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(Chest. 2006;129:1176-1187.)
© 2006 American College of Chest Physicians

Ciclesonide Reduces the Need for Oral Steroid Use in Adult Patients With Severe, Persistent Asthma*

Eric Bateman, MD, FRCP; Jill Karpel, MD, FCCP; Thomas Casale, MD; Sally Wenzel, MD, FCCP and Donald Banerji, MD

* From the University of Cape Town (Dr. Bateman), Cape Town, South Africa; North Shore University Hospital (Dr. Karpel), Long Island, NY; Creighton University (Dr. Casale), Omaha, NE; and National Jewish Medical Research Center (Dr. Wenzel), Denver, CO; and Aventis Pharmaceuticals (Dr. Banerji), Bridgewater, NJ.

Correspondence to: Eric Bateman, MD, FRCP, University of Cape Town Lung Institute, PO Box 34560, Groote Schuur 7937, Cape Town, South Africa; e-mail: ebateman{at}uctgsh1.uct.ac.za

Abstract

Study objectives: Oral corticosteroids (OCS) may be associated with systemic adverse events (AEs), which can be reduced by replacing OCS with inhaled corticosteroids (ICS). The potential of ciclesonide, a novel ICS, to reduce OCS use in patients with severe, persistent asthma was evaluated in this study.

Design: A phase III, 12-week, international, multicenter, double-blind, placebo-controlled, parallel-group study.

Patients: Adult and adolescent patients (≥ 12 years old; n = 141) with severe, persistent, oral steroid (prednisone)-dependent asthma.

Interventions: Patients were randomized to receive ciclesonide (640 µg/d or 1,280 µg/d [ex-actuator]) bid or placebo for 12 weeks. Weekly evaluations determined eligibility for prednisone dose reduction based on predetermined criteria.

Measurements and results: The prednisone dose was significantly reduced by 47% and 63% in the groups receiving ciclesonide, 640 µg/d, and ciclesonide, 1,280 µg/d, respectively, vs an increase of 4% in the placebo group (both p ≤ 0.0003) at week 12. By week 12, prednisone was discontinued by approximately 30% of patients in the ciclesonide-treated groups, vs 11% of patients in the placebo group (both p ≤ 0.04). FEV1 improved significantly at week 12 in the ciclesonide treatment groups vs placebo (p < 0.03). The occurrence of local and systemic AEs was comparable between all treatment groups.

Conclusion: Study results suggest that ciclesonide significantly reduces the need for OCS in patients with severe, persistent asthma, while maintaining asthma control.

Key Words: ciclesonide • efficacy • inhaled corticosteroids • prednisone • pulmonary • safety • severe persistent asthma

Inhaled corticosteroids (ICS) are the most effective agents for controlling persistent asthma.1 However, in very severe cases and during exacerbations, oral corticosteroids (OCS) are necessary. As systemic adverse events (AEs) are associated with OCS use, oral steroid-sparing strategies are employed234 and have been demonstrated with ICS such as beclomethasone dipropionate,5 budesonide,678 and fluticasone propionate9101112 in patients with moderate-to-severe asthma. However, ICS administered in high doses for prolonged periods are associated with AEs such as hoarseness, moniliasis, and the suppression of hypothalamic-pituitary-adrenal (HPA)-axis function.13141516 Consequently, the ideal ICS is one that is OCS sparing but has minimal AEs.

Ciclesonide is a novel ICS currently under development for the treatment of persistent asthma. Inactive in its parent form, and with a weak affinity for glucocorticoid receptors, ciclesonide is converted to its active metabolite, desisobutyryl-ciclesonide (des-CIC), by esterases, primarily in the lungs.17 Studies181920 suggest that ciclesonide may provide a high level of efficacy against the symptoms of asthma, comparable with that of available ICS, including budesonide2122 and fluticasone propionate.2324 Ciclesonide reduces airway hyperresponsiveness to adenosine-5'-monophosphate,2526 methacholine,27 and allergen challenge,28 and improves pulmonary function29 in patients with asthma. In addition, ciclesonide has a favorable safety profile and does not affect the circadian rhythm of serum cortisol,30 suggesting it has no clinically relevant effect on HPA-axis function. Importantly, des-CIC has a rapid clearance rate31 and a high degree of serum protein binding,32 potentially leading to low systemic exposure. Furthermore, low rates of oral candidiasis and other local oropharyngeal effects have been observed, presumably as a result of the low oropharyngeal deposition of ciclesonide, which is approximately half that of budesonide and fluticasone propionate, and the even lower oral deposition of des-CIC, which is 25-fold lower than that of active budesonide,33 and one tenth that of active fluticasone propionate.34 In addition, ciclesonide demonstrates limited oral conversion to des-CIC. Taken together, these data suggest that ciclesonide, with its favorable therapeutic profile, may be a suitable OCS-sparing therapy.

