Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid dependent, persistent asthma

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1 Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid dependent, persistent asthma Gail Shapiro, MD, a Louis Mendelson, MD, b Michael J. Kraemer, MD, c Mario Cruz-Rivera, PhD, MPH, d and Karen Walton-Bowen, MSc, Cstat, d and Joseph A. Smith, MD d Seattle and Spokane, Wash, West Hartford, Conn, and Westborough, Mass Background: Inhaled glucocorticosteroids are indicated for the treatment of persistent asthma; however, many young children are unable to effectively use currently available inhalers. Objective: We sought to evaluate the efficacy and safety of 3 different twice daily doses of budesonide inhalation suspension (Pulmicort Respules) in inhaled steroid dependent asthmatic children. Methods: This was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study involving 178 children (age range, 4 to 8 years) at 17 centers in the United States. Budesonide inhalation suspension doses of 0.25 mg, 0.50 mg, or 1.0 mg twice daily were administered by means of a jet nebulizer and air compressor system. Efficacy was assessed by recording at home nighttime and daytime asthma symptom scores, use of rescue medication, pulmonary function tests, and treatment discontinuation because of worsening symptoms. Safety was assessed by reported adverse events and changes in baseline and adrenocorticotrophic hormone stimulated plasma cortisol levels in a subset of patients. Results: Baseline demographics, symptom scores, and pulmonary function data were similar across treatment groups. All doses of budesonide inhalation suspension were superior to placebo in improving nighttime and daytime asthma symptom scores (P.026), reducing use of breakthrough medication (P.032), and improving morning peak expiratory flow (P.030). The number of dropouts because of worsening asthma was also significantly fewer in the budesonide groups (P.015). There were no differences between doses of budesonide. Adverse events and basal and adrenocorticotrophic hormone stimulated cortisol responses were not different between budesonide and placebo groups. Conclusion: Budesonide inhalation suspension, 0.25 mg, 0.50 mg, and 1.0 mg twice daily, is an effective and safe treatment for young children with inhaled steroid dependent, persistent asthma. (J Allergy Clin Immunol 1998;102: ) From a ASTHMA Inc, Seattle; b Connecticut Asthma & Allergy Center, West Hartford; c Spokane Allergy & Asthma Research Unit, Spokane; and d Astra USA Inc, Westborough. Supported by Astra USA, Inc. Received for publication June 16, 1998; revised July 29, 1998; accepted for publication July 31, Reprint requests: Gail Shapiro, MD, ASTHMA, Inc, Suite 200, 4540 Sand Point Way, NE, Seattle, WA Copyright 1998 by Mosby, Inc /98 $ /1/93734 Key words: Budesonide, budesonide inhalation suspension, asthma, inhaled corticosteroid, children, pediatric, pulmonary function, steroid-dependent asthma, clinical trial Bronchial asthma is the most common chronic childhood disease. It affects an estimated 4.89 million pediatric patients in the United States, causes considerable morbidity and interference with quality of life, and is associated with significant mortality. 1 It is now well established that asthma is an inflammatory disease and that chronic inflammation in asthma can lead to longterm bronchial hyperresponsiveness and airway remodeling. 2,3 Early intervention with topical antiinflammatory agents, including glucocorticosteroids (GCSs), is recommended for the management of persistent asthma 4 and to reduce the possibility of long-term bronchial damage produced by chronic asthma. 5 Inhaled budesonide is available in 2 formulations for the treatment of asthma: an inhalation-driven, multidose, dry powder inhaler (Pulmicort Turbuhaler) and a pressurized aerosol metered-dose inhaler (pmdi). The efficacy and safety of the dry powder and metered-dose formulations of budesonide for the treatment of asthma have been documented However, many pediatric patients, particularly infants and young children, are unable to use the pmdi or inhalation-driven GCS preparations effectively. Many young children do not have sufficient coordination to use a pmdi, which depends on precise timing of inhalation after activation of the spray. In addition, although a pmdi in combination with a large-volume spacer device is sometimes fitted with a face mask, there are no studies to prove conclusively that a pmdi with a face mask is more effective than