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Assessment of the Long-term Safety of Inhaled Ciclesonide on Growth in Children With Asthma

^a Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pennsylvania
^b Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania
^c Sanatorio San José, Fundacion Cidea, Buenos Aires, Argentina
^d sanofi-aventis US, Bridgewater, New Jersey

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 
OBJECTIVE. To assess the effects of the new inhaled corticosteroid ciclesonide on growth in children with asthma.

METHODS. We performed a multicenter, randomized, double-blind, placebo-controlled study to assess the effects of inhaled ciclesonide on growth in children with mild, persistent asthma. After a 6-month run-in period, 661 prepubertal children who were aged 5.0 to 8.5 years were randomly assigned to once-daily morning treatment for 1 year with ciclesonide 40 or 160 µg (ex-actuator) or placebo, followed by a 2-month follow-up period. The primary end point was the linear growth velocity (linear regression estimate) over the double-blind treatment period. Growth was recorded as the median of 4 stadiometer measurements. Adverse events and 10-hour overnight and 24-hour urinary free cortisol levels were also assessed.

RESULTS. Mean linear growth velocity during run-in was comparable between groups: 160 µg, 6.20 cm/year; 40 µg, 6.59 cm/year; placebo, 6.49 cm/year. Mean differences from placebo (5.75 cm/year) in growth velocity over the double-blind treatment period were –0.02 cm/year for ciclesonide 40 µg and –0.15 cm/year for ciclesonide 160 µg. Both ciclesonide treatments were noninferior to placebo with respect to growth velocity. The overall incidence of adverse events was comparable between groups, and no significant changes in 10-hour overnight or 24-hour urinary free cortisol levels were noted between groups during the double-blind treatment period.

CONCLUSIONS. Ciclesonide demonstrated no detectable effect on childhood growth velocity, even at the highest dosage, which may ease concerns about systemic adverse events.

Key Words: inhaled corticosteroids • ciclesonide • childhood growth • safety • hypothalamic-pituitary-adrenal axis

Abbreviations: ICS—inhaled corticosteroid • FDA—Food and Drug Administration • AE—adverse event • FEV₁—forced expiratory volume in 1 second • MDI—metered-dose inhaler • HFA—hydrofluoroalkane • CIC40—ciclesonide 40 µg/day • CIC160—ciclesonide 160 µg/day • CI—confidence interval • mITT—modified intention-to-treat • ANCOVA—analysis of covariance

Inhaled corticosteroids (ICS), which reduce both the morbidity and the mortality that are associated with asthma,¹ are recommended as first-line therapy for persistent asthma of all severities.^2,3 Consequently, ICS have become more widely used, often commencing in children aged <5 years, and for long, seamless periods⁴; however, a potential safety concern of ICS use in children is growth suppression, which may limit appropriate ICS use by physicians and individuals and, thus, the attainable therapeutic benefits. Such effects, however, are potentially transient, affording no effect on finally attained adult height.⁵

In 1998, the Food and Drug Administration (FDA) reviewed all inhaled and intranasal corticosteroid growth studies in pediatric patients. All marketed ICS showed evidence of a small effect on growth in studies with major design flaws.⁶ As a result, precautionary labeling regarding growth suppression was implemented for the entire class, and a draft guidance for the conduct of future growth studies was issued.⁷

Ciclesonide, a novel ICS that is activated by esterases in the lungs, has low oral bioavailability, rapid elimination, and high plasma protein binding.^8–10 Studies in children^11–13 with mild, moderate, and severe persistent asthma demonstrated efficacy with ciclesonide with minimal systemic and oropharyngeal adverse events (AEs). In this study, we report the effect of once-daily ciclesonide for 1 year on growth and other safety parameters in prepubertal children with mild, persistent asthma.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 
Patients
Female and male children who were aged 5.0 to 7.5 and 5.0 to 8.5 years, respectively, and had a diagnosis of mild, persistent asthma³ for 3 months before screening and a forced expiratory volume in 1 second (FEV₁) of 80% predicted (after 4-hour albuterol withhold) were enrolled. Patients were required to demonstrate effective use of the metered-dose inhaler (MDI) devices for inclusion; patients who were unable to or who refused to use study devices as required were excluded from the study. At visit 3, patients received single-blind placebo (via MDI without spacer) to practice correct dosing technique. Correct dosing technique also had to be demonstrated in front of the investigator at randomization (visit 4) and was again assessed at all study visits. Other inclusion criteria were Tanner stage 1, normal height (5th–95th percentiles inclusive) at screening, and growth velocity at the third percentile or more during the 6-month run-in period. Patients who were using noncorticosteroid asthma medication on an as-needed or daily basis or low ICS dosages were included. Patients with the following previous medication use were excluded: any ICS within 30 days before screening, at a dosage exceeding fluticasone propionate 100 µg/day or equivalent², or previous daily or alternate-day oral corticosteroid treatment for a total of >60 days within 2 years before visit 3 or within 30 days before screening.