We report here the results of a placebo-controlled study examining the efficacy of ciclesonide administered twice daily in reducing the use of the OCS prednisone in patients with severe, persistent asthma. The effects on HPA-axis function and pulmonary function were also assessed.

Methods and Materials

Male and female patients aged ≥ 12 years with OCS-dependent, severe, persistent asthma (according to the Global Initiative for Asthma guidelines35) diagnosed at least 12 months prior to screening were enrolled in a 12-week, international, randomized, double-blind, placebo-controlled, parallel-group study. Patients were required to have received oral prednisone daily or on alternate days for at least 5 of the previous 6 months (5 to 30 mg/d and/or 10 to 60 mg every other day) and to have received ICS therapy continuously during the previous 6 months, with inhaled ß2-agonists used as rescue medication for at least the preceding 2 weeks. Patients were instructed to use their currently prescribed ICS at the recommended fixed maintenance doses during the screening period (1 to 4 weeks) until the day before randomization (Table 1 ). Patients were required to be nonsmokers or ex-smokers with a < 10 pack-per-year cigarette smoking history who had not smoked for at least 6 months.


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  		Table 1. ICS Use During the Screening Period (1 to 4 Weeks Prior to Randomization) in the ITT Population*

 
Patients with a history of life-threatening asthma episodes within the last 2 years or who required a burst of prednisone during screening due to an asthma exacerbation were excluded from the study. Additional therapy permitted during the study period included previously prescribed intranasal glucocorticoids (for rhinitis), cromolyn sodium, antihistamines, and hydrocortisone cream or ointment ≤ 1%, all at a stable dose. Montelukast, theophylline, anticholinergics, oral ß2-agonists, long-acting bronchodilators, and short-acting or nebulized ß2-agonists were also permitted; however, they had to be withheld for specified time periods before the clinic visits for lung function testing. Eligible patients had to demonstrate a FEV1 of 40 to 80% of predicted normal values following the withholding of ß2-agonists for 6 h and a ≥ 12% reversibility in FEV1 following inhaled medication (with an absolute volume increase of ≥ 200 mL), either at screening/baseline or randomization, or a documented history of these pulmonary function requirements within the previous 12 months.

Prior to randomization, during the screening period, the lowest effective dose of oral prednisone was established for each patient. This was determined in one of two ways: (1) a documented history verifying failed attempts at prednisone dose reduction within 2 months prior to screening/baseline; such patients were considered to be currently on their lowest effective dose; (2) alternatively, if documentation was not available, patients were instructed to reduce their prednisone dose during screening, at weekly intervals in predefined steps until one of the following criteria was not met: FEV1 ≥ 80% of the actual value at the screening visit (week 1; for safety reasons, not ≤ 40% of the predicted normal value) or no increase in 24-h asthma symptoms, nighttime awakenings, or albuterol use. Patients who failed one or more of these criteria were returned to a dose one step higher, which was considered the lowest effective dose for that patient. Patients who did not deteriorate on doses < 5 mg/d did not qualify for inclusion and were withdrawn. All five criteria listed in Table 2 had to be met in order for prednisone dose reduction to occur. The dose reduction schedule is shown in Table 3 .


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  		Table 2. Eligibility Criteria for Prednisone Dose Reduction at Weekly Visits Throughout the 12-Week Study Period

 

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  		Table 3. Prednisone Dose Reduction Schedule During the Double-Blind Treatment Period

 
When dose reduction criteria were not met, the investigator either maintained the current dose of prednisone or stepped up the dose if the symptoms had increased (Table 4 ). When symptoms merited a greater increase, the prednisone dose was increased by up to 10 mg qd or 20 mg every other day at the investigators’ discretion. Severe increases in symptoms were treated with a prednisone burst (40 to 60 mg tapered over a 7- to 10-day period to a dose of 2.5 mg above the preburst dose for once-daily regimens or 5 mg above the preburst dose for every other day regimens). If patients required a second prednisone burst, they were discontinued from the study. Patients remaining in the study continued at their lowest effective OCS dose for at least 7 days before randomization, with albuterol hydrofluoroalkane-metered dose inhaler (HFA-MDI) canisters (Schering/Key Pharmaceuticals; Kenilworth, NJ) provided as rescue medication.