a pmdi without a face mask in young children because even this combination requires cooperation from the child. Young children may also be unable to perform the controlled inhalation required for inhalation-driven preparations. Budesonide inhalation suspension (Pulmicort Respules, Astra) permits the delivery of inhaled GCS to young children who either are too young or unable to use a pmdi or inhalation-driven preparations. Budesonide inhalation suspension has been reported to be effective in reducing asthma symptoms in infants and children but only in small trials or individual case studies. The purpose of this study was to compare the efficacy and safety of 3 different twice daily doses of budesonide 789

2 790 Shapiro et al J ALLERGY CLIN IMMUNOL NOVEMBER 1998 Abbreviations used ACTH: Adrenocorticotrophic hormone AE: Adverse event GCS: Glucocorticosteroid PEF: Peak expiratory flow pmdi: Pressurized metered dose inhaler inhalation suspension with placebo in young children dependent on inhaled steroids for treatment of persistent asthma. METHODS Subjects Children (age range, 4 to 8 years) with clinically diagnosed asthma 22 who were treated daily with an inhaled corticosteroid and were using bronchodilators for breakthrough episodes of asthma for at least 3 months were enrolled in the study. Patients were required to have an FEV 1 that was at least 50% of predicted normal value and reversibility of at least 15% after a standard dose of inhaled bronchodilator (albuterol). Patients were included in the study if they had recorded asthma symptoms and a need for breakthrough medication on at least 5 of 7 days during the baseline period. Patients with a history of severe or unstable asthma or symptoms limited to seasonal allergen exposure were excluded as were those who used a course of systemic steroids within the preceding 30 days or prolonged treatment with systemic steroids within 12 weeks of enrollment. Before patient enrollment, all aspects of the study protocol were reviewed with the patients and/or legal guardians, and informed written consent was obtained. The study protocol was approved by institutional review boards at each center and was performed according to the Declaration of Helsinki. Concurrent treatment Patients were allowed to use short-acting bronchodilators as needed for breakthrough asthma symptoms. Patients were also allowed their other usual medications for rhinitis or allergy (eg, antihistamines, intranasal or topical steroids, cromolyn, or immunotherapy) if the treatment was constant during the baseline period and throughout the double-blind phase of the study. Patients were not permitted to use any systemic or inhaled steroid preparation other than the study medication during the double-blind period. In the event that a short course of supplementary systemic steroid treatment was required for an episode of asthma or an intercurrent illness, such as hives or croup, an effort was made to retain the patient in the study. If more than 1 course of supplementary steroids was required, the patient was withdrawn. Study design This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study involving 178 patients at 17 centers located throughout the United States. The study lasted for 14 weeks and consisted of a 2-week baseline period followed by a 12-week, double-blind treatment period. Patients were required to visit the study site 6 times: at enrollment, at randomization, and after 2, 4, 8, and 12 weeks (posttreatment visit) of treatment. At each visit a medical history, physical examination, and spirometry were performed, and daily diary records were reviewed. Clinical laboratory assessments (hematology, blood chemistry, and urinalysis) and documentation of reversibility of any airway obstruction were obtained at the enrollment visit and at the end of treatment. Patients were provided with diary cards to record the severity of nighttime and daytime asthma symptoms. Asthma symptom severity was rated according to the following 4-point scale: 0 = none (no symptoms of asthma); 1 = mild symptoms (awareness of asthma symptoms and/or signs that were easily tolerated); 2 = moderate symptoms (asthma symptoms and/or signs with some discomfort, causing interference with daily activities or sleep); 3 = severe symptoms (incapacitating symptoms and/or signs, with inability to perform daily activities or inability to sleep). Daily use of bronchodilator medications for breakthrough asthma symptoms and morning and evening measurements of peak expiratory flow (PEF) obtained with