At screening, previous steroidal therapy was discontinued, and, as per treatment guidelines, all patients had access to albuterol as needed for temporary symptom relief.^2,3 When asthma symptoms were unresponsive to nonsteroidal medications, patients were permitted limited inhaled or intranasal corticosteroid treatments. Any patient who received >2 14-day courses of intranasal corticosteroids (which had to be separated by 3 months) or ICS treatment for >14 days during the run-in period were to be excluded from the study. No oral corticosteroids were permitted during the run-in period, and no corticosteroids (oral, intranasal or inhaled) other than study medication were permitted during the double-blind treatment period. The following asthma medications were permitted as needed during the run-in and double-blind treatment periods: inhaled short-acting β-agonists, leukotriene receptor antagonists, chromones, and xanthine derivatives.

Written informed consent was obtained from patients' parents or legal guardians. All protocol and informed consent forms were approved by an independent institutional review board. The study was conducted in accordance with the principles of the Declaration of Helsinki and its amendments and the guidelines of good clinical practice.

Study Design
This randomized, double-blind, multicenter, placebo-controlled, parallel-group study consisted of 3 phases (run-in, double-blind treatment, and follow-up) and 14 visits (Fig 1). The run-in period lasted 6 months. Patients who fulfilled the enrollment criteria were then randomly assigned to double-blind study treatment with ciclesonide (administered via hydrofluoroalkane [HFA] MDI without a spacer) 40 µg (CIC40), ciclesonide 160 µg (CIC160; all dosages ex-actuator), or placebo, once daily in the morning for 12 months. Compliance to study medication was monitored via patient diaries and also by canister weight (measured before dispensing of medication [visits 3–12] and on next visit [visits 4–13]), both of which were reviewed by study personnel at each visit. A patient was considered to be compliant on a given day when he or she took the study medication as per protocol (ie, 1 puff in the morning) for that given day. Patients who had poor compliance (<85%) or who were noncompliant on 5 consecutive days were counseled by physicians to improve adherence; when noncompliance was further anticipated or demonstrated, patients could be withdrawn from the study.

View larger version (18K): [in this window] [in a new window]   FIGURE 1 Study design. a Albuterol taken as needed for asthma control; b no corticosteroids (oral, intranasal, or inhaled) other than study medication were permitted during the double-blind treatment period; c during the qualification phase, subjects received single-blind placebo to practice proper dosing technique (subject compliance was monitored at all study visits and via telephone calls at months 5, 7, 9, and 11). qd indicates once daily; AM, in the morning.

Growth Data
All investigators were provided with detailed written and visual instructions, took part in onsite training, and attended workshops before study initiation to standardize stadiometer measurements. In addition, the majority of investigators had previous experience with Harpenden stadiometers. Study centers were supplied with identical Harpenden stadiometers, which were calibrated within 4 hours of each measurement, and height was measured at all visits using standard techniques.¹⁴ Measurements were taken by a trained technician, with an effort to use the same technician at each visit. The median of 4 acceptable serial measurements was used in the analysis. The primary estimate of growth velocity was the linear regression estimate of the slope of the linear regression height versus time line (during double-blind treatment) using all (3) available height measurements. Baseline growth velocity was calculated as the linear regression estimate of growth velocity during the 6-month run-in period.