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  		Table 4. Prednisone Dose Escalation Schedule During the Double-Blind Treatment Period

 
At randomization, current ICS were stopped and the patients were randomized to receive ciclesonide delivered via HFA-MDI at 640 µg/d (CIC640; 80 µg x four puffs bid); ciclesonide delivered via HFA-MDI at 1,280 µg/d (CIC1280; 160 µg x four puffs bid); or placebo (all received at 8 AM and 8 PM). During each of the 12 weekly follow-up visits, patients were evaluated to determine their eligibility for prednisone dose reduction based on the criteria described in Table 2. Doses were adjusted according to the dosing steps described in Tables 3, 4.

The protocol was approved by an independent ethics review committee and institutional review boards, and the study was conducted in accordance with the principles of good clinical practice, as outlined in the Declaration of Helsinki. Informed consent was obtained from patients prior to the conduct of any study-related procedures.

Efficacy Assessments
All assessments were performed at the weekly clinic visits. The primary efficacy measure was the percentage change from baseline to week 12 in prednisone dose. Additional outcome measures included the percentage of patients reducing or discontinuing prednisone use, within specific ranges; changes from baseline in FEV1 and patient-measured morning peak expiratory flow (PEF); the time to study discontinuation due to a lack of efficacy or an asthma-aggravated AE; and the change from baseline in 24-h symptom scores and daily albuterol use.

Patients were instructed to use daily diary cards to record prednisone use, concomitant medications, PEF, 24-h asthma symptom rating score, and albuterol use (puffs per day). The asthma symptom scores were based on a 5-point asthma symptom score over 24 h and defined as the sum of the daytime and nighttime asthma symptom scores. These were assessed twice daily (prior to measuring PEF) by the patient, using the following criteria: 0 = no symptoms; 1 = occasional wheezing, cough, or shortness of breath but no interference with daily activities or sleep; 2 = occasional wheezing, cough, or shortness of breath, with interference of daily activities or sleep; 3 = frequent or continuous wheezing, cough, or shortness of breath, with interference of daily activities or sleep; 4 = symptoms that prevent the patient from engaging in daily activities or sleep.

Safety
The investigators assessed patients for AEs; in addition, patients reported AEs in their patient diaries. Data from physical examinations and clinical laboratory tests were collected at screening and week 12. HPA-axis function was assessed at randomization and at week 12 via cosyntropin stimulation.3637 Blood samples for serum cortisol measurements were collected before and after stimulation with low-dose (1 µg) cosyntropin. Fasting basal serum cortisol levels were measured at 8:15 AM and 20, 30, and 60 min after stimulation with cosyntropin. Cortisol testing was performed using high-performance liquid chromatography (Waters Corporation; Milford, MA). For this study, HPA-axis function was considered normal if the basal serum cortisol level was ≥ 5 µg/dL and the post–low-dose cosyntropin stimulation peak serum cortisol level was ≥ 18 µg/dL; or, for women receiving oral contraceptives or hormone therapy, if low-dose peak serum cortisol levels (defined as the post–low-dose peak serum cortisol level minus the pre–low-dose serum cortisol level) were ≥ 7 µg/dL from the pre–low-dose cortisol level.

Statistical Analysis
A sample size of approximately 150 patients (approximately 50 in each treatment group) was needed for the study to have 90% power (with a two-sided test significance level of {alpha} = 0.05) to detect a difference of 40 percentage points in the percentage baseline to endpoint change in prednisone dose (approximately 4.8 mg) between the ciclesonide and placebo treatment groups. The primary efficacy end point was the percentage change from baseline to end point (week 12 or early termination) in prednisone dose in the intent-to-treat (ITT) population, defined as those patients who received at least one dose of the study medication and had a valid baseline and at least one post-baseline efficacy assessment. The primary efficacy end point was assessed using an analysis of covariance (ANCOVA) model. Supportive analyses of the primary efficacy end point were done to assess ANCOVA model assumptions. ANCOVA models were also used to analyze baseline to end point changes in FEV1, weekly changes from baseline for PEF measured in the morning, 24-h asthma symptom scores, albuterol use, and serum cortisol levels. Safety analyses were conducted in the safety population, which included all patients who received at least one dose of the study medication. The proportion of patients reducing or discontinuing prednisone use at study end and the changes in laboratory data were analyzed using Cochran-Mantel-Haenszel and Kruskal-Wallis tests, respectively. Analysis of withdrawal rates and the Kaplan-Meier analysis of time to withdrawal (days since date of randomization) were conducted using Fisher Exact Test and the log-rank test, respectively.

