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Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal-axis function in infants and young children with persistent asthma
Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal–axis function in infants and young children with persistent asthma Anne-Marie Irani, MD*; Mario Cruz-Rivera, PhD, MPH†; Sherahe Fitzpatrick, MD†; Julie Hoag, DVM†; and Joseph A. Smith, MD†
Background: The initial 12-week, double-blind phases of three studies demonstrated that budesonide inhalation suspension (BIS) is effective and well tolerated in infants and young children (6 months to 8 years of age) with persistent asthma. Objective: Open-label, 52-week extensions to these studies were conducted to evaluate long-term safety of BIS, including effects of treatment with the lowest effective dose of BIS on hypothalamic-pituitary-adrenal (HPA)–axis function, as compared with conventional asthma therapy (CAT). Complete results of the earlier phases of the studies and of long-term safety are reported elsewhere; only results pertaining to HPA-axis function are summarized here. Methods: Patients eligible for the open-label phases of the three trials were randomized to treatment with nebulized BIS (n ⫽ 447) or CAT (n ⫽ 223). CAT included short-acting oral or inhaled 2-agonists, methylxanthines, or cromolyn sodium; in two of the studies, CAT could have included other inhaled corticosteroids. HPA-axis function, which had been evaluated during the 12-week doubleblind studies, was again evaluated at the beginning and end of the 52-week study period using basal plasma cortisol concentrations and response to stimulation with a 250-g dose of adrenocorticotropic hormone. Results: There was no evidence of altered HPA-axis function attributable to BIS treatment. No clinically or statistically significant differences in basal or adrenocorticotropic hormone–stimulated plasma cortisol concentrations were observed between BIS and CAT in either the 12-week, double-blind or 52-week, open-label phases of the three studies. Conclusions: The results indicate that treatment with BIS does not result in clinically significant suppression of HPA-axis function in infants and young children. Ann Allergy Asthma Immunol 2002;88:306–312.
INTRODUCTION Inhaled corticosteroids (ICSs) are recommended in National Heart, Lung, and Blood Institute guidelines as firstline anti-inflammatory therapy for the treatment of asthma.1 Corticosteroids reduce the severity of asthma symp-
* Department of Pediatrics, Division of Allergy, Immunology & Rheumatology, Virginia Commonwealth University, Richmond, Virginia. † AstraZeneca LP, Wilmington, Delaware. This study was supported by AstraZeneca LP. Received for publication September 22, 2001. Accepted for publication in revised form November 13, 2001.
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toms,2,3 improve peak expiratory flow rate and spirometry assessments,2,4 decrease requirements for 2-agonists,2 and prevent asthma exacerbations.3 However, concern about the potential for systemic adverse events, including suppression of hypothalamic-pituitaryadrenal (HPA)-axis function and growth in children, has resulted in reluctance on the part of many physicians and parents to use ICSs. HPA-axis function is an important indicator of systemic exposure to corticosteroids. Higher-dose corticosteroid therapy has been associated with HPA-axis suppression, which results from reduced
adrenocorticotropic hormone (ACTH) production and reduced cortisol secretion by the adrenal gland. HPA-axis function has been evaluated after use of ICSs, with inconsistent results.5 Various tests have been applied to evaluate HPAaxis function, including measurement of basal morning plasma cortisol concentrations, integrated plasma cortisol concentrations over the course of ⬎12 to 24 hours, and urinary free cortisol concentrations. The ACTH-stimulation test and 24-hour integrated serial plasma cortisol concentrations are methods recommended by the US Food and Drug Administration (FDA) to evaluate HPAaxis function.6 The ACTH-stimulation test directly measures the function of cortisol-secreting cells and is considered the most useful screening procedure for suspected adrenal insufficiency. In the standard-dose ACTH (cosyntropin)-stimulation test, plasma cortisol concentrations are measured 30 and 60 minutes after an intramuscular or intravenous injection of cosyntropin (typically 250 g) or during a 6- to 8-hour cosyntropin infusion.6 Although the 250-g dose of cosyntropin is well established for studies in adults, no standard dose is accepted for use in children, particularly those ⬍4 years old. Low-dose (0.5 g/1.73 m2), short ACTH stimulation can also be used to evaluate HPA-axis function. Budesonide is an ICS with a favorable ratio of topical anti-inflammatory to systemic activity.7 The low systemic activity of budesonide is likely a result of its extensive first-pass hepatic metabolism (85 to 95% from the orally absorbed drug) and low-potency me-
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tabolites with minimal systemic effects.8 –12 Budesonide inhalation suspension (BIS) was developed for nebulization to meet the specific needs of infants and young children who may be unable to use metered-dose or drypowder inhalers. It is the first nebulized corticosteroid approved in the United States for pediatric patients with asthma and the first ICS approved for use in children as young as 12 months. The availability of a nebulized corticosteroid for infants and young children is especially valuable considering the increasing prevalence and morbidity of pediatric asthma13 and the lack of other FDA-approved therapeutic options for these patients. A series of three recent, 12-week, double-blind studies demonstrated the efficacy and safety of BIS for the treatment of infants and young children with persistent asthma.14 –16 Three 52week extensions to these studies were designed to compare the long-term safety of the lowest maintenance dose of BIS with that of conventional asthma therapy (CAT) in children with persistent asthma. BIS was safe and well tolerated for up to 15 months of treatment (double-blind plus openlabel treatment).17 Evaluation of safety included an evaluation of HPA-axis function at the beginning and end of the 12- and 52-week study periods by measurement of the basal and ACTHstimulated plasma cortisol concentrations in a subset of patients. These results are discussed here, comparing patients who received BIS with those who received placebo or CAT.