Safety Data
Urine samples were collected for 24-hour (39 centers) and 10-hour overnight (36 centers) cortisol measurements (corrected and uncorrected for creatinine) at visits 3 (before randomization) and 13 (after completion of double-blind treatment; Appendix 1).^15,16 Patients were instructed to report AEs in their diaries. Periodically throughout the study, physical examinations were conducted and Tanner staging, vital signs, and body weight were monitored. Oropharyngeal examinations were performed, and suspected cases of oral candidiasis were verified by culture in a central laboratory. Bone age was assessed in a blinded manner using wrist radiographs.¹⁷ Spirometry (FEV₁) was conducted¹⁸ in the morning, 24 (±1) hours after the previous dose of study medication, and after albuterol withhold for 4 hours to monitor pulmonary function.

Statistical and Analytical Procedures
A sample size of at least 405 patients (135 patients per treatment group) was estimated, assuming a SD of 1.4 cm/year, to show a noninferiority of 0.5 cm/year (per draft industry guidance recommendations and a previous study)^7,19 with 90% power, based on a 95% 1-sided confidence interval (CI). All growth analyses were conducted by using the modified intention-to-treat (mITT) population, which included all randomly assigned patients who completed 4 months of study treatment and who had stadiometry measurements at baseline and 4 months.

The primary end point was growth velocity during double-blind treatment, assessed by using an analysis of covariance (ANCOVA) model of the linear-regression estimate of growth velocity for the mITT population. All height observations that were measured before either treatment discontinuation or progression beyond Tanner stage 1 were included. The ANCOVA model included factors for treatment, pooled center, baseline growth velocity, height at randomization, age and age² (age = age at randomization), gender, gender-by-age interaction, race, previous corticosteroid use, and the age at which asthma was first diagnosed. The noninferiority of ciclesonide was assessed by comparing both ciclesonide dosages against placebo using a 2-sided 95% CI.

Secondary end points were shift analyses of change in growth velocity percentile²⁰; shift analyses of the ratio of chronologic age to an extended bone age range (lower limit: –1; upper limit: +1; treatment comparisons made using a ² test); and change from baseline in stadiometer height (ANCOVA).

Patients who received 1 dose of study medication were included in the safety population (AE reporting and cortisol measurements). Changes in urinary cortisol levels were assessed using an ANCOVA model, and 95% CIs were calculated.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 
Patients
A total of 1127 patients were screened at 85 centers in 4 countries (United States [63 centers], Argentina [12 centers], Venezuela [6 centers], and Chile [4 centers]). Of these, 661 fulfilled the enrollment criteria and were randomly assigned to receive treatment (safety population; CIC40: n = 221; CIC160: n = 219; placebo: n = 221; first patient enrolled on December 29, 2000; last patient intervention on September 15, 2004; Appendix 2). A total of 111 patients discontinued double-blind treatment (CIC40: 18.1%; CIC160: 14.2%; placebo: 18.1%). The most common reason for study discontinuation in all treatment groups was AEs (CIC40: 6.3%; CIC160: 3.7%; placebo: 6.3%), of which worsening asthma was the most frequent (CIC40: 5.4%; CIC160: 2.7%; placebo: 4.1%). Fifty-two patients did not receive 4 months' treatment or did not have valid (prebaseline and postbaseline) height measurements for 4 months, resulting in a total of 609 patients in the mITT population (CIC40: n = 206; CIC160: n = 202; placebo: n = 201). Overall, 16 patients in the mITT population discontinued the study because of either a lack of efficacy or an asthma-related AE (CIC40: 3.9%; CIC160: 2.0%; placebo: 2.0%). Leukotriene receptor antagonists were used by approximately half of the patients (safety population) during double-blind treatment (CIC40: n = 125; CIC160: n = 118; placebo: n = 125). Overall, 25 of the randomly assigned patients used oral corticosteroids during double-blind treatment (CIC40: n = 10; CIC160: n = 4; placebo: n = 11), and the majority of these patients were discontinued from the study (n = 20).

Baseline growth velocity was slightly lower in the CIC160 treatment group compared with the other groups, although this difference was not significant (Table 1). Compliance with treatment was high (Appendix 3); the percentage of patients who achieved >85% compliance was comparable across treatment groups, as assessed by diaries (93.7%–99.1%) and canister weight (79.6%–81.9%).

View larger version (18K): [in this window] [in a new window]   FIGURE 2 Growth analyses (mITT population). A, Cumulative distribution of growth velocity for CIC40, CIC160, and placebo during double-blind treatment. B, Mean change in stadiometer height (cm) from baseline. a Subjects were monitored for 6 months before double-blind treatment initiation at month 0 (baseline).

