and ‡ 4 h after rescuemedication use. The highest of three measurements wasrecorded. Morning and evening PEF measurements wererecorded daily and the average of the measurements fromthe last 4 -- 7 days prior to study visits was used inthe assessment.
Asthma symptom scores were recorded on 5-point scales:daytime scores ranged from 0 (very well, no symptoms) to4 (asthma very bad, unable to carry out daily activities asusual); and night-time scores ranged from 0 (no symptoms,slept through the night) to 4 (bad night, awake most of thenight because of asthma).
In the extension phase of the study, visits were conducted atweeks 16, 26, 39 and 52. FEV1, FVC and PEF were assessedas at previous visits.
Patients were withdrawn from the study because of asthmaexacerbations if they experienced more than one exacerbationrequiring oral corticosteroids, or when the exacerbation hadnot resolved after 1 week of treatment with oral corticoste-roids. Oral corticosteroids were permitted during the studyonly for treatment of an asthma exacerbation.
2.4 Safety measuresAt each study visit throughout both study phases, patientswere asked to recall AEs. There was no routine monitoringof oral candidiasis by swab, although patient-reported casesof oral candidiasis were recorded. At the start of the run-in period and at the end of both study phases (week 12 and52) patients underwent a physical examination, including anelectrocardiogram (ECG). Routine laboratory work-up wasperformed at the start of the run-in period and after 12,26 and 52 weeks.
At the start of the treatment period (baseline) and after 12,26 and 52 weeks, blood was drawn from patients between08.00 and 10.00 h to determine serum cortisol levels. In addi-tion, serum markers of bone metabolism (osteocalcin, totaland bone-specific alkaline phosphatase [AP], total hydroxy-proline, pyridinium crosslinks [pyrilinks-D] and calcium)were measured. At these visits, 24-h urine was also collected
to determine free cortisol, with collection in the morningbefore the visit to the study site. Cortisol levels were correctedfor creatinine in random or incomplete urine collections.
2.5 Statistical analysisStatistical analysis was conducted in the intention-to-treat(ITT) population (patients who received at least one dose ofciclesonide). In the 12-week treatment phase, the primary var-iable was change in morning PEF from baseline to end oftreatment. Secondary variables were evening PEF, asthmasymptoms and rescue medication use. For early withdrawals,last valid measurements during treatment were carried for-ward to treatment after 12 weeks, resulting in the end-point value. In the long-term extension phase, the primaryvariable was safety, including clinical laboratory and cortisollevels. Secondary variables were clinic FEV1, FVC and PEF.
All efficacy variables were analyzed for superiority of cicle-sonide 640 µg twice daily versus 320 µg twice daily based onthe ITT analysis.
After logarithmic transformation, the end-point/baselineratios were compared within groups by the paired t test(two-sided, significance level a = 0.05) and between groupsby the Student 2-sample t test, or its Welch modification incase of variance in homogeneity (one-sided, significance levela = 0.05). In this setting, a sample size of 120 patients pergroup was sufficient to ensure a power of 80% in correctlyconcluding superiority of 640 µg ciclesonide twice daily over320 µg ciclesonide twice daily, under the assumption of theStudent’s 2-sample t test (one-sided, 5% level), a ratio cicleso-nide 1600:800 of 1.05 and a coefficient of variation ofapproximately 15%.
For the long-term extension-phase lung-function variables,the differences between week 52 and the start of the long-term phase were calculated, and an analysis of covariancewith sex and pooled center as fixed factors and age as covariatewas applied. All tests were performed two-sided at the signif-icance level a = 0.05. The last observation was carried forwardfor the end-point analysis. Site effects were not included in thestatistical analysis because the number of patients per sitewas limited.
The use of rescue medication and the sum of asthmasymptom scores during the last week prior to each visit wereanalyzed non-parametrically. Within-group comparisonswere performed with Pratt’s modified Wilcoxon signed-ranktest. Between-treatment comparisons were conducted withMann--Whitney U tests. Safety and AEs were analyzed in adescriptive manner. Differences within treatment groups andbetween treatment groups for cortisol and bone markerswere analyzed, for which mean and 95% confidence intervalswere calculated on the basis of paired and independent t tests,respectively. Only patients who had not taken any oral or top-ical steroids during both phases of the study were included inthe ITT analyses of cortisol and bone markers. The propor-tions of patients experiencing an asthma exacerbation inboth treatment groups were analyzed by Fisher’s exact test.