METHODS
evaluation. Basal cortisol concentrations were determined from blood samples obtained between 6:00 and 8:30 AM before and after 12 weeks of double-blind treatment. ACTH (Cortrosyn, Organon, West Orange, NJ) was administered (0.25 mg intravenously in children ⬎2 years of age or 0.125 mg intramuscularly in children ⱕ2 years), and ACTH-stimulated cortisol concentrations were determined from blood samples taken 60 minutes after ACTH administration. Plasma samples were transported by SmithKline Beecham Clinical Laboratories (Van Nuys, CA), and analysis of the samples was performed by Analytico (formerly BCO Medical Services BV, Breda, The Netherlands). The assay was based on high-performance liquid chromatography with ultraviolet detection and modified from van den Berg et al.18 Patients with both a basal plasma cortisol concentration of at least 150 nmol/L and an ACTH-stimulated plasma cortisol concentration that was at least 400 nmol/L or that increased by at least 200 nmol/L above the basal concentration after 60 minutes were defined as having “normal” adrenal function for the purpose of statistical analysis.
Double-Blind Treatment A summary of the three double-blind studies is shown in Table 1. Patients’ age ranged from 6 months to 8 years. The first study15 included patients with mild, persistent asthma who had not received previous ICS therapy. The second study16 included patients with moderateto-severe asthma who had received previous ICS therapy. The third study14 included patients with moderate, persistent asthma who may or may not have received previous ICS therapy. BIS doses were based on asthma severity and ranged from 0.25 to 2.0 mg daily in the three studies. Medications used before enrollment included 2-agonists, cromolyn, nedocromil, bronchodilators, and ICSs via pressurized metered-dose inhaler. BIS was provided for both the double-blind and open-label phases of the studies in 2.0-mL white polyethylene ampoules (Pulmicort Respules, AstraZeneca LP, Wilmington, DE). A Pari LC-Jet Plus Nebulizer and a Pari Master compressor (Pari Respiratory Equipment, Inc, Midlothian, VA) were used to administer BIS or placebo in both phases of the studies. All three of these multicenter, randomized, doubleblind, placebo-controlled studies included evaluations of efficacy and safety, as described in detail elsewhere.14 –16 As part of the evaluation for safety, basal and ACTH-stimulated plasma cortisol concentrations were evaluated in a subset of patients who were enrolled at study sites that were equipped to consistently perform the
Open-Label Treatment Patients who completed the 12-week, double-blind phase of each study or who discontinued the study because of worsening of asthma symptoms were eligible to participate in the optional open-label extension of each study. The 52-week extensions were multi-
Table 1. Summary of Three Double-Blind, Placebo-Controlled Studies of BIS in Pediatric Patients Study (yr)
No. of patients
Patient age range
Kemp et al (1999)
359
6 mo to 8 yr
Shapiro et al (1998)
178
4 to 8 yr
Baker et al (1999)
480
6 mo to 8 yr
Active treatment groups BIS BIS BIS BIS BIS BIS BIS BIS BIS BIS
0.25 mg qd 0.5 mg qd 1.0 mg qd 0.25 mg bid 0.5 mg bid 1.0 mg bid 0.25 mg qd 0.25 mg bid 0.5 mg bid 1.0 mg qd
Disease characteristics Mild persistent asthma; no previous inhaled corticosteroids Moderate-to-severe asthma; previous treatment with inhaled corticosteroids Moderate persistent asthma; previous treatment with inhaled corticosteroids optional
qd ⫽ once daily; bid ⫽ twice daily.