a Vitalograph peak flow meter were also recorded. All children and parents/guardians performed PEF measurements and were instructed as to the proper use of PEF meters before beginning the study. After a 2-week baseline period, eligible patients discontinued taking their chronic asthma medications and were randomized into 1 of the following 4 treatment groups: budesonide 0.25 mg twice daily, budesonide 0.5 mg twice daily, budesonide 1.0 mg twice daily, or placebo twice daily. Budesonide inhalation suspension was provided by Astra USA, Inc, and was packaged in 2.0 ml polyethylene ampules (Pulmicort Respules); ampules containing placebo were identical in appearance. Medication or placebo was administered by a Pari LC-Jet Plus Nebulizer (with mouthpiece) and a Pari Master compressor (Pari Respiratory Equipment, Inc, Richmond, Va). Neither the patient nor medical personnel were aware of the drug or the dose administered. Safety was assessed by evaluating the incidence and severity of adverse events (AEs) reported during the study on diary cards, by active questioning at each visit, and by changes from baseline in plasma cortisol at the end of the 12-week treatment period. A subset of patients had basal and adrenocorticotrophic hormone (ACTH) stimulated cortisol levels checked at the enrollment visit and after the 12-week treatment period. Blood samples were obtained for basal cortisol levels between 6 AM and 8:30 AM on these days. Following the blood sample, ACTH 0.25 mg (Cortrosyn, Organon) was administered intravenously, and then 60 minutes later another blood sample was obtained for ACTH-stimulated cortisol levels. All plasma samples were analyzed by means of HPLC by BCO Medical Services B.V. (The Netherlands). The limit of quantification (sensitivity) of the cortisol assay is 20 nmol/l (0.725 µg/dl). Secondary safety variables included changes from baseline in clinical laboratory values, oropharyngeal and/or nasal fungal cultures, and physical examination. Statistical analysis The primary efficacy variables were changes from baseline (mean of the 7 days before randomization) in nighttime and daytime asthma symptom scores over the double-blind study phase (mean over treatment weeks 0 to 12). Secondary efficacy variables included patient outcomes (proportion of patients who were discontinued from the study), the change from baseline in number of days that breakthrough medication was required, morning and evening PEF assessments, and pulmonary function tests performed in the clinics. The analysis included all patients who received at least 1 dose of study medication and had at least 1 observation taken while receiving study medication. Data for patients who terminated the study early or had missing data were carried forward and included in subsequent analyses. ANOVA was used to compare each active budesonide treatment group with placebo for all efficacy variables, with the exception of patient outcomes, which was assessed with Fisher s exact test. Sample size was chosen to provide 80% power to detect a mean difference of 0.30 points in the primary efficacy variables of nighttime and daytime asthma symptom scores (SD = 0.45 points)

3 J ALLERGY CLIN IMMUNOL VOLUME 102 NUMBER 5 Shapiro et al 791 TABLE I. Baseline demographics and asthma history Budesonide inhalation suspension Placebo 0.25 mg BID 0.50 mg BID 1.0 mg BID Total Charactersitic (n = 44) (n = 47) (n = 42) (n = 45) (n = 178) Gender, n (%) M 20 (45.5) 31 (66.0) 30 (71.4) 29 (64.4) 110 (61.8) F 24 (54.5) 16 (34.0) 12 (28.6) 16 (35.6) 68 (38.2) Age (mo) Mean ± SD 80.7 ± ± ± ± ± 16.1 Range Race, n (%) White 37 (84.1) 38 (80.9) 35 (83.3) 40 (88.9) 150 (84.3) Black 6 (13.6) 7 (14.9) 3 (7.1) 2 (4.4) 18 (10.1) Hispanic 1 (2.3) 2 (4.3) 2 (4.8) 3 (6.7) 8 (4.5) Other 0 (0.0) 0 (0.0) 2 (4.8) 0 (0.0) 2 (1.1) Duration of asthma (mo) Mean ± SD 49.8 ± ± ± ± ± 22.5 Range Nighttime asthma symptom scores* Mean ± SD 1.18 ± ± ± ± ± 0.59 Daytime asthma symptom scores* Mean ± SD 1.33 ± ± ± ± ± 0.50 BID, Twice daily. *Symptom scoring scale of 0 to 3 (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms). One patient was missing nighttime symptom score data (n = 44). TABLE II. Baseline pulmonary function data Budesonide inhalation suspension Placebo 0.25 mg BID 0.50 mg BID 1.0 mg BID Total Variable (n = 44) (n = 47) (n = 42) (n = 45) (n = 178) FEV 1 (L/min) 1.14 ± ± ± ± ± 0.32 % Predicted ± SD* 79.2 ± ± ± ± ± 14.5 % Reversibility ± SD 30.3 ± ± ± ± ± 17.7 Morning PEF (L/min) Mean ± SD ± ± ± ± ± 53.1 Evening PEF (L/min) Mean ± SD ± ± ± ± ± 53.9 