Results

Patient Characteristics
The trial was conducted between July 2001 and March 2003. Overall, 241 patients were screened, and 141 patients (80 in the United States and 61 in South Africa) were randomized to receive treatment at 60 sites within these countries (CIC640, n = 47; CIC1280, n = 49; placebo, n = 45). Patient disposition throughout the clinical trial is shown in Figure 1 . The ITT population consisted of 140 patients; 1 patient in the CIC1280 group was excluded due to not having postbaseline measurements. All 141 randomized patients were included in the safety population. All patient characteristics, including the mean lowest effective prednisone dose, were comparable between the treatment groups at baseline (Table 5 ).


Figure 1
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  		Figure 1. Disposition of patients throughout the trial (patients may have had more than one reason for discontinuation; therefore, numbers are not additive).

 

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  		Table 5. Patient Demographics and Characteristics at Study Entry: ITT Population

 
Concomitant asthma medication received by ≥ 5% of patients in the safety population during the double-blind study period (not including albuterol) included long-acting selective ß2-adrenoceptor agonists (63.8%), xanthines (43.3%), leukotriene receptor antagonists (39.0%), anticholinergic agents (18.4%), and combination short-acting selective ß2-adrenoceptor agonists and anticholinergic agents (14.2%). The use of these medications was comparable among the treatment groups. Non-asthma concomitant medication taken during the study period by ≥ 40% of the patient population included analgesics, nasal preparations, dermatologic corticosteroid preparations, medications for gastric acid-related disorders, antihistamines, and obstructive airway diseases.

The ICS used by patients in the ITT population at randomization included budesonide (37.9%), fluticasone (31.4%), fluticasone/salmeterol combined (27.1%), beclomethasone (2.9%), triamcinolone (2.1%), beclomethasone hydrofluoroalkane (0.7%), and flunisolide (0.7%). Previous use of ICS was comparable among the study treatment groups.

More than 93% of patients in each treatment group had a compliance rate of ≥ 90% with the study medication. This rate was calculated from the daily diary recordings at the end of the study.

Efficacy Assessments
Reduction in Prednisone Dose:
At end point, the mean oral prednisone dose was lower in the ciclesonide groups compared with placebo (CIC640, 8.60 µg/d; CIC1280, 4.66 µg/d; placebo, 13.63 µg/d). Mean use was reduced by 47.39% (SE 10.10; 95% confidence interval [CI] – 67.40 to – 27.38) and 62.54% (SE 9.80; 95% CI, – 81.94 to – 43.14) in patients in the CIC640 and CIC1280 groups, respectively, compared with an increase in the placebo group of 4.21% (SE 10.34; 95% CI, – 16.27 to 24.68) at end point. For both doses of ciclesonide, the differences vs placebo were statistically significant (Fig 2 ). Although the CIC1280 group had a larger percentage reduction in prednisone dose than the CIC640 group, this difference (15.15% [SE 13.80]; 95% CI, – 42.48 to 12.18) was not statistically significant (p = 0.274; Fig 2).


Figure 2
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  		Figure 2. Mean percentage change in prednisone dose from baseline to study end in patients with severe, persistent asthma receiving treatment with ciclesonide, 320 µg bid (CIC640); ciclesonide, 640 µg bid (CIC1280); or placebo (PBO). *p = 0.0003 vs placebo. {dagger}p = 0.0001 vs placebo.

