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

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1 CHEST 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 Original Research ASTHMA 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 g/d or 1,280 g/d [exactuator]) 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 g/d, and ciclesonide, 1,280 g/d, respectively, vs an increase of 4% in the placebo group (both p < ) 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). FEV 1 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. (CHEST 2006; 129: ) Key words: ciclesonide; efficacy; inhaled corticosteroids; prednisone; pulmonary; safety; severe persistent asthma Abbreviations: AE adverse event; ANCOVA analysis of covariance; CI confidence interval; CIC640 ciclesonide delivered via hydrofluoroalkane metered-dose inhaler at 640 g/d; CIC1280 ciclesonide delivered via hydrofluoroalkane metered-dose inhaler at 1,280 g/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 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 employed 2 4 and have been demonstrated with ICS such as beclomethasone dipropionate, 5 budesonide, 6 8 and fluticasone propionate 9 12 in patients with moderateto-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 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 Studies suggest that ciclesonide may provide a 1176 Original Research

2 high level of efficacy against the symptoms of asthma, comparable with that of available ICS, including budesonide 21,22 and fluticasone propionate. 23,24 Ciclesonide reduces airway hyperresponsiveness to adenosine-5 -monophosphate, 25,26 methacholine, 27 and allergen challenge, 28 and improves pulmonary function 29 in patients with asthma. For editorial comment see page 1124 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 rate 31 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 *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. Data from this study have been previously reported in the form of an abstract to the American Thoracic Society International Congress, San Diego, CA 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. Manuscript received July 15, 2005; revision accepted December 14, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Eric Bateman, MD, FRCP, University of Cape Town Lung Institute, PO Box 34560, Groote Schuur 7937, Cape Town, South Africa; ebateman@uctgsh1.uct.ac.za 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 guidelines 35 ) 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 2 -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. 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 2 -agonists, long-acting bronchodilators, and short-acting or nebulized 2 -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 FEV 1 of 40 to 80% of predicted normal values following the withholding of 2 -agonists for6handa 12% reversibility in FEV 1 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: FEV 1 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. CHEST / 129 / 5/ MAY,

3 Table 1 ICS Use During the Screening Period (1 to 4 Weeks Prior to Randomization) in the ITT Population* Corticosteroid Placebo (n 45) CIC640 (n 47) CIC1280 (n 48) Budesonide, g/d 1,000.0 (392.8) 1,070.0 (441.4) (334.7) No. (%) 15 (33.3) 20 (42.6) 18 (37.5) Fluticasone, g/d (218.9) (351.8) 1,048.6 (452.3) No. (%) 13 (28.9) 17 (36.2) 14 (29.2) Fluticasone/salmeterol, g/d (246.2) 1,055.6 (583.3) (166.1) No. (%) 12 (26.7) 9 (19.1) 17 (35.4) Triamcinolone, g/d 1,600.0 (NA) 1,200.0 (NA) (NA) No. (%) 1 (2.2) 1 (2.1) 1 (2.1) Beclomethasone, g/d (321.5) (NA) No. (%) 3 (6.7) 1 (2.1) 0 (0.0) Beclomethasone hydrofluoroalkane, g/d (NA) No. (%) 1 (2.2) 0 (0.0) 0 (0.0) Flunisolide, g/d 3,000.0 (NA) No. (%) 1 (2.2) 0 (0.0) 0 (0.0) *Data are presented as mean (SD) unless otherwise indicated. Patients may have taken one or more asthma medications (placebo, one patient; CIC640, one patient; CIC1280, two patients); therefore, numbers are not additive. NA not applicable. 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. At randomization, current ICS were stopped and the patients were randomized to receive ciclesonide delivered via HFA-MDI at 640 g/d (CIC640; 80 g four puffs bid); ciclesonide delivered via HFA-MDI at 1,280 g/d (CIC1280; 160 g 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 FEV 1 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 Table 2 Eligibility Criteria for Prednisone Dose Reduction at Weekly Visits Throughout the 12-Week Study Period Criteria Definition 1 FEV 1 80% of baseline FEV 1 and 40% of predicted FEV 1 values 2 Morning PEF 80% of baseline mean morning PEF on all days since last visit* 3 Mean nighttime awakenings 50% increase over the baseline period (per night), 150% of the baseline mean 4 Albuterol use for any 2 consecutive days since the last visit, not more than 4 puffs/d above the mean baseline value or 12 puffs/d 5 No prednisone burst required since the previous visit *Baseline means for morning PEF, nighttime awakenings, and albuterol use were calculated on a per-night or per-day basis using patient diary card information from the 7 days prior to randomization (visit 3) Original Research