View larger version (24K): [in this window] [in a new window]   FIGURE 3 Scatter plots of growth velocity during the double-blind treatment versus baseline for individual subjects (mITT population). For reference, diagonal lines indicate x = y. A, Placebo; B, CIC40; C, CIC160.

Safety
Hypothalamic-Pituitary-Adrenal Axis Function
Cortisol levels at the end of double-blind treatment were comparable with those at baseline. No statistically significant differences between treatment groups were observed for the mean change from baseline to the end of double-blind treatment in 24-hour and 10-hour overnight urinary free cortisol levels (Appendix 8).

Adverse Events
Both ciclesonide dosages were well tolerated. The overall incidence of treatment-emergent AEs was comparable among treatment groups (CIC40: 94.6%; CIC160: 90.0%; placebo: 89.6%). Cases of oral candidiasis (CIC40: 0%; CIC160: 0%; placebo: 0.5%), pharyngitis (CIC40: 19.9%; CIC160: 16.9%; placebo: 19.0%), and hoarseness (no cases reported) were comparable between groups. No oropharyngeal AEs were considered related to study medication. Only 3 patients experienced treatment-emergent AEs that were considered possibly related to study medication: abnormal behavior (CIC40); idiopathic thrombocytopenic purpura (CIC40); and precocious puberty (placebo).

No clinically relevant differences in vital signs, body weight, BMI (Appendix 9), or physical examinations were observed among treatment groups. Three patients (1 per group) had progressed to Tanner stage >1.

Pulmonary Function
FEV₁ was maintained in all groups during the study period. Treatment groups experienced similar mean (± SE) changes in FEV₁ (L) from baseline to study end (CIC40: 0.126 ± 0.014; CIC160: 0.150 ± 0.011; placebo: 0.124 ± 0.015).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 
This study, which incorporates many of the current growth study design recommendations,⁷ demonstrated conclusively that ciclesonide was noninferior to placebo with respect to growth, showing no detectable effect on the 1-year growth rate of children with mild, persistent asthma. In previous studies,^21,22 ICS have been associated with an early growth effect that decreased with time; however, no such effect was observed with ciclesonide, as shown by data from month 3. In addition, the importance of a long run-in period was illustrated: the slightly lower growth velocity in the CIC160 group during double-blind treatment had already been noted in that group at baseline. It is also notable that the mean outcomes from the study for each treatment group seem to be applicable to individual patients per group; very few patients with extreme growth velocities were noted throughout the study period in any group (Appendix 5). In addition, mild asthma has been reported as the most prevalent severity of the disease among children^23,24; as such, results from this study are particularly relevant to pediatricians in their everyday practice. Prudence should be taken, however, when extrapolating these results to patients with moderate or severe asthma.

In the context of currently available ICS, it is notable that each has demonstrated growth suppression to a small degree,⁶ which is reflected in current labeling information^25,26; therefore, a lack of effect with ciclesonide could be considered surprising. This is especially true when considering the rigorous study design parameters incorporated into this trial compared with earlier studies. This suggestion raises the possibility that ciclesonide may actually cause a growth effect that was not detected in this study, potentially as a result of low adherence or poor inhalation technique (without a spacer), resulting in low lung deposition; however, these possibilities are very unlikely. Given the limitations of all compliance measures, adherence rates that were reported in this study using 2 different methods were excellent. Moreover, patients needed to demonstrate adequate inhaler technique and, therefore, pulmonary deposition to enter and remain in the trial. The lack of spacer use is consistent with study design recommendations,⁷ because their use can alter lung deposition and, consequently, the systemic bioavailability compared with that achieved by the agent administered without spacer device.^27,28 In addition, 2 separate studies of ciclesonide in children with asthma, during which the efficacy of ciclesonide 160 µg/day was demonstrated without the use of a spacer,^11,12 support good lung delivery from the device, potentially as a result of its formulation as a solution HFA MDI, relatively high pulmonary deposition (52% in adults),²⁹ and small particle size (1.1–2.1 µm).³⁰ Furthermore, a recent study in adults demonstrated that the pharmacokinetic/pharmacodynamic profile of ciclesonide is unaltered when inhaled either with or without a spacer.³¹ With good adherence and inhalation technique, and thus no need for a spacer, systemic activity and growth suppression with ciclesonide could potentially be expected unless there were additional, mitigating pharmacokinetic/pharmacodynamic factors. Such factors have been reported for ciclesonide, including a high degree of plasma protein binding (resulting in a low concentration of pharmacologically active drug systemically available), low oral bioavailability, and rapid apparent clearance.^8–10 In support of the low systemic effect of ciclesonide, this study also showed no effect on urinary cortisol levels, and previous studies showed a lack of effect on short-term lower leg growth rate (assessed by knemometry)³² and HPA axis function.^11–13,32