 
Patients in both ciclesonide treatment groups were able to reduce their prednisone dose as early as week 2 of the study, and this reduction was sustained for the study duration. Overall, 74.4% of patients treated with CIC640 and 85.4% of patients treated with CIC1280 were able to reduce or discontinue prednisone, compared with 40% of patients in the placebo group (Fig 3 ). Almost one third of patients receiving ciclesonide (29.8% and 31.3% in the CIC640 and CIC1280 groups, respectively) were able to discontinue their use of prednisone entirely, compared with 11.1% of patients receiving placebo (p = 0.0386 and p = 0.0233 for the CIC640 and CIC1280 groups, respectively, vs placebo). An increase in prednisone use was observed in 23.4% and 10.4% of patients in the CIC640 and CIC1280 groups, respectively, at the end of the study, compared with 53.3% of patients in the placebo group.


Figure 3
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  		Figure 3. The distribution of patients in the ITT population grouped by percentage change in prednisone use at the end of the study, after treatment with ciclesonide, 320 µg bid (CIC640); ciclesonide, 640 µg bid (CIC1280); or placebo. CIC640, p ≤ 0.05; CIC1280, p = 0.0001 both vs placebo at the end of the study. Note that a percentage of patients showed no change in prednisone use at the end of study: 6.7% of patients from the placebo group, 2.1% of patients from the CIC640 group, and 4.2% of patients from the CIC1280 group. See Figure 2 legend for expansion of abbreviation.

 
Pulmonary Function:
There was no significant change from baseline in FEV1 for either ciclesonide treatment group; however, both groups showed a trend toward higher FEV1 values. In contrast, FEV1 values worsened significantly from baseline to end point in the placebo group (95% CI, – 0.24 to – 0.02). The between-treatment differences in FEV1 were statistically significant vs placebo for the CIC1280 group (p = 0.0277; 95% CI, 0.02 to 0.31) and the CIC640 group (p = 0.0237; 95% CI, 0.02 to 0.31) [Fig 4 ].


Figure 4
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  		Figure 4. Mean (SE) change in FEV1 over 12 weeks from baseline to end of study (last observation carried forward) in patients with severe asthma receiving treatment with ciclesonide, 320 µg bid (CIC640); ciclesonide, 640 µg bid (CIC1280); or placebo. See Figure 2 legend for expansion of abbreviation. p < 0.03 for both the CIC640 and CIC1280 treatment groups vs placebo at week 12; BL = baseline; EOS = end of study).

 
Greater baseline to end point improvements were also observed in mean morning PEF scores in both ciclesonide groups (CIC640, 4.32 L/min [SE 6.55]; CIC1280, 15.97 L/min [SE 6.50]) compared with placebo (– 0.7 L/min [SE 6.86]); this improvement from baseline was statistically significant in the CIC1280 group (95% CI, 3.10 to 28.84).

Symptoms and Rescue Medication Use:
There were no significant between-treatment differences in baseline to end point changes in mean 24-h asthma symptom scores (CIC640, 0.1 [SE 0.22]; CIC1280, – 0.31 [SE 0.21]; placebo, – 0.24 [SE 0.23]) or in mean daily albuterol use (CIC640, – 0.07 puffs per day [SE 0.51]; CIC1280, – 0.08 puffs per day [SE 0.51]; placebo, 0.32 puffs per day [SE 0.54]) in any of the treatment groups.

Discontinuation Due to Lack of Efficacy:
A total of 114 patients (80.9%) completed the study. There was a significant difference across the treatment groups with regard to the number of patients who discontinued prematurely due to a lack of efficacy; the withdrawal rate was significantly higher in the placebo group (CIC640, 6 patients [12.8%]; CIC1280, 3 patients [6.3%]; placebo, 13 patients [28.9%]; p = 0.0108) [Fig 5 ].


Figure 5
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  		Figure 5. Kaplan-Meier plot of patient discontinuation from the study due to a lack of efficacy in patients with severe asthma receiving treatment with ciclesonide, 320 µg/d bid (CIC640); ciclesonide, 640 µg/d bid (CIC1280); or placebo. p = 0.0108 for both CIC640 and CIC1280 treatment groups compared with placebo. See Figure 2 legend for expansion of abbreviation.

 
Safety
AEs:
Overall, both ciclesonide doses were well tolerated during the 12 weeks of therapy; however, 14.9%, 8.2%, and 26.7% of patients in the CIC640, CIC1280, and placebo groups, respectively, discontinued the study due to treatment-emergent AEs (TEAEs), the most common of which, across all treatment groups, was worsening asthma. A higher percentage of patients in the placebo group had at least one TEAE compared with the ciclesonide groups (CIC640, 85.1%; CIC1280, 79.6%; placebo, 88.9%). Over 12 weeks, 17.0%, 14.3%, and 22.2% of patients in the CIC640, CIC1280, and placebo groups, respectively, reported at least one TEAE that was considered possibly related to the study medication. Eight patients (CIC640, four patients [8.5%]; CIC1280, two patients [4.1%]; placebo, two patients [4.4%]) had a serious TEAE, none of which were considered possibly related to the study medication. There were no deaths during the study.