4 Table 3 Prednisone Dose Reduction Schedule During the Double-Blind Treatment Period Prednisone Dosing 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. 36,37 Blood samples for serum cortisol measurements were collected before and after stimulation with low-dose (1 g) 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, HPAaxis function was considered normal if the basal serum cortisol level was 5 g/dl and the post low-dose cosyntropin stimulation peak serum cortisol level was 18 g/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 g/dl from the pre low-dose cortisol level. Statistical Analysis Present Dose of Prednisone, mg Prednisone Dose Reduction, mg Daily regimen Every-other-day regimen 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 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 FEV 1, weekly changes from baseline for PEF measured in the morning, 24-h asthma symptom scores, albuterol use, and serum cortisol levels. Safety Table 4 Prednisone Dose Escalation Schedule During the Double-Blind Treatment Period Prednisone Dosing Present Dose of Prednisone, mg Prednisone Dose Increase, mg Daily regimen Every-other-day regimen 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 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). 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 2 -adrenoceptor agonists (63.8%), xanthines (43.3%), leukotriene receptor antagonists (39.0%), anticholinergic agents (18.4%), and combination short-acting selective 2 - 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 acidrelated 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. CHEST / 129 / 5/ MAY,

5 Figure 1. Disposition of patients throughout the trial (patients may have had more than one reason for discontinuation; therefore, numbers are not additive). 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 g/d; CIC1280, 4.66 g/d; placebo, g/d). Mean use was reduced by 47.39% (SE 10.10; 95% confidence interval [CI] to 27.38) and 62.54% (SE 9.80; 95% CI, 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, 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, to 12.18) was not statistically significant (p 0.274; Fig 2). Patients in both ciclesonide treatment groups were able to reduce their prednisone dose as early as Table 5 Patient Demographics and Characteristics at Study Entry: ITT Population Variables Placebo (n 45) CIC640 (n 47) CIC1280 (n 48) Gender, No. (%) Male 11 (24.4) 15 (31.9) 18 (37.5) Female 34 (75.6) 32 (68.1) 30 (62.5) Mean (SE) age, yr 48.3 (2.1) 48.3 (2.2) 48.2 (1.7) Range Race, No. (%) White 23 (51.1) 29 (61.7) 26 (54.2) Black 7 (15.6) 6 (12.8) 11 (22.9) Other 15 (33.3) 12 (25.5) 11 (22.9) Mean (SE) duration of asthma, yr (2.69) (2.26) (1.78) Range Mean (SE) prednisone dose, mg/d 12.0 (1.0) 13.6 (1.1) 11.5 (0.9) Asthma characteristics Mean (SE) FEV 1,L (0.065) (0.080) (0.073) Mean (SE) FEV 1, % predicted (1.58) (1.46) (1.87) Mean (SE) morning PEF, L/min (12.03) (12.94) (14.09) Mean (SE) 24-h asthma symptom score 2.32 (0.24) 2.58 (0.22) 2.22 (0.22) Mean (SE) albuterol use, puffs/d 4.86 (0.49) 5.04 (0.41) 4.67 (0.48) Mean (SE) nighttime awakenings 0.71 (0.12) 0.51 (0.09) 0.42 (0.09) 1180 Original Research