A positive efficacy signal would have supported the assertion that adherence and inhaler technique were good in this study; however, no efficacy signal for changes in FEV₁ was detected. This most likely relates to the study design and mild severity of patients' asthma (FEV₁ 80% predicted), allowing minimal opportunity for improvement with any treatment. Patients with mild asthma were included as per strict guidance published by the FDA on the conduct of growth studies with ICS⁷ and to minimize any confounding growth effect as a result of poor disease control and/or oral corticosteroid use. Moreover, because of ethical considerations and the usual patient attrition rates in studies of this length, the use of nonsteroidal medications, such as montelukast, for asthma control was permitted as required. This would be expected to maintain the lung function of placebo-treated children and lessen the magnitude of any efficacy signal from ciclesonide. These factors likely resulted in the observed low rate of discontinuation as a result of lack of efficacy or asthma exacerbations in all treatment groups. Importantly, however, as previously mentioned, ciclesonide 160 µg/day has demonstrated efficacy in children with greater disease severity than those in this study,^11,12 indicating that an adequate dosage to provide efficacy was administered in this study.

The benefits of enrolling patients with mild asthma in a safety study could, however, also be interpreted as a potential limitation. Asthma diagnosis was based on patient history, previous asthma medication use at screening (Table 1), physical examination, and lung-function measurements, including FEV₁; however, FEV₁ reversibility after β₂-agonist was not assessed for study entry as is normally required for efficacy trials. Such a criterion would be difficult to impose in young children and would have made recruitment for such a large study even more difficult. One could argue that some patients may have had mild intermittent asthma. Such factors, however, are unlikely to have influenced our study results. The recommended population included in this study,⁷ namely prepubertal rather than pubertal children^5,33 and patients with mild rather than severe asthma,^34,35 could in fact be expected to be the most susceptible to systemic AEs of ICS. Previous studies have suggested that healthy individuals or those with milder forms of asthma are more susceptible to systemic effects from ICS, potentially as a result of greater deposition and absorption of ICSs from the lungs.^34,35 Thus, the study population, even in the unlikely event that it included some patients with mild, intermittent asthma, likely had the highest risk for systemic bioavailability and growth suppression and may in fact represent a "worst-case scenario" for ciclesonide 40 and 160 µg/day with regard to growth suppression.

Confidence in the result of this study may have been heightened by the inclusion of an active control agent with a documented growth effect (ie, old ICS). Detection of such an effect would have proved that the study design and methods were capable of finding an effect if one existed. This study was designed according to the FDA guidance on the conduct of growth studies⁷ and thus should have had the capability to detect an effect. To include an active control, it would ideally be delivered with the same device, formulation, and propellant as the test drug (ie, solution HFA MDI) to control for potential differences in adherence and airway delivery across devices. Such a control was not available at the time that this study was conducted; therefore, detecting a suppressive effect on growth from another ICS delivered with a different device would not have guaranteed that any signal from ciclesonide would be detected. Moreover, inclusion of a positive control would have required more study patients, and the relatively steroid-naive patients needed for such studies are increasingly difficult to find given recommendations for first-line ICS use in national and international guidelines.^2,3 Despite these limitations, these results strongly support the safety of ciclesonide with regard to growth suppression, at a dosage previously shown to be effective in children.^11,12 Taken together, these observations support the adequate use of an effective dosage of ciclesonide that did not elicit growth suppression, rather than a false-negative result.

The slight slowing of growth rates during the double-blind treatment period compared with the run-in period, which was noted in all 3 groups to a similar degree, may have been attributable to several reasons. The first and most likely is that it was attributable to the normal slowing of growth rates in prepubertal children as they approach puberty.³⁶ Furthermore, deceleration in growth velocity before puberty may be heightened in children with asthma by a delayed onset of puberty.^37,38 During this study, the mean growth velocity of the total population was shown to be slowing even during the run-in period, before double-blind treatment. A recent growth study by Becker et al³⁹ that incorporated a 16-week run-in period also showed a slight slowing of growth rates in all treatment groups (placebo, montelukast, and beclomethasone dipropionate) from run-in to double-blind treatment periods.