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center, parallel-group, randomized, active-controlled, open-label studies designed to evaluate the long-term safety of a minimum effective dose of BIS compared with CAT; efficacy variables were also evaluated. There was no washout period between the doubleblind and open-label phases of the studies. At entry to the open-label phase, patients within each doubleblind treatment group were rerandomized in a 2:1 ratio to receive either BIS or CAT for 52 weeks. At the start of the open-label phase, BIS 0.5 mg was administered once or twice daily at the investigator’s discretion, and attempts were made at each clinic visit to titrate to the minimum effective dose. If possible, dose reductions were made to BIS 0.25 mg once or twice daily, BIS 0.25 mg every other day, or BIS discontinuation. Patients who discontinued BIS treatment were treated with CAT at the discretion of the investigator. Treatment with CAT was limited to 2-agonists (short-acting oral and inhaled), methylxanthines, or cromolyn sodium in the study by Kemp et al15; the studies by Shapiro et al16 and Baker et al14 also allowed ICSs as CAT. Any exacerbations of symptoms were managed by increasing the dose of breakthrough medications and/or BIS, or administering courses of oral prednisone, as judged necessary by the investigator. Long-acting inhaled 2-agonists, astemizole, and nonprescription asthma medications were not allowed during the open-label treatment phase. Statistical Methods The analysis of efficacy variables in the double-blind phase of each of the three studies has been described previously.14 –16 The evaluation of safety in both the 12-week, double-blind and 52-week, open-label phases of each study included evaluations of the incidence and severity of adverse events, changes in physical examinations, vital signs, and clinical laboratory tests, as well as measurements of cortisol concentrations in patients from approximately half the study sites. Baseline and posttreatment cortisol concentrations were required for inclusion in the
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HPA-axis analysis. Further, cortisol data were used in the analysis only if the blood sample was obtained before 9:30 AM on the day of the patient’s visit. In the 52-week open-label study phases, ACTH-stimulation data were summarized, as were the numbers and proportions of patients with HPA-axis suppression. Analysis of variance, adjusted for study center, was used to compare mean ACTH responses between active treatments and placebo. The double-blind studies were powered to demonstrate a response for the efficacy variables. Sample sizes for the open-label periods were not determined by any formal statistical criteria. RESULTS Patient Characteristics Double-blind phase. The studies by Kemp et al, Shapiro et al, and Baker et al included 359, 178, and 481 patients, respectively, who were assessable for safety after the 12-week, double-blind phase (Fig 1). Of these 1,018 patients, 185, 229, 327, and 45 patients were randomized to initial treatment with 0.25-, 0.5-, 1.0-, and 2.0-mg daily doses of BIS, respectively. Treatment groups were well balanced with regard to sex and race, but other characteristics reflected the higher minimum age (4 years) of patients enrolled in the
study by Shapiro et al; age, weight, height, and duration of asthma were higher in the group that received the highest BIS dose group. Baseline pulmonary function test results were similar for all treatment groups.14 –16 Open-label phase. The three openlabel extensions evaluated 670 patients for safety (447 randomized to BIS and 223 randomized to CAT; Fig 1). In the open-label extensions of the studies by Kemp et al, Shapiro et al, and Baker et al, 182, 61, and 204 patients, respectively, were randomized to BIS, and 90, 30, and 103 patients, respectively, were randomized to CAT. The overall mean duration of exposure to treatment was 342 ⫾ 83 days in patients who received BIS (n ⫽ 447) and 304 ⫾ 119 days for patients who received CAT (n ⫽ 223). The median length of treatment was 365 days for both groups. A total of 387 patients (87%) in the BIS treatment group and 160 patients (72%) in the CAT group completed open-label treatment (Fig 1). Median total daily doses of BIS were 0.5 mg, 0.8 to 1.0 mg (0.8 mg for weeks 1 to 36 and 1.0 mg for weeks 36 to 44⫹), and 0.5 mg in the studies by Kemp et al, Shapiro et al, and Baker et al, respectively. As with the 12-week doubleblind study periods, treatment groups in the 52-week, open-label study peri-