6 Figure 2. Mean percentage change in prednisone dose from baseline to study end in patients with severe, persistent asthma receiving treatment with ciclesonide, 320 g bid (CIC640); ciclesonide, 640 g bid (CIC1280); or placebo (PBO). *p vs placebo. p vs placebo. 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 and p 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. Pulmonary Function: There was no significant change from baseline in FEV 1 for either ciclesonide treatment group; however, both groups showed a trend toward higher FEV 1 values. In contrast, FEV 1 values worsened significantly from baseline to end point in the placebo group (95% CI, 0.24 to 0.02). The between-treatment differences in FEV 1 were statistically significant vs placebo for the CIC1280 group (p ; 95% CI, 0.02 to 0.31) and the CIC640 group (p ; 95% CI, 0.02 to 0.31) [Fig 4]. 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, 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 pla- CHEST / 129 / 5/ MAY,

7 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 g bid (CIC640); ciclesonide, 640 g bid (CIC1280); or placebo. CIC640, p 0.05; CIC1280, p 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. cebo group (CIC640, 6 patients [12.8%]; CIC1280, 3 patients [6.3%]; placebo, 13 patients [28.9%]; p ) [Fig 5]. 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%) Original Research

8 Figure 4. Mean (SE) change in FEV 1 over 12 weeks from baseline to end of study (last observation carried forward) in patients with severe asthma receiving treatment with ciclesonide, 320 g bid (CIC640); ciclesonide, 640 g 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). HPA-Axis Evaluation: Unstimulated (basal) mean serum cortisol levels increased significantly from baseline to end point in the CIC640 group (3.58 g/dl [SE 0.97]; 95% CI, 1.66 to 5.51) and the CIC1280 group (2.34 g/dl [SE 1.01]; 95% CI, 0.33 to 4.35). Cortisol levels within the placebo group also rose but not significantly (1.33 g/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 ; CIC1280, p ; Table 6). After stimulation with low-dose cosyntropin (1 g), a significant increase from baseline to end point in low-dose peak serum cortisol levels was seen in the CIC640 group (5.28 g/dl [SE 1.3]; 95% CI, 2.63 to 7.93) and the CIC1280 group (3.55 g/dl [SE 1.3]; 95% CI, 0.95 to 6.14). In contrast, no significant change was observed in the placebo group ( 0.16 g/dl [SE 1.4]; 95% CI, 2.92 to 2.61). This difference vs placebo was statistically significant for the CIC640 treatment group (p ) but not for the CIC1280 group (p ; Table 6). 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 HPAaxis 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 g/d and 1,280 g/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 FEV 1 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 CHEST / 129 / 5/ MAY,

9 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 g/d bid (CIC640); ciclesonide, 640 g/d bid (CIC1280); or placebo. p for both CIC640 and CIC1280 treatment groups compared with placebo. See Figure 2 legend for expansion of abbreviation. 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 OCSsparing studies 8,12 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 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 g bid; Ciclesonide, 640 g bid; or Placebo Variables Placebo CIC640 CIC1280 Basal serum cortisol, g/dl n 32 n 36 n 32 Baseline mean Mean (SE) change from baseline 1.33 (1.006) 3.58 (0.967) 2.34 (1.011) 95% CI Mean (SE) treatment difference vs placebo 2.25 (1.372) 1.01 (1.430) p value vs placebo Low-dose peak serum cortisol, g/dl n 35 n 37 n 40 Baseline mean Mean (SE) change from baseline 0.16 (1.390) 5.28 (1.332) 3.55 (1.304) 95% CI Mean (SE) treatment difference vs placebo 5.43 (1.876) 3.70 (1.891) p value vs placebo Original Research

10 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 al 38 to evaluate the effect of mometasone furoate. The rapid (weekly) stepdown 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 al 12 was only 2 weeks, rather than 4 weeks as in our current study. In a second study 8 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 bioavailability 13,40 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 studies 19,29,41 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 study 23 examining the effects of fluticasone propionate on HPA-axis function found that 9 days of treatment with fluticasone propionate, 500 g (ex-valve), decreased plasma cortisol levels by 29% and the 24-h urinary cortisol profile by approximately 44%, while 1,000 g (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 longterm 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 asthma and, in addition, is associated with minimal local or systemic AEs. 30,33,34 Conclusion In conclusion, the results of this study suggest that twice-daily treatment with inhaled ciclesonide (640 g/d or 1,280 g/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. ACKNOWLEDGMENT: 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; CHEST / 129 / 5/ MAY,