BID, Twice daily. *Percent of predicted value for age, height, and gender. between the budesonide inhalation suspension and placebo treatment groups for a 2-sided test (α =.05). RESULTS Patients A total of 178 patients (110 boys and 68 girls) were randomized into the 4 treatment groups. Demographic features and baseline asthma characteristics are shown in Tables I and II. The treatment groups were comparable with regard to age, sex, race, and duration of asthma. The mean age was 6.7 years (range, 4 to 9 years), and patients had a history of asthma lasting an average of 4.2 years (range, 0.5 to 8.5 years). Before randomization, beclomethasone (59%) was the most frequently used inhaled GCS. The mean nighttime and daytime asthma symptom scores at baseline were 1.10 ± 0.59 and 1.34 ± 0.50, respectively. Pulmonary function tests at baseline were similar across the 4 treatment groups (Table II). Mean morning and evening PEF values were similar, and mean baseline FEV 1 was 79.7% of predicted value with 33.7% reversibility. Rescue medication was required during the 2-week baseline period on a mean of 11.8, 11.6, 12.0, and 10.8 days in the placebo, 0.25 mg, 0.50 mg, and 1.0 mg twice daily budesonide treatment groups, respectively. Of the 178 patients randomized, 139 patients (78%) completed the study, and 39 patients (19 in the placebo group, 6 in the budesonide 0.25 mg twice daily group, 5 in the 0.50 mg twice daily group, and 9 in the 1.0 mg twice daily group) discontinued before completion. The proportion of patients in the placebo group who discontinued was significantly greater than the proportion of patients in the budesonide inhalation suspension groups (P.023). The proportion of patients who discontinued because of worsening of asthma symptoms was also sig-

4 792 Shapiro et al J ALLERGY CLIN IMMUNOL NOVEMBER 1998 FIG 1. Mean change from baseline nighttime (top panel) and daytime (bottom panel) asthma symptoms scores during treatment weeks 0 to 12. *P.05 versus placebo; P.01 versus placebo. BID, Twice daily. TABLE III. Changes from baseline to double-blind treatment in efficacy variables* Budesonide inhalation suspension Variable Placebo (n = 44) 0.25 mg BID (n = 47) 0.50 mg BID (n = 42) 1.0 mg BID (n = 45) Nighttime asthma symptom score Daytime asthma symptom score Morning PEF (L/min) Evening PEF (L/min) FEV 1 (L/min) BID, Twice daily. *Data expressed as the adjusted mean change from baseline over the 12-week treatment phase, all patients treated, last value carried forward. P.05 versus placebo. P.01 versus placebo. nificantly greater in the placebo group (36%) than in the budesonide groups (9%, P.015); 11%, 2%, and 13% of patients in the 0.25 mg, 0.50 mg, and 1.0 mg twice daily budesonide groups, respectively, discontinued treatment because of worsening asthma. A higher proportion of placebo patients received a course of parenteral/oral steroids during the course of the study; 36% of placebo patients received supplemental steroids compared with

5 J ALLERGY CLIN IMMUNOL VOLUME 102 NUMBER 5 Shapiro et al 793 FIG 2. Mean change from baseline (± 95% confidence interval) in number of days bronchodilator (pmdi or nebulizer) was required over the 12-week treatment period. *P.05 versus placebo; P.01 versus placebo. BID, Twice daily. 11%, 5%, and 18% of patients who received 0.25 mg, 0.5 mg, and 1.0 mg budesonide twice daily, respectively. Efficacy Table III summarizes the adjusted mean changes from baseline in efficacy variables at the end of the 12-week, double-blind treatment period. The mean changes from baseline for nighttime and daytime asthma symptom scores were significantly greater in patients who received 0.25 mg twice daily, 0.50 mg twice daily, and 1.0 mg twice daily budesonide inhalation suspension compared with patients who received placebo (P.026). The efficacy of budesonide inhalation suspension was similar across all treatment groups. Mean changes from baseline in nighttime and daytime asthma symptom scores for each group during the 12- week treatment period are shown in Fig 1. In the placebo group, nighttime and daytime asthma symptom scores remained constant throughout the treatment phase of the study. In each of the budesonide groups there was improvement in mean asthma symptom scores by 2 weeks of treatment. The improvement was sustained through the end of the 12-week treatment period. Improvements in pulmonary function were associated with budesonide inhalation suspension treatment (Table III). When each budesonide group was compared with the placebo