Local TEAEs that were possibly related to the study medication included hoarseness (CIC640, three patients [6.4%]; CIC1280, zero patients [0%]; placebo, one patient [2.2%]); pharyngitis (CIC640, one patient [2.1%]; CIC1280, zero patients [0%]; placebo, three patients [6.7%]); and oral candidiasis (CIC640, three patients [6.4%]; CIC1280, four patients [8.2%]; placebo, zero patients [0%]). Overall, the percentage of patients with possibly related TEAEs was lower in the ciclesonide treatment groups (CIC640, 17.0%; CIC1280, 14.3%) than in the placebo-treated group (22.2%).

HPA-Axis Evaluation:
Unstimulated (basal) mean serum cortisol levels increased significantly from baseline to end point in the CIC640 group (3.58 µg/dL [SE 0.97]; 95% CI, 1.66 to 5.51) and the CIC1280 group (2.34 µg/dL [SE 1.01]; 95% CI, 0.33 to 4.35). Cortisol levels within the placebo group also rose but not significantly (1.33 µg/dL [SE 1.01]; 95% CI, – 0.67 to 3.34). Between-treatment differences in the baseline to end point change in basal serum cortisol levels were not statistically significant (CIC640, p = 0.1052; CIC1280, p = 0.4829; Table 6). After stimulation with low-dose cosyntropin (1 µg), a significant increase from baseline to end point in low-dose peak serum cortisol levels was seen in the CIC640 group (5.28 µg/dL [SE 1.3]; 95% CI, 2.63 to 7.93) and the CIC1280 group (3.55 µg/dL [SE 1.3]; 95% CI, 0.95 to 6.14). In contrast, no significant change was observed in the placebo group (– 0.16 µg/dL [SE 1.4]; 95% CI, – 2.92 to 2.61). This difference vs placebo was statistically significant for the CIC640 treatment group (p = 0.0049) but not for the CIC1280 group (p = 0.0537; Table 6 ).


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  		Table 6. Change From Baseline to End of Study in Unstimulated (Basal) Serum Cortisol Levels and in Low-Dose Peak Serum Cortisol Levels in the ITT Population of Patients With Severe Asthma Receiving Treatment With Ciclesonide, 320 µg bid; Ciclesonide, 640 µg bid; or Placebo

 
At baseline, 66.0% of patients in the CIC640 group, 60.4% of patients in the CIC1280 group, and 62.2% of patients in the placebo group had suppressed HPA-axis function (according to criteria outlined in the "Materials and Methods" section). At end point, a lower proportion of patients in both ciclesonide treatment groups had suppressed HPA-axis function compared with placebo (CIC640, 46.8%; CIC1280, 43.8%; placebo, 53.3%).

Other Laboratory and Clinical Tests:
Laboratory tests, physical examinations, and vital signs showed no clinically meaningful changes in patients from any of the treatment groups.

Discussion

This study was designed to assess the OCS-sparing potential of ciclesonide in adult and adolescent patients with OCS-dependent, severe, persistent asthma. The results suggested that the substitution of twice-daily inhaled ciclesonide for high doses of other forms of ICS significantly reduced the dose of prednisone required by these patients. Although no significant dose-response effect was noted between the 640 µg/d and 1,280 µg/d dosages, the higher dose demonstrated a greater numeric trend toward improvement. In contrast, prednisone use was increased in the placebo group. Additionally, asthma control in the ciclesonide population was maintained or improved, as judged by the trends for improvements in FEV1 and morning PEF; these measures worsened in the placebo group. The OCS-sparing effect of ciclesonide was apparent by week 2 of the treatment and continued throughout the study, enabling almost one third of ciclesonide-treated patients to discontinue OCS use, vs approximately 11% of placebo-treated patients. The potential benefit of this switch to ciclesonide from other forms of ICS on the long-term AEs of OCS is suggested by evidence implying diminished HPA-axis suppression in patients who received ciclesonide. Conversely, a larger proportion of patients receiving placebo had HPA-axis suppression. These and other potential benefits of the oral steroid-sparing effects of ciclesonide will need to be confirmed in longer-term clinical studies.