11 van Zyl, Louis; Viljoen, Johann; Wait, Juliette; Weinberg, Eugene; White, Martha; Wyatt, Richard; Yarbrough, John. References 1 National Institutes of Health, National Heart Lung and Blood Institute. National Asthma Education and Prevention Program: expert panel report; guidelines for the diagnosis and management of asthma, update on selected topics J Allergy Clin Immunol 2002; 110(5 Suppl):S141 S29 2 Lazenby JP, Guzzo MR, Harding SM, et al. Oral corticosteroids increase esophageal acid contact times in patients with stable asthma. Chest 2002; 121: Adachi JD. Corticosteroid-induced osteoporosis. Int J Fertil Womens Med 2001; 46: Barnes PJ. Current therapies for asthma: promise and limitations. Chest 1997; 111:17S 26S 5 Lacronique J, Renon D, Georges D, et al. High-dose beclomethasone: oral steroid-sparing effect in severe asthmatic patients. Eur Respir J 1991; 4: O Connell EJ. Efficacy of budesonide in moderate to severe asthma. Clin Ther 2002; 24: Tan WC, Chan TB, Lim TK, et al. The efficacy of high dose inhaled budesonide in replacing oral corticosteroid in Asian patients with chronic asthma. Singapore Med J 1990; 31: Nelson HS, Bernstein IL, Fink J, et al. Oral glucocorticosteroid-sparing effect of budesonide administered by Turbuhaler: a double-blind, placebo-controlled study in adults with moderate-to-severe chronic asthma. Pulmicort Turbuhaler Study Group. Chest 1998; 113: Okamoto LJ, Noonan M, deboisblanc BP, et al. Fluticasone propionate improves quality of life in patients with asthma requiring oral corticosteroids. Ann Allergy Asthma Immunol 1996; 76: McMurtry SA, Nimmagadda SR. High dose inhaled fluticasone propionate improves FEV 1 and results in reduction of oral glucocorticoid dose in glucocorticoid-dependent children with severe asthma. Allergy Asthma Proc 2001; 22: Wenzel SE, Morgan K, Griffin R, et al. Improvement in health care utilization and pulmonary function with fluticasone propionate in patients with steroid-dependent asthma at a national asthma referral center. J Asthma 2001; 38: Nelson HS, Busse WW, deboisblanc BP, et al. Fluticasone propionate powder: oral corticosteroid-sparing effect and improved lung function and quality of life in patients with severe chronic asthma. J Allergy Clin Immunol 1999; 103: Holt PR, Lowndes DW, Smithies E, et al. The effect of an inhaled steroid on the hypothalamic-pituitary-adrenal axis: which tests should be used? Clin Exp Allergy 1990; 20: Pedersen S, Fuglsang G. Urine cortisol excretion in children treated with high doses of inhaled corticosteroids: a comparison of budesonide and beclomethasone. Eur Respir J 1988; 1: Crowley S. Inhaled glucocorticoids and adrenal function: an update. Paediatr Respir Rev 2003; 4: Lipworth B. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: Dietzel K, Engelstatter R, Keller A. Ciclesonide: an on-site activated steroid. Prog Respir Res 2001; 31: Drollmann A, Langdon C, Engelstaetter R, et al. Ciclesonide is effective in the treatment of bronchial asthma. Eur Respir J 2001; 18:S94 19 Chapman K, Patel P, Boulet L, et al. Efficacy and long-term safety of ciclesonide in asthmatic patients as demonstrated in a 52-week long study. Eur Respir J 2002; 20(suppl 38):373s 374s 20 Engelstatter R, Benezet O, Kafe H, et al. Comparative study in asthma patients treated with inhaled ciclesonide (80 mcg or 320 mcg once daily) for 12 weeks [abstract]. Am J Respir Crit Care Med 2003; 167:A Biberger C. Efficacy and safety of ciclesonide compared with budesonide in asthma patients: a randomized 12-week study [abstract]. Am J Respir Crit Care Med 2003; 167:A Boulet L, Engelstaetter R, Magyar P, et al. Ciclesonide is at least as effective as budesonide in the treatment of patients with bronchial asthma [abstract]. Am J Respir Crit Care Med 2003; 167:A Derom E, Van de Velde V, Marissens S, et al. Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5 monophosphate in asthmatic patients. Pulm Pharmacol Ther 2005; 18: Buhl R, Vinkler I, Magyar P, et al. Once daily ciclesonide is as effective as fluticasone propionate given twice daily in treating patients with asthma [abstract]. Am J Respir Crit Care Med 2004; 169:A91 25 Taylor DA, Jensen MW, Kanabar V, et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5 -monophosphate in asthmatic patients. Am J Respir Crit Care Med 1999; 160: Kanniess F, Richter K, Bohme S, et al. Effect of inhaled ciclesonide on airway responsiveness to inhaled AMP, the composition of induced sputum and exhaled nitric oxide in patients with mild asthma. Pulm Pharmacol Ther 2001; 14: Lee DK, Haggart K, Currie GP, et al. Effects of hydrofluoroalkane formulations of ciclesonide 400 microgram once daily vs fluticasone 250 microgram twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Br J Clin Pharmacol 2004; 58: Larsen BB, Nielsen LP, Engelstatter R, et al. Effect of ciclesonide on allergen challenge in subjects with bronchial asthma. Allergy 2003; 58: Postma DS, Sevette C, Martinat Y, et al. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Respir J 2001; 17: Weinbrenner A, Huneke D, Zschiesche M, et al. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab 2002; 87: Nave R, Bethke T, Marle SV, et al. Pharmacokinetics of [14C] ciclesonide after oral and intravenous administration to healthy subjects. Clin Pharmacokinetics 2004; 43: Rohatagi S, Luo Y, Shen L, et al. Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther 2005; 12: Nave R, Zech K, Bethke TD. Lower oropharyngeal deposition of inhaled ciclesonide via hydrofluoroalkane metered-dose inhaler compared with budesonide via chlorofluorocarbon metereddose inhaler in healthy subjects. Eur J Clin Pharmacol 2005; 61: Richter K, Kanniess F, Biberger C, et al. Comparison of the oropharyngeal deposition of inhaled ciclesonide and fluticasone propionate in patients with asthma. J Clin Pharmacol 2005; 45: Bousquet J. Global Initiative for Asthma (GINA) and its objectives. Clin Exp Allergy 2000; 30(suppl 1): Casale TB, Nelson HS, Stricker WE, et al. Suppression of 1186 Original Research

12 hypothalamic-pituitary-adrenal axis activity with inhaled flunisolide and fluticasone propionate in adult asthma patients. Ann Allergy Asthma Immunol 2001; 87: Ringdal N, Lundback B, Alton M, et al. Comparable effects of inhaled fluticasone propionate and budesonide on the HPAaxis in adult asthmatic patients. Respir Med 2000; 94: Fish JE, Karpel JP, Craig TJ, et al. Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma. J Allergy Clin Immunol 2000; 106: Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. National Institutes of Health, National Heart, Lung, and Blood Institute NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health, 2002; publication Brown PH, Blundell G, Greening AP, et al. High dose inhaled steroid therapy and the cortisol stress response to acute severe asthma. Respir Med 1992; 86: Lipworth B, Kaliner M, LaForce C, et al. Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal axis function in adults with mild-to-moderate persistent asthma. Ann Allergy Asthma Immunol 2005; 94: Belvisi MG, Brown TJ, Wicks S, et al. New glucocorticosteroids with an improved therapeutic ratio? Pulm Pharmacol Ther 2001; 14: CHEST / 129 / 5/ MAY,