group, morning PEF was found to be greater in each budesonide group (P.030). A statistically significant improvement in FEV 1 was observed in the 0.50 mg twice daily budesonide group compared with the placebo group (P =.043). Other lung function measures (forced vital capacity, forced expiratory flow during midportion of forced vital capacity, and evening PEF) showed numerical improvements compared with placebo that were statistically significant for only some doses (data not shown). There was a significant reduction in the number of days medications were required for treatment of breakthrough asthma symptoms in each budesonide dose group compared with the placebo group (P.032) (Fig 2). Safety The overall incidence, type, and severity of nonasthmarelated AEs were similar across all treatment groups throughout the study. Five patients had AEs resulting in discontinuation from the study: otitis media/sinusitis (placebo), lymphadenopathy (placebo), chest pain (0.50 mg budesonide twice daily), rhinitis/sinusitis (1.0 mg budesonide twice daily), and respiratory infection (1.0 mg budesonide twice daily). Two AEs were considered serious (lymphadenopathy in a patient receiving placebo and a left radius/ulnar fracture as a result of a fall from a jungle gym in a patient receiving 0.50 mg budesonide twice daily) but were judged not to be related to the study medication. There were no clinically significant differences between the budesonide inhalation suspension and placebo treatment groups in clinically significant changes in vital signs, physical examination findings, or laboratory tests (including nasal or oral fungal cultures) during the course of the study. In addition, although this was only a short-term study, the measured heights and weights observed over the 12 weeks of treatment were similar in each of the budesonide groups and the placebo group. Fig 3 shows mean basal and ACTH-stimulated cortisol levels at baseline and after the 12-week treatment period

6 794 Shapiro et al J ALLERGY CLIN IMMUNOL NOVEMBER 1998 FIG 3. Mean basal and ACTH-stimulated cortisol levels (± SD) at baseline and after the 12-week treatment period for each group. BID, Twice daily. for the subset of patients in each group that had cortisol levels determined. There were no differences between placebo and budesonide inhalation suspension groups with respect to clinically relevant changes in basal and ACTH-stimulated cortisol levels during the 12-week treatment period. The adjusted mean changes from baseline to week 12 in ACTH-stimulated cortisol levels were 9.1 nmol/l for patients in the placebo group (n = 8) compared with 41.2, 54.7, and 56.3 nmol/l for patients in the 0.25 (n = 14), 0.50 (n = 11), or 1.0 mg (n = 13) budesonide inhalation suspension treatment groups, respectively. In addition, there were no differences between groups in the number of individuals showing a shift from normal to abnormal response from baseline to week 12. DISCUSSION The results of this study demonstrate that administration of budesonide inhalation suspension 0.25 mg, 0.50 mg, and 1.0 mg twice daily resulted in significant improvements in nighttime and daytime asthma symptom scores after 12 weeks of treatment compared with placebo in young children (4 to 8 years old) with inhaled steroid dependent asthma. Despite fairly low baseline symptom scores for these steroid-dependent children, treatment with budesonide inhalation suspension reduced symptom scores an additional 30% to 40%. The number of patients discontinued because of worsening of asthma symptoms and the number of days that bronchodilators were used for breakthrough asthma symptoms were significantly lower in all active treatment groups than in the placebo group. Significant improvements, on the order of 8% to 10%, were also observed in morning PEF measurements in all budesonide groups relative to the placebo group. FEV 1 measurements showed statistical improvement in the 0.50 mg twice daily group; other active treatment groups showed numerical improvement. Overall, the results of this study are consistent with the findings of smaller studies and case reports that describe the efficacy of budesonide inhalation suspension in infants and young children with asthma The efficacy and safety of a wide range of daily doses of budesonide inhalation suspension (0.50 mg, 1.0 mg, and 2.0 mg) were demonstrated in a patient population whose moderate-to-severe asthma was not being controlled with other inhaled GCSs. Although this study did not show a dose-response relationship across budesonide inhalation suspension doses, the results are consistent with other studies showing that budesonide doses ranging from 0.50 to 4.0 mg daily were equally effective in children with mild-to-moderate asthma. 