Figure 1. Disposition of patients: pooled by Kemp et al, Shapiro et al, and Baker et al. AE, adverse event; LT/DD, lack of therapeutic effect/disease deteriorated; NPM, nonprotocol use of medication; NC, noncompliance with study procedures; WC, withdrew consent; LFU, lost to followup. (Reproduced with permission from Leflein.29
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ods were well balanced with regard to sex and race (Table 2). Among patients who were able to perform pulmonary function tests consistently (42%), these parameters were similar in the BIS and CAT groups (Table 2). HPA-Axis Function Double-blind phase. No clinically relevant differences in basal or ACTHstimulated plasma cortisol concentrations were observed between the placebo groups and any of the BIS treatment groups over the 12-week study period (Fig 2A). At the beginning and end of the 12-week, double-blind phase, mean
basal plasma cortisol concentrations for all treatment groups were within the normal range. Mean changes from baseline in ACTH-stimulated cortisol concentrations at the end of the 12-week, doubleblind phase are shown in Table 3. None of the differences observed between the BIS treatment groups and the placebo group were statistically significant (P ⱖ 0.07). The nearly statistically significant difference (P ⫽ 0.073) between the BIS 0.25-mg treatment group and the placebo group observed actually reflects a decline in ACTH-stimulated response observed in the placebo group (ie, pa-
Table 2. Patient Demographics and Baseline Asthma Characteristics From Analysis of 52-Week, Open-Label Studies: Pooled Data
Sex Male Female Race White Black Latino Asian Other Age (mo) Mean ⫾ SD Range Weight (kg) N Mean ⫾ SD Range Height (cm) N Mean ⫾ SD Range FEV1 (% predicted) N Mean ⫾ SD FVC (L) N Mean ⫾ SD Range FEF25%–75% (L/sec) N Mean ⫾ SD Range Morning PEFR (L/min) N Mean ⫾ SD Range
CAT (n ⴝ 223)
BIS (n ⴝ 447)
142 (63.7%) 81 (36.3%)
291 (65.1%) 156 (34.9%)
165 (74.0%) 35 (15.7%) 17 (7.6%) 0 (0%) 6 (2.7%)
357 (79.9%) 60 (13.4%) 21 (4.7%) 2 (0.4%) 7 (1.6%)
63.0 ⫾ 27.8 11–112
60.9 ⫾ 25.9 8–113
223 21.3 ⫾ 8.4 8.6–58.9
446 20.7 ⫾ 7.7 7.7–76.6
222 110.4 ⫾ 17.8 72.0–150.1
443 109.1 ⫾ 16.5 68.6–155.3
96 83.4 ⫾ 17.3
184 84.2 ⫾ 18.2
96 1.62 ⫾ 0.38 0.73–2.48
187 1.56 ⫾ 0.47 0.67–3.64
96 1.25 ⫾ 0.47 0.40–2.61
187 1.21 ⫾ 0.52 0.23–3.06
107 166.9 ⫾ 45.7 80.0–285.3
213 169.4 ⫾ 55.6 56.3–461.4
FEV1 ⫽ forced expiratory volume in 1 second; FVC ⫽ forced vital capacity; FEF25%–75% ⫽ forced expiratory flow during the middle half of the forced vital capacity; PEFR ⫽ peak expiratory flow rate.
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tients in the BIS 0.25-mg group actually had a more favorable ACTH response than patients in the placebo group). The percentage of patients shifting from “normal” to “abnormal” ACTH-stimulated response at week 12 were similar between the placebo and BIS treatment groups (Table 4). Open-label phase. Long-term safety of BIS treatment was evaluated in 670 children. Basal plasma cortisol concentrations were measured in 189 patients, and ACTH-stimulated cortisol concentrations were measured in 180 patients (Fig 2B). No clinically significant differences in basal or ACTHstimulated cortisol concentrations were observed between the BIS and the CAT group over the 52-week treatment period (P ⫽ 0.312; Table 2). Further, the proportions of patients with shifts in response from “normal” to “abnormal” at week 52 in ACTHstimulated cortisol concentrations were not different between the BIS and the CAT groups (24% of patients in the BIS treatment group and 21% of patients in the CAT group). DISCUSSION Many short- and long-term studies have shown ICSs to be of benefit in children with asthma. However, most efficacy and safety studies in asthmatic children have been limited to children ⬎6 years old. In addition, comparable data in this age group using a nebulized delivery for ICSs are limited. Therefore, three 12-week, placebocontrolled studies evaluating BIS in infants and young children aged 6 months to 8 years were continued as 52-week, open-label extension studies to provide additional information on the safety of nebulized budesonide in this age group. No clinically relevant or statistically significant differences in basal or ACTH-stimulated cortisol concentrations were detected between the BIS and placebo groups in the controlled studies, nor between the BIS and CAT groups in the open-label studies. These results are consistent with those of a previous study in which no detectable adrenal suppression (as evaluated by measurement of over-
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Figure 2. Mean basal and ACTH-stimulated plasma cortisol concentrations at baseline and week 12 of the double-blind study period (A) and at baseline and week 52 of the open-label treatment period (B).