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3. Results
3.1 Study populationOf 608 patients enrolled during the run-in period,365 patients (ITT population) were eligible and were ran-domized to receive ciclesonide 320 µg (n = 177) or 640 µg(n = 188) twice daily. During the 12-week treatment phase,21 patients withdrew from the 320 µg twice-daily groupand 32 from the 640 µg twice-daily group. The most com-mon reasons for discontinuation were lack of efficacy(n = 6), AEs (n = 8) or other reasons (n = 39, including viola-tion of inclusion criteria or other protocol violations). Patientdemographics were similar in both treatment groups(Table 1).Of 312 patients who completed the double-blind phase per
protocol, 275 continued into the 40-week extension phase.All 275 patients had been pretreated with high doses ofICSs (mean daily dose: 1383 µg BDP or equivalent in the320 µg twice-daily group and 1415 µg BDP or equivalentin the 640 µg twice-daily group) (Table 1). In the extensionphase, 31 (11%) patients withdrew prematurely. Reasons forwithdrawal included AEs (n = 10), unresolved asthma exacer-bations or more than two exacerbations requiring treatmentwith oral steroids (n = 6) and other medical or non-medicalreasons (n = 15).The median daily dose of ciclesonide at week 52 was
1280 µg ex-actuator. From the ITT population, a total of43 patients received an average daily dose of ciclesonide of320 -- 640 µg and 322 patients received an average dailydose of 640 -- 1280 µg.
3.2 Efficacy3.2.1 Peak expiratory flow (diary records)During 12 weeks of treatment, morning PEF significantlyincreased by 16 l/min in the ciclesonide 320 µg twice-daily group (p < 0.001; two sided) and by 14 l/min in theciclesonide 640 µg twice-daily group (p = 0.001; two-sided)(Table 2; Figure 1). The improvement in lung functionwas evident within the first 4 weeks of treatment (Figure 1).Evening PEF increased by 8 and 7 l/min in the 320 µgtwice-daily group (p = 0.039; two-sided) and 640 µg twice-daily group (p = 0.069; two-sided), respectively (Table 2).There were no significant differences between treatmentgroups for morning or evening PEF (one-sided analysis:p = 0.59 and 0.57, respectively).
3.2.2 Lung function (clinic)FEV1 increased by 110 ml after 12 weeks of treatment withciclesonide 320 µg twice daily (p < 0.001; two-sided) and by30 ml after treatment with ciclesonide 640 µg twice daily(p = 0.258; two-sided) (Table 2). Similarly, FVC increasedwith ciclesonide 320 µg twice daily (p = 0.0001; two-sided)and ciclesonide 640 µg twice daily (p = 0.069) (Table 2).There were no significant differences between treatmentgroups for FEV1 and FVC (one-sided analysis). Statistically
significant increases in clinic PEF from baseline were observedfor the 320 µg group (p < 0.001; two-sided) and the 640 µggroup (p = 0.027; two-sided) (Table 2). Both doses achievedcomparable improvements in clinic PEF.
The increases in FEV1 (Figure 2), FVC and PEF observedwith ciclesonide after the 12-week treatment period weremaintained throughout the long-term extension phase ofthe study.
3.2.3 Asthma symptom scores and use of rescue
medicationTotal asthma symptom scores were significantly reduced by0.29 in both treatment groups (both p < 0.0001; two-sided);there was no significant difference between groups (p = 0.713,one-sided analysis). Night-time asthma symptom scoressignificantly improved in both treatment groups (bothp < 0.0001; two-sided). Daytime scores also significantlyimproved in both treatment groups (p = 0.011 and < 0.001;two-sided for the 320 and 640 µg twice-daily groups, respec-tively). There were no significant differences betweentreatment groups for daytime or night-time scores.
Use of rescue medication significantly decreased in the320 µg twice-daily group from a median of 3.14 to2.86 puffs/day (median reduction of 0.21 puffs/day;p = 0.005; two-sided). The reduction in the 640 µg twice-daily group from a median of 3.43 to 2.43 puffs/day (medianreduction of 0.29 puffs/day) was not significant (p = 0.077;two-sided) and there were no significant differences betweentreatment groups with regard to rescue medication use.