20,23 Other studies in patients with moderate-to-severe asthma have shown a dose-response relationship with budesonide inhalation suspension. 17,24 For example, Grimfeld et al 17 found that budesonide 2.0 mg daily (1.0 mg twice daily) was significantly more effective than 0.50 mg daily (0.25 mg twice daily) in relieving nighttime and daytime asthma symptoms in young children with moderate-to-severe asthma. In another study by Pedersen and Hansen, 25 a significant dose-response relationship with budesonide suspension (0.50 mg, 1.0 mg, or 2.0 mg twice daily) was observed in measures of pulmonary function (FEV 1, PEF, and forced midexpiratory flow), but not in morning and evening asthma symptoms, in 6- to 15-year-old children with moderate asthma. 25 The variation in methodology for patient classification into severity categories and the ages of the patients may have affected these comparisons. These factors also may have been partly responsible for not demonstrating a dose response in this study. It is well known that it is extremely difficult to demonstrate a dose-response relationship with inhaled corticosteroids in adults, and the same is true for children. Children may be a less favorable population to demonstrate a doseresponse relationship because of the difficulty in conducting pediatric studies and in obtaining accurate responses directly from the children. Symptom scores in

7 J ALLERGY CLIN IMMUNOL VOLUME 102 NUMBER 5 Shapiro et al 795 this study were defined by the caregiver rather than the child, blunting the possibility of demonstrating a dose response. Furthermore, it is more likely to demonstrate a dose response in patients with more severe asthma because lower doses may be not be as effective for those patients. Similarly, the minimal effective dose for patients who require daily inhaled steroids to control more severe asthma is likely different from the minimal effective dose required for patients with less severe disease. In this study the lowest dose of budesonide inhalation suspension, 0.25 mg twice daily, significantly improved asthma in inhaled steroid dependent children. In contrast, in another study 26 the lowest dose of budesonide inhalation suspension, 0.25 mg once daily, used in children with less severe asthma, was also shown to be the minimal effective dose. Thus it is important to individualize treatment on the basis of the patient population, asthma severity, and resultant symptom control. Improvement in asthma symptoms was evident within 2 weeks after the initiation of treatment with budesonide inhalation suspension and was consistently maintained with no loss of efficacy over a 3-month period. Asthma symptoms would be expected to worsen in the placebo group during the treatment period because these patients were dependent on inhaled steroids but were not allowed treatment with inhaled steroids while in the study. This may have resulted from a large proportion of the patients in the placebo group being discontinued from the study because of worsening of symptoms, although their symptom data before discontinuation were carried forward and included in the efficacy analysis. If the placebo patients who were discontinued had remained in the study, their asthma may have continued to worsen and would have been reflected by worsening symptom scores during the 12-week treatment period. Second, it is evident that patients receiving placebo who completed the study were able to control their symptoms with breakthrough medication as indicated by the significantly higher use of bronchodilators observed in the placebo group compared with the budesonide groups. Had the patients receiving placebo who remained in the study continued to get worse over the 12-week treatment period, it would have amplified the benefit of budesonide; the loss of these patients probably has made the data appear less significant than it actually is. Although inhaled GCSs are indicated as first-line treatment of asthma in adults, their use for the treatment of asthma in children is not as widely accepted because of concerns of potential systemic side effects that usually are associated with oral GCS administration. This study demonstrated that administration of budesonide inhalation suspension was well tolerated and associated with few adverse effects. The frequency and distribution of adverse experiences were similar across budesonide and placebo-treated study groups in this study and similar to previously reported findings. 