night urinary free cortisol excretion) was observed with administration of budesonide at doses up to 1,250 g daily in asthmatic children.19 The systemic effects of ICSs are dependent on many factors, including delivery device used, pharmacokinetic properties of the drug, site and degree of drug deposition, delivered dose, concurrent medications, and individual patient responses.20 Budesonide has several unique features that may have contributed to the study results. First, the bioavailability of nebulized budes-
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onide in children is the lowest of all currently approved ICSs at 6% of the nominal dose. The low bioavailability of budesonide in children is attributable, in part, to relatively low delivery to the lungs, as well as high (85 to 95%) first-pass hepatic metabolism of swallowed drug.8,12 This low bioavailability alone would predict minimal HPA-axis suppression at the doses studied. Budesonide clearance in children is 30 mL/minute/kg2, approximately 50% faster than in adults. Finally, BIS is effective in many children
with once-daily dosing,15 which may contribute to minimizing the effect on the diurnally sensitive HPA axis. Fundamental differences between corticosteroids are also apparent. Studies comparing the effects of different ICSs on the HPA axis have been reviewed and include evaluations of beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolide, and triamcinolone acetonide,20 with differences in the risk for HPA-axis effects demonstrated in studies of both asthmatic adults and children.21 Budesonide seems to suppress HPA-axis function to a lesser extent than either beclomethasone dipropionate or fluticasone propionate at comparable doses,20 –25 although some dependence on specific inhaler devices used is evident in the available data. In an evaluation of beclomethasone and budesonide for asthmatic children, a greater effect on the HPA axis was observed for beclomethasone than budesonide.24 In a study of 10 children, single-dose inhaled fluticasone resulted in greater adrenal suppression than inhaled budesonide.19 The short ACTH test as the standard evaluation of HPA-axis function is not without controversy, and the optimal dose of ACTH is controversial as well. In some studies, lowdose ACTH (0.5 g/1.73 m2 body surface) was used to identify individuals with mild adrenal insufficiency not identified with standard-dose ACTH stimulation.26,27 However, a recent trial comparing low- and standard-dose ACTH stimulation with the insulin tolerance test for HPA-axis evaluation in children with idiopathic multiple pituitary hormone deficiencies demonstrated a similar high sensitivity and specificity in detecting secondary adrenal insufficiency with both lowand standard-dose ACTH stimulation tests,28 supporting use of standarddose ACTH testing in this open-label safety program. Many open-label safety studies evaluate safety in patient groups without a positive control, often after FDA approval. Thus, these safety studies can be affected by patient selection or prior treatment biases. The BIS open-label
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Table 3. Changes in Basal and ACTH-Stimulated Plasma Cortisol Levels by Total Daily Dose of BIS (Pooled Data) Basal (nmol/L) Total daily dose (mg/day)
12-week, double-blind phase Placebo BIS 0.25 BIS 0.5 BIS 1.0 52-week, open-label phase BIS CAT
ACTH-stimulated (nmol/L)
N
Baseline (mean)
End (mean)
N
Baseline (mean)
End (mean)
Adjusted change*
64 56 69 91
300 288 312 301
290 296 293 298
61 58 66 92
669 652 675 658
635 662 671 647
⫺27.9 22.5 ⫺2.8 ⫺2.3
132 57
294 296
280 296
125 55
654 621
563 570
⫺98.4 ⫺67.7
95% CI on adjusted change ⫺69, ⫺21, ⫺44, ⫺37,
14 66 38 32
P Value
0.073 vs placebo 0.355 vs placebo 0.313 vs placebo
⫺140, ⫺57 ⫺124, ⫺12
0.312 vs CAT
* Mean change from baseline in ACTH-stimulated cortisol level from ANOVA. Table 4. Shifts in ACTH-Stimulation Test from Baseline to End of Double-Blind Phase (Week 12) by Total Daily Dose
Baseline
Abnormal (%) Normal (%)
Placebo (n ⴝ 61)
BIS total daily dose 0.25 mg (n ⴝ 55)
0.5 mg (n ⴝ 64)
1.0 mg (n ⴝ 90)
2.0 mg (n ⴝ 13)
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal
1 (13%) 8 (15%)
7 (88%) 45 (85%)
1 (25%) 6 (12%)
3 (75%) 45 (88%)
1 (11%) 7 (13%)
8 (89%) 48 (87%)
3 (38%) 8 (10%)
5 (63%) 74 (90%)
— 1 (9%)
2 (100%) 10 (91%)
extension program was designed to randomly assign patients to either BIS or CAT to provide safety data on BIS in the context of current pediatric asthma management and to ensure that patient demographics were comparable between active treatment groups. However, because study medications were not blinded in the open-label phase of this study, and because only a subset of study sites evaluated HPAaxis function, bias in patient selection or study conduct can not be ruled out. CONCLUSION BIS is a valuable therapeutic option for administration of ICSs to infants and young children with asthma who may lack the understanding or coordination necessary to use pressurized metereddose or dry-powder inhalers. The 52week extension studies suggest that BIS causes no clinically significant suppression of HPA-axis function, as reflected by both basal plasma cortisol concentrations and ACTH-stimulated cortisol response.