3.2.4 Asthma exacerbationsDuring the 12-week treatment phase, 26 patients developedan asthma exacerbation that required treatment with an oralcorticosteroid (13 [7%] in each group). Four patients (2%)in the ciclesonide 320 µg twice-daily group and two patients(1%) in the ciclesonide 640 µg twice-daily group withdrewfrom the study due to lack of efficacy. The difference betweentreatment groups was not statistically significant.
A total of 39 (14%) patients experienced an asthma exacer-bation that required treatment with oral corticosteroids dur-ing the 40-week open-label extension phase and six patientsdiscontinued during this phase due to exacerbations. Of thepatients who discontinued, four patients discontinued owingto lack of efficacy, while the outcome was unknown for theremaining two patients.
3.3 Safety
3.3.1 Adverse eventsIn the 12-week treatment phase, 76 of 177 (43%) patients inthe 320 µg twice-daily group and 92 of 188 (49%) patients inthe 640 µg twice-daily group experienced AEs. The most fre-quently reported AEs involved the respiratory system (Table 3).The incidence of oropharyngeal AEs was < 3% in all patients,and no dose dependency was observed between the twogroups. In particular, there were no patient-reported cases of
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oral candidiasis in either treatment group. Serious AEs werereported for 10 patients; all were judged by the investigatoras ‘unrelated’ or ‘unlikely related’ to ciclesonide. Vital signs,ECG and laboratory tests did not reveal any clinically relevantchanges with either ciclesonide dose.
During the 40-week extension phase, 168 (61%) patientsreported 382 AEs (Table 3). The majority of AEs were mild-to-moderate in severity, and 96% were assessed as ‘not related’or ‘unlikely related’ to study medication by the investigators.The most frequently reported AEs, including asthma,
Table 1. Patient demographics and baseline characteristics (intention-to-treat analysis).
*320 and 640 µg = ex-actuator doses, equivalent to 400 and 800 µg ex-valve, respectively.zValues represent non-transformed lung function measurements.§N = 274.
AR: Adrenoreceptor; BDP: Beclomethasone dipropionate; FEV1: Forced expiratory volume in 1 sec; PEF: Peak expiratory flow; SD: Standard deviation.
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bronchitis and upper respiratory tract infection, were relatedto underlying disease. Four percent of all AEs were considered‘likely related’ to the study drug and all of these were mild-to-moderate in intensity. Local oropharyngeal AEs considered‘likely related’ to the study drug were rare and included onecase of suspected oral candidiasis (n = 1; not confirmed by aswab test, in a patient taking antibiotics), pharyngitis(n = 2), sore throat (n = 2), taste perversion (n = 1), voicealteration (n = 2) and cough increase (n = 1).Two deaths occurred: one from bronchial carcinoma
that developed during the treatment period and one froma myocardial infarction. An additional 18 (7%) patientsexperienced 21 nonfatal serious AEs, including surgery, dip-lopia, joint disorder, duodenal ulcer and accidental injury.All serious AEs were rated ‘not related’ or ‘unlikely related’to study medication. Thirteen (5%) patients withdrewfrom the study prematurely due to nonfatal AEs, four of
which were considered serious. Investigators concluded thatfor 12 of these patients, AEs leading to premature studywithdrawal were ‘not related’ or ‘unlikely related’ to studymedication. One patient reported a subcutaneous hema-toma, which the investigator judged as being ‘likely related’to study medication. Physical examination and vital signsdid not reveal any significant or clinically meaningfulchanges during the 40-week extension phase and routinetests revealed no apparent changes in median laboratoryvalues. Two clinically relevant ECG abnormalities weredetected at week 52 or follow-up; these were assessed as‘not related’ to study medication.
3.3.2 Cortisol levels and bone markersDuring treatment in the 12-week, double-blind phase, meanserum cortisol levels increased from 345 to 416 nmol/l inthe ciclesonide 320 µg twice-daily group and from 334 to
Table 2. Change in pulmonary function after 12 weeks of treatment (intention-to-treat analysis).