15,19,21 In addition, administration of budesonide inhalation suspension did not produce measurable changes in basal or ACTH-stimulated cortisol levels after 12 weeks of treatment compared with placebo. There was an approximate 10% decrease in stimulated cortisol levels in the highest budesonide dose group (1 mg twice daily) following the double-blind treatment period. Although it is well known that cortisol suppression is dose dependent, the observed decrease in the high-dose group was not statistically different from other groups in this small population, and it is uncertain whether this decrease has any clinical value. It is perhaps more clinically relevant to examine the data regarding a shift from a normal cortisol response at baseline to an abnormal cortisol response after 12 weeks of treatment. Only one patient in the high-dose budesonide group shifted from a normal to an abnormal response during the course of the study. The safety of budesonide in this study is further strengthened by studies of the effects of long-term treatment with budesonide on growth and bone mineral density in asthmatic children. Agertoft and Pedersen 5 measured growth and pulmonary function in children with asthma who were treated with inhaled budesonide for over 3 years in a controlled prospective study. In this study 216 children were assessed every 6 months for a 1- to 2-year run-in period and then for 3 to 6 years during treatment with inhaled budesonide. A control group of 62 children were treated with theophylline, β 2 -agonists, and cromolyn sodium, but not inhaled GCSs, during a 3- to 7-year period. Compared with baseline and with the control group, no significant changes in growth velocity or weight gain were observed during the 3 to 5 years of treatment with inhaled budesonide. Agertoft and Pedersen 27 recently reported results of a study of bone mineral density in 157 asthmatic children treated with budesonide for 3 to 6 years. At an average daily dose of 504 µg, long-term treatment with inhaled budesonide had no adverse effects on total bone mineral density, total bone mineral capacity, total bone calcium, or body composition in children with persistent asthma. Understanding the chronic inflammatory nature of asthma has led to the recommendation that treatment with inhaled GCSs should begin at an early stage in the disease in an attempt to prevent airway remodeling, 5 as well as to stabilize symptoms and maximize quality of life. Many young children are not able to effectively administer inhaled GCSs with pmdis or inhalation-driven devices because of coordination problems. In the past these children also have been treated with nebulized bronchodilators or nonsteroidal antiinflammatory medications with undetermined benefits regarding airway remodeling. The results of this study demonstrate that budesonide inhalation suspension 0.25 to 1.0 mg twice daily is safe and effective for the treatment of steroid-dependent, persistent asthma in young children. Because most young children with asthma find it difficult to effectively use traditional and newer inhalation devices, nebulization may be the preferred route of administration of inhaled GCSs for this patient population. Budesonide inhalation suspension offers an additional treatment option for the control of chronic, persistent asthma in young children.

8 796 Shapiro et al J ALLERGY CLIN IMMUNOL NOVEMBER 1998 We acknowledge the time and efforts of the following clinical investigators: James W. Baker, MD (Portland, Ore); Edwin A. Bronsky, MD (Salt Lake City, Utah); Howard Eigen, MD (Indianapolis, Ind); Stanley P. Galant, MD (Orange, Calif); David Geller, MD (Orlando, Fla); John W. Georgitis, MD (Winston- Salem, NC); Sherwin Gillman, MD (Orange, Calif); Bobby Lanier, MD (Fort Worth, Tex); Jeffrey Leflein, MD (Ypsilanti, Mich); Bennie C. McWilliams, MD (Albuquerque, NM); Ned T. Rupp, MD (Augusta, Ga); Maryanne B. Scott, MD (Norwalk, Conn); Howard J. Silk, MD (Atlanta, Ga); and William S. Silvers, MD (Englewood, Colo). We also extend our appreciation to Marc S. Eisenberg, PhD, and Nancy M. Bormann, PhD, for their technical and editorial assistance, and Norma Andersson and Christer Hultquist for their critical review of this manuscript. REFERENCES 1. Centers for Disease Control & Prevention. Asthma United States. MMWR 1995;43: Haathela T. 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