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REFERENCES 1. National Heart, Lung, and Blood Institute/National Institutes of Health.
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7.
National Asthma Education Program Expert Panel Report. Guidelines for the diagnosis and management of asthma. Expert panel report no. 2. Bethesda, MD: National Institutes of Health, 1997. Publication no 97– 4051. Haahtela T, Ja¨rvinen M, Kava T, et al. Comparison of a 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388 –392. Juniper EF, Kline PA, Vanzieleghem MA, et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832– 836. Pedersen S, Hansen OR. Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol 1995; 95:29 –33. Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148: S1–S26. Chrousos GP, Harris AG. Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 1. General principles. Neuroimmunomodulation 1998;5:277–287. Clissold SP, Heel RC. Budesonide. A preliminary review of its pharmacody-
8.
9.
10.
11.
12.
13.
14.
namic properties and therapeutic efficacy in asthma and rhinitis. Drugs 1984;28:485–518. Agertoft L, Andersen A, Weibull E, Pedersen S. Systemic availability and pharmacokinetics of nebulised budesonide in preschool children. Arch Dis Child 1999;80:241–247. Bisgaard H, Pedersen S, Damkjær Nielsen M, Østerballe O. Adrenal function in asthmatic children treated with inhaled budesonide. Acta Pædiatr Scand 1991;80:213–217. Lipworth BJ, Seckl JR. Measures for detecting systemic bioactivity with inhaled and intranasal corticosteroids. Thorax 1997;52:476 – 482. Pulmicort Turbuhaler 200 g (budesonide inhalation powder) product information. AstraZeneca LP. Physicians’ Desk Reference, 55th edition. Montvale, NJ: Medical Economics Company, 2001:591–595. Szefler SJ. Pharmacodynamics and pharmacokinetics of budesonide: a new nebulized corticosteroid. J Allergy Clin Immunol 1999;104: S175–S183. Mannino D, Homa DM, Pertowski CA, et al. Surveillance for asthma–United States, 1960 –1995. Mor Mortal Wkly Rep CDC Surveill Summ 1998:47:1–27. Baker JW, Mellon M, Wald J, et al. A multiple-dosing, placebo-controlled
311
15.
16.
17.
18.
19.
312
study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103:414 – 421. Kemp J, Skoner D, Szefler SJ, et al. Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999; 83:231–239. Shapiro G, Mendelson L, Kraemer MJ, et al. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998; 102:789 –796. Scott MB, Skoner DP. Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999;104: 200 –209. van den Berg JH, Mol CR, Deelder RS, Thijssen JH. A quantitative assay of cortisol in human plasma by high performance liquid chromatography using a selective chemically bonded stationary phase. Clin Chim Acta 1977;78:165–172. Clark DJ, Clark RA, Lipworth BJ. Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic
children. Thorax 1996;51:941–943. 20. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998;157:S1–S53. 21. O’Byrne PM, Pedersen S. Measuring efficacy and safety of different inhaled corticosteroid preparations. J Allergy Clin Immunol 1998;102:879 – 886. 22. Bisgaard H, Damkjær Nielsen M, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol 1988;81:1088 –1095. 23. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55–58. 24. 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: 433– 435. 25. Wilson AM, Clark DJ, Devlin MM, et al. Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults. Eur J Clin Pharmacol 1998;53:317–320. 26. Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in pa-
tients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995;80: 1243–1246. 27. Crowley S, Hindmarsh PC, Honour JW, Brook CG. Assessment of cortisol secretion in children with asthma treated with inhaled steroids. Pediatr Res 1993;33:S13. 28. Weintrob N, Sprecher E, Josefsberg Z, et al. Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitary-adrenal axis in children with idiopathic multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 1998;83:88 –92. 29. Leflein JG, Gawchik SM, Galant SP, et al. Safety of budesonide inhalation suspension (Pulmicort Respules) after up to 52 weeks of treatment in infants and young children with persistent asthma. Allergy Asthma Proc 2001;22: 359 –366.