The second possibility is that the population underwent a brief growth acceleration on entry into the study either as a result of discontinuation of a previous ICS or as a result of improved health care on randomization into the study; however, these possibilities are questionable because of the limited number of patients on ICS before study entry (Table 1) and also the lack of information regarding differences in prestudy and poststudy health care that could lead to such a marked increase in growth velocity. Finally, it could be suggested that there was a growth slowing in all 3 groups during the double-blind period caused by a constituent of the delivery formulation used for all 3 treatments (ie, HFA MDI); however, there is no previous scientific evidence for this effect,⁴⁰ and many patients' growth velocity accelerated during the double-blind period (Fig 3), reducing the plausibility of a negative effect on growth caused by a constituent of the formulation.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 
The findings reported in this study show that treatment with once-daily inhaled ciclesonide (40 and 160 µg) during a period of 12 months had no clinically or statistically significant effect on growth velocity versus placebo in children with mild, persistent asthma. This observation, which was noted even with the highest studied dosage of ciclesonide and with a dosing regimen that has previously been shown to be effective in treating asthma,¹² may ease concerns about ICS-related systemic AEs and encourage their appropriate use in children.

	APPENDIX 1 Study Visit Schedule

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 

	APPENDIX 2

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

View larger version (30K): [in this window] [in a new window]   Patient disposition throughout study.a The mITT population included all randomly assigned subjects who completed 4 months of study treatment and had valid stadiometry measurements at baseline and 4 months.

	APPENDIX 3

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

View larger version (18K): [in this window] [in a new window]   Compliance to study medication the during double-blind treatment period. A, Compliance rates via subject diary cards. B, Compliance rates via canister weight. a Compliance rates from subject diaries were calculated by using the following equation: (total number of puffs inhaled during double-blind treatment)/([date of last dose of study medication – date of first dose of study medication] + 1); compliance rates from canister weight were calculated by using the following equation: (total number of puffs inhaled based on canister weight difference)/(total number of study days); for both calculations the compliance rate could be >100% if the number of puffs exceeded the number of study days (ie, the prescribed dosing regimen was exceeded).

	APPENDIX 4 Ranges of 4 Stadiometer Height Measurements Over All Visits According to Country (mITT Population)

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

	APPENDIX 5 Growth Velocity During the Double-blind Treatment Period (Linear Regression Estimate) Relative to Normal Percentiles (mITT Population)

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

	APPENDIX 6

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

View larger version (11K): [in this window] [in a new window]   Change in mean stadiometer height (cm) over time (mITT population).

	APPENDIX 7 Shifts in Chronologic Age to Bone Age Ratio From Baseline to End of the Double-blind Treatment Period

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

	APPENDIX 8 Change From Baseline to Study End in 24- and 10-Hour Urinary Free Cortisol Levels

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

	APPENDIX 9 Change From Baseline to Study End in Weight and BMI

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

	ACKNOWLEDGMENTS

 
Financial support for this study was provided by sanofi-aventis US and Altana Pharma US, Inc, a Nycomed company.