Compared with this study, other published OCS-sparing studies812 using the ICS fluticasone propionate and budesonide have reported larger reductions in prednisone usage and higher prednisone discontinuation rates. However, a comparison of the results of such studies is hampered by differences in the patient populations and study designs. In particular, there are differences in the method of ensuring that patients are receiving a minimum effective dose of OCS before the initiation of the study treatments, and in the procedure for reducing the dose of OCS throughout the study. Both the size of the dosage steps and the duration of each step may influence the results. Sufficient time must be allowed between dose reductions to permit evaluation of the full effects of each change in treatment.

The step-down approach used to establish the minimum effective OCS dose in this study is identical to that used by Fish et al38 to evaluate the effect of mometasone furoate. The rapid (weekly) step-down routine is based on criteria for asthma control that, although not ideal (ie, do not represent complete control as recommended in guidelines),39 may be considered satisfactory when viewed against the potential harm caused by prolonged use of OCS.38 The same criteria and dosing steps were used during the active treatment phase. This approach is slow enough to ensure little carryover of efficacy between the doses but rapid enough to avoid seasonal and other temporal factors that influence asthma control.

In a study by Nelson et al,12 who examined the OCS-sparing effect of fluticasone propionate in patients with severe asthma, the minimal effective dose was not established at baseline, and all patients entered the study receiving the same dose of OCS as they were at recruitment. Additionally, the screening period in the study by Nelson et al12 was only 2 weeks, rather than 4 weeks as in our current study. In a second study8 involving budesonide, all patients had their OCS dose increased at baseline, calling into question the significance of the reductions in OCS dosage that were achieved later in the study.

Criteria for selecting an ICS for OCS-sparing therapy must include improved safety, with respect to both systemic and local AEs. The safety profile of an ICS is influenced by many factors, including the degree of systemic bioavailability. Suppression of HPA-axis function and adrenal insufficiency are indicative of a higher degree of systemic bioavailability1340 and are best assessed with measures such as the cosyntropin test, which reflects the capacity of the adrenal cortex response to physiologic stimulation. In our study, patients in all three treatment groups exhibited suppressed HPA-axis function at baseline, which was attributed to the use of OCS. Treatment with ciclesonide appeared to facilitate the recovery of normal HPA-axis function at the end of the study in a significant proportion of patients, as demonstrated by the increased peak serum cortisol levels after cosyntropin stimulation. This improvement in HPA-axis function may have been due to greater OCS reduction in the ciclesonide groups and the substitution of other forms of ICS with ciclesonide. These findings are consistent with results from other published ciclesonide studies192941 in patients with asthma in which little, if any, suppression of cortisol levels was evident, even with high doses of ciclesonide. In contrast, a direct comparative study23 examining the effects of fluticasone propionate on HPA-axis function found that 9 days of treatment with fluticasone propionate, 500 µg (ex-valve), decreased plasma cortisol levels by 29% and the 24-h urinary cortisol profile by approximately 44%, while 1,000 µg (ex-valve) reduced plasma cortisol levels by 59% and the 24-h urinary cortisol profile by 69%. The suppressed functioning of the HPA-axis seen at the beginning of the current study is a common effect associated with the long-term use of OCS. This effect, along with reduced bone growth in the young, is attributable to the endocrine activity of corticosteroids and is identical to the syndrome of endogenous corticosteroid excess (Cushing syndrome).42

The therapeutic margin of ciclesonide may be attributed to its novel pharmacokinetic/pharmacodynamic properties, which include its low oral bioavailability,34 high serum protein binding,32 and rapid elimination.31 Importantly, ciclesonide is formulated as a solution for delivery via HFA-MDI, which results in high lung deposition. It is inactive until converted to des-CIC in the target tissues, which, together with its pharmacologic properties, contribute to its potentially improved therapeutic margin. Initial data indicate that ciclesonide demonstrates comparable efficacy with other ICS in patients with persistent asthma21222324 and, in addition, is associated with minimal local or systemic AEs.303334

Conclusion

In conclusion, the results of this study suggest that twice-daily treatment with inhaled ciclesonide (640 µg/d or 1,280 µg/d) is a well-tolerated method for reducing (and potentially discontinuing) OCS use in patients with severe, persistent asthma, thus minimizing the risk of the AEs associated with OCS use.