Requests for reprints should be addressed to: Anne-Marie Irani, MD Department of Pediatrics/Allergy, Immunology & Rheumatology Virginia Commonwealth University MCV Station, Box 980 –225 Richmond, VA 23298-0225 E-mail: [email protected]
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Background: The initial 12-week, double-blind phases of three studies demonstrated that budesonide inhalation suspension (BIS) is effective and well tolerated in infants and young children (6 months to 8 years of age) with persistent asthma. Objective: Open-label, 52-week extensions to these studies were conducted to evaluate long-term safety of BIS, including effects of treatment with the lowest effective dose of BIS on hypothalamic-pituitary-adrenal (HPA)–axis function, as compared with conventional asthma therapy (CAT). Complete results of the earlier phases of the studies and of long-term safety are reported elsewhere; only results pertaining to HPA-axis function are summarized here. Methods: Patients eligible for the open-label phases of the three trials were randomized to treatment with nebulized BIS (n ⫽ 447) or CAT (n ⫽ 223). CAT included short-acting oral or inhaled 2-agonists, methylxanthines, or cromolyn sodium; in two of the studies, CAT could have included other inhaled corticosteroids. HPA-axis function, which had been evaluated during the 12-week doubleblind studies, was again evaluated at the beginning and end of the 52-week study period using basal plasma cortisol concentrations and response to stimulation with a 250-g dose of adrenocorticotropic hormone. Results: There was no evidence of altered HPA-axis function attributable to BIS treatment. No clinically or statistically significant differences in basal or adrenocorticotropic hormone–stimulated plasma cortisol concentrations were observed between BIS and CAT in either the 12-week, double-blind or 52-week, open-label phases of the three studies. Conclusions: The results indicate that treatment with BIS does not result in clinically significant suppression of HPA-axis function in infants and young children. Ann Allergy Asthma Immunol 2002;88:306–312.
INTRODUCTION Inhaled corticosteroids (ICSs) are recommended in National Heart, Lung, and Blood Institute guidelines as firstline anti-inflammatory therapy for the treatment of asthma.1 Corticosteroids reduce the severity of asthma symp-
* Department of Pediatrics, Division of Allergy, Immunology & Rheumatology, Virginia Commonwealth University, Richmond, Virginia. † AstraZeneca LP, Wilmington, Delaware. This study was supported by AstraZeneca LP. Received for publication September 22, 2001. Accepted for publication in revised form November 13, 2001.
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toms,2,3 improve peak expiratory flow rate and spirometry assessments,2,4 decrease requirements for 2-agonists,2 and prevent asthma exacerbations.3 However, concern about the potential for systemic adverse events, including suppression of hypothalamic-pituitaryadrenal (HPA)-axis function and growth in children, has resulted in reluctance on the part of many physicians and parents to use ICSs. HPA-axis function is an important indicator of systemic exposure to corticosteroids. Higher-dose corticosteroid therapy has been associated with HPA-axis suppression, which results from reduced
adrenocorticotropic hormone (ACTH) production and reduced cortisol secretion by the adrenal gland. HPA-axis function has been evaluated after use of ICSs, with inconsistent results.5 Various tests have been applied to evaluate HPAaxis function, including measurement of basal morning plasma cortisol concentrations, integrated plasma cortisol concentrations over the course of ⬎12 to 24 hours, and urinary free cortisol concentrations. The ACTH-stimulation test and 24-hour integrated serial plasma cortisol concentrations are methods recommended by the US Food and Drug Administration (FDA) to evaluate HPAaxis function.6 The ACTH-stimulation test directly measures the function of cortisol-secreting cells and is considered the most useful screening procedure for suspected adrenal insufficiency. In the standard-dose ACTH (cosyntropin)-stimulation test, plasma cortisol concentrations are measured 30 and 60 minutes after an intramuscular or intravenous injection of cosyntropin (typically 250 g) or during a 6- to 8-hour cosyntropin infusion.6 Although the 250-g dose of cosyntropin is well established for studies in adults, no standard dose is accepted for use in children, particularly those ⬍4 years old. Low-dose (0.5 g/1.73 m2), short ACTH stimulation can also be used to evaluate HPA-axis function. Budesonide is an ICS with a favorable ratio of topical anti-inflammatory to systemic activity.7 The low systemic activity of budesonide is likely a result of its extensive first-pass hepatic metabolism (85 to 95% from the orally absorbed drug) and low-potency me-
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tabolites with minimal systemic effects.8 –12 Budesonide inhalation suspension (BIS) was developed for nebulization to meet the specific needs of infants and young children who may be unable to use metered-dose or drypowder inhalers. It is the first nebulized corticosteroid approved in the United States for pediatric patients with asthma and the first ICS approved for use in children as young as 12 months. The availability of a nebulized corticosteroid for infants and young children is especially valuable considering the increasing prevalence and morbidity of pediatric asthma13 and the lack of other FDA-approved therapeutic options for these patients. A series of three recent, 12-week, double-blind studies demonstrated the efficacy and safety of BIS for the treatment of infants and young children with persistent asthma.14 –16 Three 52week extensions to these studies were designed to compare the long-term safety of the lowest maintenance dose of BIS with that of conventional asthma therapy (CAT) in children with persistent asthma. BIS was safe and well tolerated for up to 15 months of treatment (double-blind plus openlabel treatment).17 Evaluation of safety included an evaluation of HPA-axis function at the beginning and end of the 12- and 52-week study periods by measurement of the basal and ACTHstimulated plasma cortisol concentrations in a subset of patients. These results are discussed here, comparing patients who received BIS with those who received placebo or CAT.