We thank the following investigators in the Ciclesonide Pediatric Growth Study Group for participation in the study: R. Ahrens (University of Iowa, Iowa City, IA); O. Aldrey (Instituto Medico La Floresta, Caracas, Venezuela); D. Atkinson (Oklahoma Allergy and Asthma Clinic, Oklahoma City, OK); J. Baker (Allergy, Asthma and Dermatology Research Center, Lake Oswego, OR); A. Balanzat (Hospital de Clinicas de la Universidad de Buenos Aires, Buenos Aires, Argentina); C. Banov (National Allergy, Asthma and Urticaria Centers of Charleston, Charleston, SC); M. Baz (ABM Research Institute, Fresno, CA); G. Bensch (Bensch Research Associates, Stockton, CA); G. Berman (Clinical Research Institute, Minneapolis, MN); D. Bernstein (Bernstein Clinical Research Center, LLC, Cincinnati, OH); L. Bielory (University of Medicine and Dentistry of New Jersey, Division of Allergy/Immunology, Newark, NJ); M. Blumberg (Virginia Adult and Pediatric Allergy and Asthma, Richmond, VA); P. Boggs (Allergy-Asthma Clinic, Shreveport, LA); D. Bukstein (Medical Center, Madison, WI); C. Baena-Cagnani (Hospital Infantil de Cordoba, Cordoba, Argentina); F. Caballero-Fonseca (Centro Medico Caracas, San Bernardino, Caracas, Venezuela); E. Campbell (National Clinical Resources, Inc, Salt Lake City, UT); A. Capriles (Hospital Pediatrico San Juan de Dios, Municipio Baruta, Caracas, Venezuela); R. Coifman (Allergy and Asthma of South Jersey, PA, Millville, NJ); R. Covar (National Jewish Hospital, Denver, CO); C. Crisci (Clinica del Torax, Rosario, Argentina); V. Croce (Instituto de Alergia e Inmunopatologia Infantil, Cordoba, Argentina); C. Daul (Clinical Research Specialists, Metairie, LA); A. Davidson (Allergy and Asthma Consultants, LLP, Mt Pleasant, SC); D. Dreyfus and Christopher Randolph, MD (Waterbury, CT); F. Ferrero (Hospital General de Ninos "Pedro de Elizalde," Buenos Aires, Argentina); J. Fink (Medical College of Wisconsin, Milwaukee, WI); L. Ford (Asthma and Allergy Center, PC, Papillion, NE); B. Friedman (Allergy, Asthma and Clinical Immunology, Adult and Pediatric, Fountain Valley, CA); S. Galant (Clinical Trials of Orange County, Orange, CA); E. Gatti (Delaware Valley Clinical Research, Cherry Hill, NJ); S. Gawchik (Asthma and Allergy Research Associates, Upland, PA); D. Geller (Nemours Children's Clinic, Orlando, FL); S. Gillman (CHOC PSF Division of Allergy, Asthma, and Immunology, Orange, CA); G. Girardi (Hospital Exequiel Gonzales Cortes, San Miguel, Santiago, Chile); J. Given (Allergy and Respiratory Center, Canton, OH); P. Goldberg (Clinical Research Center of Indiana, Indianapolis, IN); F. Grogan (Allergy and Asthma Care, Germantown, TN); R. Grubbe (Center of Research Excellence, LLC, Oxford, AL); J. Harris (South Bend Clinic, South Bend, IN); O. Herrera (Hospital Luis Calvo Mackenna, Providencia, Santiago, Chile); G. Hudes (Montefiore Medical Park, Bronx, NY); A.-M. Irani (Children's Medical Center, Richmond, VA); E. Keklikian (Hospital Frances, Buenos Aires, Argentina); E. Kent, Jr (Timber Lane Allergy and Asthma Associates, South Burlington, VT); E. Kerwin (Clinical Research Institute of Southern Oregon, LLC, Medford, OR); K. Kim (West Coast Clinical Trials, Inc, Long Beach, CA); W. Kniker (Allergy and Asthma Research Center, PA, San Antonio, TX); P. Konig (Peds Specialty-University Physicians, Columbia, MO); M. Kraemer (Spokane Allergy and Asthma Clinical Research, Spokane, WA); A. Levy (Spartanburg Pharmaceutical Research, Spartanburg, SC); P. LoGalbo (Long Island Jewish Medical Center, New Hyde Park, NY); C. Maccia (Allergy Asthma Care Clinical Research Center, Warren, NJ); T. Mahr (Gunderson Clinic Ltd Pediatric Allergy/Immunology, La Crosse, WI); S. Malka (Hospital de Clinicas Caracas, San Bernardino, Caracas, Venezuela); J. Mallol (Clasificador 23, Correo 9, Providencia, Santiago, Chile); L. Mansfield (El Paso Institute for Medical Research and Development, El Paso, TX); B. Martin (Southwest Allergy and Asthma Center, San Antonio, TX); I. Melamed (First Allergy and Clinical Research Center, Englewood, CO); S. Meltzer (Allergy and Asthma Care Center, Long Beach, CA); K. Murphy (Midwest Allergy and Asthma Clinic, Omaha, NE); A. Nayak (ICSL-Clinical Studies, Bloomington, IL); H. Neffen (Centro de Alergia e Inmunologia, Santa Fe, Argentina); M. Noonan (Allergy Associates Research Center, LLC, Portland, OR); R. Onder (Allergy, Asthma and Internal Medicine, St Louis, MO); A. Patel (Integrated Research Group, Corona, CA); A. Patel (Academy Allergy, Asthma, Immunology Center, Pueblo, CO); A. Perez (Urologico San Roman, Caracas, Venezuela); B. Pfuetze (Multi-Specialty Clinical Research, Overland Park, KS); P. Ratner (Sylvana Research, San Antonio, TX); W. Rees (PI-Coor Clinical Research, LLC, Burke, VA); D. Ricker (Pediatrics Northwest, Tacoma, WA); R. Rosenberg (NTouch Research Corp, Decatur, GA); A. Ruben Cavallo (Hospital de Ninos de San Roque, Parana, Argentina); M. Ruff (Pharmaceutical Research and Consulting, Inc, Dallas, TX); G. Salazar (Sun Research Institute, San Antonio, TX); M. Sanchez, Clinica El Avila, Caracas, Venezuela); M. Sanjurjo (Hospital Cetrangolo, Buenos Aires, Argentina); F. Sauceda (Quality Assurance Research Center, San Antonio, TX); E. Schenkel (Valley Clinical Research Center, Easton, PA); N. Segall (Clinical Research Atlanta, Stockbridge, GA); L. Sher (Peninsula Research Associates, Rolling Hills Estates, CA); W. Sinclair (Montana Medical Research, Missoula, MT); J. Stahlman (Allergy and Asthma Clinical Research, Lawrenceville, GA); G. Stewart II (Allergy and Asthma Care of Florida, Ocala, FL); R. Stoloff (Adult/Pediatric Asthma and Allergy, Plattsburgh, NY); A. Teper (Hospital de Ninos Ricardo Gutierrez, Buenos Aires, Argentina); C. Ubilla (Hospital Roberto del Rio, Santiago, Chile); J. Wald (Kansas City Allergy and Asthma Associates, Overland Park, KS); R. Wasserman Pediatric Allergy/Immunology Associates, Dallas, TX); J. Winder (Toledo Center for Clinical Research, Sylvania, OH); and A. Yanez (Hospital Aeronautico-Bueno Aires, Buenos Aires, Argentina.