Variable Ciclesonide
320 mg* twice daily
Ciclesonide
640 mg* twice daily
DiaryMorning PEF, l/secn 176 178Baseline 5.03 5.15End point 5.30 5.38Week 12/baseline (95% CI) 1.05 (1.02, 1.08) 1.05 (1.02, 1.07)p value vs baseline < 0.001 0.001
Evening PEF, l/secn 176 177Baseline 5.43 5.53End point 5.57 5.65Week 12/baseline (95% CI) 1.02 (1.00, 1.05) 1.02 (1.00, 1.04)p value vs baseline 0.039 0.069
ClinicFEV1, mln 168 174Baseline 1890 1990End point 2000 2020Week 12/baseline (95% CI) 1.06 (1.03, 1.10) 1.02 (0.99, 1.04)p value vs baseline < 0.001 0.258FVC, Ln 168 174Baseline 2.84 3.05End point 3.04 3.12Week 12/baseline (95% CI) 1.07 (1.04, 1.10) 1.02 (1.00, 1.05)p value vs baseline 0.0001 0.069
PEF, l/secn 166 172Baseline 4.75 4.90End point 5.07 5.12Week 12/baseline (95% CI) 1.07 (1.03, 1.11) 1.04 (1.00, 1.08)p value vs baseline < 0.001 0.027
Data are presented as geometric means. Change versus baseline is presented as the ratio for Week 12/baseline; p values are two sided.
*320 and 640 µg = ex-actuator doses, equivalent to 400 and 800 µg ex-valve, respectively.
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330
320
310
300
290
280M
ean
mo
rnin
g P
EF,
l/m
in
270
260
2500 4
Weeks
CIC320 BIDCIC640 BID
8 12
Figure 1. Morning peak expiratory flow during 12 weeks of therapy. Data are presented for the intention-to-treat analysis as
geometric mean ± standard error of the mean. Ciclesonide 320 and 640 µg are ex-actuator doses, equivalent to 400 and 800 µgex-valve, respectively.BID: Twice daily; CIC320: Ciclesonide 320 µg; CIC640: Ciclesonide 640 µg; PEF: Peak expiratory flow.
2400
2300
2200
2100
FE
V1,
ml
200012 16 26 39
Weeks
52
Figure 2. Time course of forced expiratory volume in 1 sec in patients during the open-label extension phase of the study.
Values are presented as mean ± standard error of the mean. During the first 4 weeks of the open-label extension phase,
ciclesonide 640 µg twice daily was administered; thereafter, doses could be individualized. The differences between the start
of the extension phase of the study (week 12) and each subsequent visit were not statistically significant. At study baseline
(i.e., the start of the 12-week, randomized phase), mean (± SD) FEV1 was 2030 (± 800) ml for the 320 µg twice-daily group and
2160 (± 830) for the 640 µg twice-daily group.FEV1: Forced expiratory volume in 1 sec.
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390 nmol/l in the ciclesonide 640 µg twice-daily group (ITTanalysis of all patients not using concomitant steroids).Similarly, 24-h urine cortisol levels increased from 5.8 to9.8 nmol/mmol creatinine in the 320 µg twice-daily groupand from 6.1 to 7.5 nmol/mmol creatinine in the 640 µgtwice-daily group (ITT analysis of all patients not usingconcomitant steroids).During the long-term extension phase, serum and 24-h
urine cortisol levels remained basically unchanged from thoseafter 12 weeks of treatment with both doses of ciclesonide(Table 4). After 1 year of treatment, bone-specific AP, serumosteocalcin and urine pyrilinks-D levels showed statisticallysignificant increases from baseline (p < 0.05; two-sided forITT analysis of all patients not using concomitant steroids),whereas urine calcium and urine hydroxyproline remainedunchanged (Table 5).
4. Discussion
Ciclesonide administered over a 1-year period (320 µg or640 µg twice daily during the double-blind, 12-week periodfollowed by a 40-week open-label period) to patients withmoderate-to-severe persistent asthma previously treated withhigh-dose ICSs (BDP 1600 µg/day), provided effectiveasthma control and a good tolerability and safety profile. Dur-ing the 12-week, double-blind phase, lung function andasthma symptoms were sustained and there was a reductionin rescue medication use. These findings were reflected by alow and comparable number of asthma exacerbations inboth treatment groups. Furthermore, lung function was wellmaintained over 40 weeks of continued treatment withindividualized ciclesonide dosing.In terms of safety, the results of the 40-week extension
phase demonstrated that long-term use of high doses ofciclesonide (640 -- 1280 µg/day) did not lead to cortisolsuppression, as indicated by serum and 24-h urine cortisolvalues, and resulted in very few local AEs. Bone metabolismparameters indicated a varied response. This is difficult to
interpret, as there is ongoing debate as to which of the cur-rently available markers might be relevant and be predictiveof long-term bone health.