Acknowledgements

We thank the following investigators for their participation in the study: Abdool-Gaffar, Mohamed; Abdullah, Ismail; Albery, Richard; Algatt-Bergstrom, Pamela; Bailey, William; Baz, Malik; Bernstein, David; Busse, William; Butterfield, Joseph; Caldwell, Jacques; Calhoun, William; Chipps, Bradley; Colice, Gene; Condemi, John; Conway, Michael; Cook, David; Craig, Timothy; Daffern, Pamela; D’Alonzo, Gilbert; Duvenhage, Cornelia; Fidelholtz, James; Fink, Jordan; Fino, Gregory; Foden, Alwyn; Fox, Roger; Garay, Stuart; Gawchik, Sandra; Gilman, Ronald; Grammer, Leslie; Hassell, Ann-Marie; Hussain, Iftikhar; Irusen, Elvis; Jordaan, Pierre; Kaiser, Harold; Karetzky, Monroe; Kent, Edward; Kerwin, Edward; Korenblat, Phillip; Kreitzer, Stephen; Kundu, Sudeep; Lalloo, Umesh; Laughlin, David; Leflein, Jeffrey; Levy, Arden; Mahfouz, Michael; Manjra, Ahmed; Mans, Winifred; Mansfield, Lyndon; McNeil, Donald; Meltzer, Steven; Middle, Michelle; Moy, James; Murray, John; Nadar, Rajesvaran; Nayak, Anjuli; Neilan, Martin; Noth, Imre; O’Brien, John; Patel, Amit; Peters, Stephen; Raad, George; Ras, Gerhard; Sarvan, Mahomed; Schenkel, Eric; Sher, Lawrence; Shim, Chang; Smith, Clifford; Smith, William; Spangenthal, Selwyn; Summer, Warren; Theron, FC; van Zyl, Louis; Viljoen, Johann; Wait, Juliette; Weinberg, Eugene; White, Martha; Wyatt, Richard; Yarbrough, John.

Footnotes

Abbreviations: AE = adverse event; ANCOVA = analysis of covariance; CI = confidence interval; CIC640 = ciclesonide delivered via hydrofluoroalkane metered-dose inhaler at 640 µg/d; CIC1280 = ciclesonide delivered via hydrofluoroalkane metered-dose inhaler at 1,280 µg/d; des-CIC = desisobutyryl-ciclesonide; HFA-MDI = hydrofluoroalkane metered-dose inhaler; HPA = hypothalamic-pituitary-adrenal; ICS = inhaled corticosteroid/corticosteroids; ITT = intent-to-treat; OCS = oral corticosteroid/corticosteroids; PEF = peak expiratory flow; TEAE = treatment-emergent adverse event

Data from this study have been previously reported in the form of an abstract to the American Thoracic Society International Congress, San Diego, CA 2005.

This was an international study conducted in the United States and South Africa.

Dr. Bateman has served as a consultant and is a member of an advisory board for Aventis Pharma. Dr. Karpel is a member of an advisory board for ALTANA and Schering-Plough; is on the Speaker’s Bureau for Boehringer-Ingelheim, Genentech, Glaxo, Novartis, Pfizer, and Schering-Plough; and has received grants from AstraZeneca, ALTANA, Boehringer-Ingelheim, Dey, and Genentech. Dr. Casale has served as a consultant for Allux, Aperon, Aventis, Corixa, Genentech, Merck, Novartis, and Sugitomo; is a member of a Data Monitoring Board for Hoffman-LaRoche; is on a Speaker’s Bureau and has given talks sponsored by Aventis, Genentech, Novartis, and Merck; and is an investigator for contract research performed through Creighton University for Capnia, Corixa, Dynavax, IDEC, MediciNova, Merck, NIAID/ITN, Novartis, Ono, and Pfizer. Dr. Wenzel has received grants from and has served as a consultant and is a member of an advisory board for ALTANA and sanofi-aventis. Dr. Banerji is an employee of sanofi-aventis and holds stock options in the company.

This study was funded by sanofi-aventis U.S. Inc., a member of the sanofi-aventis Group, and ALTANA Pharma AG.

Received for publication July 15, 2005. Accepted for publication December 14, 2005.

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