We also thank S. Kundu, PhD, and M. Lloyd, BS, of Sanofi-Aventis US (Bridgewater, NJ) for contributions to the study and Andrew Owen, MSc, Medicus International, for editorial assistance.

	FOOTNOTES

 
Accepted Jun 8, 2007.

Address correspondence to David P. Skoner, MD, Allegheny General Hospital, Department of Pediatrics, 320 E North Ave, South Tower, Seventh Floor, Pittsburgh, PA 15212. E-mail: dskoner{at}wpahs.org

This trial has been registered at www.clinicaltrials.gov (identifier NCT00270348).

Financial Disclosure: Dr Skoner has served on speakers' bureaus for AstraZeneca, Aventis Pharmaceuticals (sanofi-aventis US), GlaxoSmithKline, Merck & Co, Inc, Schering Plough Laboratories, Inc, and Novartis Pharmaceuticals Corp has received grant support from AstraZeneca, Aventis Pharmaceuticals (sanofi-aventis US), GlaxoSmithKline, Novartis Pharmaceuticals Corp, and Merck & Co, Inc, and has served as a consultant to Merck & Co, Inc; Dr Maspero has served on the advisory board for Merck & Co, Inc, and GlaxoSmithKline, has received grant support from Merck & Co, Inc, and has conducted clinical research for Merck & Co, Inc, GlaxoSmithKline, Schering Plough Laboratories, Inc, Novartis Pharmaceuticals Corp, Pfizer, Aventis Pharmaceuticals (sanofi-aventis US), AstraZeneca, and Altana Pharma US, Inc, a Nycomed company; and Dr Banerji is employed by sanofi-aventis.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1 Study Visit... APPENDIX 2 APPENDIX 3 APPENDIX 4 Ranges of... APPENDIX 5 Growth Velocity... APPENDIX 6 APPENDIX 7 Shifts in... APPENDIX 8 Change From... APPENDIX 9 Change From... REFERENCES

 

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