The efficacy results of this study are consistent with thoseseen in previous placebo-controlled trials, where patients pre-treated with ICS therapy experienced either maintenance orimprovement in lung function when switched to ciclesonidetherapy at doses of 160 -- 640 µg/day [16-19]. As with previousstudies with other ICSs [23], a dose-dependent improvementin pulmonary function was not observed with increasing cicle-sonide doses in the current study. This may be because themaximal dose-response has already been reached with thelower 320 µg/day dose. However, during a previous study,ciclesonide 1280 µg/day was shown to offer greater numericalbenefits with regard to reductions in oral corticosteroid usecompared with ciclesonide 640 µg/day in patients with severe,oral corticosteroid-dependent asthma [24]. In addition, a dose--response study in patients with severe asthma indicatedimproved lung function and asthma symptoms, as well asreduced rescue medication use with ciclesonide 320 µg twicedaily compared with 160 µg once daily [19]. The disparitybetween the previous studies and the current study in termsof a dose-dependent effect may be due to differences in thepopulations studied.
A placebo arm was not included in the current study,as 12 weeks of treatment with placebo in patients withmoderate-to-severe asthma would have been deemed ethi-cally unacceptable [25], and could also have resulted indiscontinuation of a large number of patients, thereby reduc-ing the value of such an arm. Prior to the start of ciclesonidetherapy, patients had been receiving high ICS doses(> 1300 µg/day BDP equivalent) and all patients receivedBDP 1600 µg/day for 2 weeks during the run-in period ofthe study. In addition, some patients additionally requiredlong-acting b2-agonists or xanthines. Therefore, the majorityof patients in this study would be classified with severe per-sistent asthma, according to definitions available at thetime of the study [26].
Table 3. Adverse events reported by > 3% of patients in either of the treatment groups or either treatment phase
(intention-to-treat analysis).
Adverse event, n (%) 12-week randomized phase Long-term safety phase
Efficacy and safety of ciclesonide in patients with severe asthma
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For the purpose of interpreting the clinical implications ofthe study, severe persistent asthma can be considered as equiv-alent to asthma suboptimally controlled with high-dose ICSs.In this study, a lack of optimal control with high doses ofICSs was achieved by giving patients high doses of ICSs dur-ing the run-in phase and by only allowing those patientsshowing features of suboptimal disease control to be random-ized. It is notable that ciclesonide sustained lung function andother measures of asthma severity in this group of patientsalready receiving regular high-dose ICS therapy. This maybe because the ciclesonide HFA formulation has a higherlung deposition, including higher deposition in the small air-ways, compared with the CFC-BDP formulation that thepatients previously received [13,27].
ICSs are frequently associated with local side effects,including dysphonia and oral candidiasis [9]. Clinical oral can-didiasis has been reported in approximately 4 -- 13% and dys-phonia in 5 -- 50% of patients receiving ICSs [9]. In the12-week phase of the present study, the incidence of localAEs was £ 3% for both ciclesonide groups and there wereno cases of patient-reported oral candidiasis, even with totaldaily doses as high as 1280 µg. Similarly, the long-term exten-sion phase demonstrated that high-dose ciclesonide is associ-ated with a low incidence of local AEs even after 1 yearof treatment.
The low incidence of local AEs has been confirmed in acombined analysis of studies including 7706 patients whowere treated with ciclesonide 40 -- 1280 µg/day, whichshowed a similar incidence of oral candidiasis and hoarsenessbetween ciclesonide and placebo [28]. The low incidence oflocal AEs seen with ciclesonide may be, in part, due to mini-mal conversion to the active metabolite in the oropharynx andthe large proportion of highly respirable, ultrafine particlesgenerated with the HFA--MDI formulation, which leads tolow oropharyngeal deposition [12,13,15,29].
Marked adrenal suppression has been reported with highdoses of ICSs (such as BDP, budesonide, triamcinolone ace-tate and fluticasone propionate) [6,23,30]. In contrast, cicleso-nide did not suppress markers of endogenous cortisolproduction in the current study, despite the high doses (upto 1280 µg/day) tested. In fact, cortisol levels increased dur-ing the 12-week randomized phase of the study in bothgroups. This possibly indicates a normalization of previouslysuppressed hypothalamic--pituitary--adrenal (HPA)-axisfunction with high-dose ICS therapy before randomiza-tion [23,31]. The lack of a suppressive effect of ciclesonideon cortisol production is in agreement with previous reports,in which ciclesonide had no clinically relevant negative effecton the HPA axis [32-34], including high-dose ciclesonide(1280 µg/day) in a placebo-controlled study [35]. Thereduced potential for systemic effects (adrenal function)observed with ciclesonide is in line with the pharmacokineticfeatures of the molecule. The high protein binding and rapidclearance of ciclesonide reduce the potential for systemicexposure to the drug [10,11].
5. Conclusions
In summary, during the 12-week, double-blind, random-ized phase of the study, ciclesonide 320 and 640 µg twicedaily both sustained lung function, asthma symptoms andrescue medication use in patients with severe persistentasthma, despite patients having received high ICS doses(> 1300 µg/day BDP equivalent) prior to the start ofthe study and BDP 1600 µg/day for 2 weeks during therun-in period of the study. The higher ciclesonide dosedid not provide additional benefits over the lower dose.Lung function was maintained with individualized cicle-sonide dosing during the 40-week extension phase ofthe study. Long-term use of ciclesonide, even at highdaily doses, was associated with a lack of negative effectson HPA-axis function and a very low incidence oflocal AEs.
Acknowledgments
The data presented in our manuscript have been previouslypresented at the American Thoracic Society meeting in2002 as an abstract (O’Connor et al, AJRCCM 165,A767, 2002).
The authors thank Medicus International for editorial assis-tance. Editorial support was funded by Nycomed GmbH,Konstanz, Germany.
The following investigators participated in the study:From the United Kingdom: JG Ayres (Birmingham);
MD Blagden (Chesterfield); ID Brown (Barnoldswick);A Connolly (Bradford)*; GJ Gibson (Newcastle-upon-Tyne); IGV James (Bolton)*; S Kilfeather (Newcastle-upon-Tyne); AJ Knox (Nottingham); AM Miller (Doncaster)*;B O’Connor (London); BD Silvert (Bolton); SC Stenton(Newcastle upon Tyne); IK Taylor (Sunderland).
From Belgium: J Aumann (Hasselt); W de Backer(Edegem)*; P Gris (Jumet); M Radermecker (Liege); Y Sibille(Godinne)*; L Siemons (St Truiden); P de Vuyst (Brussels)*.
From The Netherlands: R Aalbers (Groningen);TA Bantje (Breda); AJM Bax (Bilthoven); D Cheung(Leiden); JPHM Creemers (Eindhoven); APM Greefhorst(Hengelo)*; AJ van Harreveld (Apeldoorn); P Hekking(Rotterdam); J Kersbergen (Leiderdorp)*; DRAJ de Munck(Veldhoven); JA van Noord (Heerlen); N Schl€osser (Utrecht);HEJ Sinnighe-Damste (Almelo); RALM Stallaert (Hoorn).
From France: R Aguilaniu (Grenoble); J-M Braun (Evry)*;C Delaisements-Pol (Evry); P Delaval (Rennes)*; A Didier(Toulouse)*; P Dugue (Grasse); R Escamilla (Toulouse)*;P Godard (Montpellier); B Housset (Creteil)*; J-J Innocenti(Albi); H Kafe (Saint-Quentin); F-X Lebas (Le Mans);F Leynadier (Paris); J-P Orlando (Aubagne); G Peiffer(Metz); A Prud’homme (Tarbes)*; P Terrioux (Meaux)*;B Wallaert (Lille); P Zuck (Metz)*.
*Investigator took part in the 12-week randomizedtreatment phase only.
O’Connor, Kilfeather, Cheung, et al.
Expert Opin. Pharmacother. (2010) 11(17) 2801
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Declaration of interest
This study was funded and sponsored by Nycomed GmbH,Konstanz, Germany. BJ O’Connor has received hono-raria from GlaxoSmithKline and Chiesi, and has alsoreceived consultancy fees from Chiesi. BJ O’Connor hasbeen an investigator in clinical trials for several companiesincluding Chiesi, Pfizer, GlaxoSmithKline and TOPIGEN,
and has received grant income to his institution (King’sCollege School of Medicine, London). BJ O’Connor hadno personal control of this income, which was utilized bysenior academics in the division to fund their research.H-J Weber and R Engelstatter are employees of NycomedGmbH. S Kilfeather, D Cheung, H Kafe, MD Blagden,N Schl€osser and JG Ayres have no potential conflicts ofinterest to disclose.
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AffiliationBrian J O’Connor†1, Stephen Kilfeather2,