METHODS
evaluation. Basal cortisol concentrations were determined from blood samples obtained between 6:00 and 8:30 AM before and after 12 weeks of double-blind treatment. ACTH (Cortrosyn, Organon, West Orange, NJ) was administered (0.25 mg intravenously in children ⬎2 years of age or 0.125 mg intramuscularly in children ⱕ2 years), and ACTH-stimulated cortisol concentrations were determined from blood samples taken 60 minutes after ACTH administration. Plasma samples were transported by SmithKline Beecham Clinical Laboratories (Van Nuys, CA), and analysis of the samples was performed by Analytico (formerly BCO Medical Services BV, Breda, The Netherlands). The assay was based on high-performance liquid chromatography with ultraviolet detection and modified from van den Berg et al.18 Patients with both a basal plasma cortisol concentration of at least 150 nmol/L and an ACTH-stimulated plasma cortisol concentration that was at least 400 nmol/L or that increased by at least 200 nmol/L above the basal concentration after 60 minutes were defined as having “normal” adrenal function for the purpose of statistical analysis.
Double-Blind Treatment A summary of the three double-blind studies is shown in Table 1. Patients’ age ranged from 6 months to 8 years. The first study15 included patients with mild, persistent asthma who had not received previous ICS therapy. The second study16 included patients with moderateto-severe asthma who had received previous ICS therapy. The third study14 included patients with moderate, persistent asthma who may or may not have received previous ICS therapy. BIS doses were based on asthma severity and ranged from 0.25 to 2.0 mg daily in the three studies. Medications used before enrollment included 2-agonists, cromolyn, nedocromil, bronchodilators, and ICSs via pressurized metered-dose inhaler. BIS was provided for both the double-blind and open-label phases of the studies in 2.0-mL white polyethylene ampoules (Pulmicort Respules, AstraZeneca LP, Wilmington, DE). A Pari LC-Jet Plus Nebulizer and a Pari Master compressor (Pari Respiratory Equipment, Inc, Midlothian, VA) were used to administer BIS or placebo in both phases of the studies. All three of these multicenter, randomized, doubleblind, placebo-controlled studies included evaluations of efficacy and safety, as described in detail elsewhere.14 –16 As part of the evaluation for safety, basal and ACTH-stimulated plasma cortisol concentrations were evaluated in a subset of patients who were enrolled at study sites that were equipped to consistently perform the
Open-Label Treatment Patients who completed the 12-week, double-blind phase of each study or who discontinued the study because of worsening of asthma symptoms were eligible to participate in the optional open-label extension of each study. The 52-week extensions were multi-
Table 1. Summary of Three Double-Blind, Placebo-Controlled Studies of BIS in Pediatric Patients Study (yr)
No. of patients
Patient age range
Kemp et al (1999)
359
6 mo to 8 yr
Shapiro et al (1998)
178
4 to 8 yr
Baker et al (1999)
480
6 mo to 8 yr
Active treatment groups BIS BIS BIS BIS BIS BIS BIS BIS BIS BIS
0.25 mg qd 0.5 mg qd 1.0 mg qd 0.25 mg bid 0.5 mg bid 1.0 mg bid 0.25 mg qd 0.25 mg bid 0.5 mg bid 1.0 mg qd
Disease characteristics Mild persistent asthma; no previous inhaled corticosteroids Moderate-to-severe asthma; previous treatment with inhaled corticosteroids Moderate persistent asthma; previous treatment with inhaled corticosteroids optional
qd ⫽ once daily; bid ⫽ twice daily.
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center, parallel-group, randomized, active-controlled, open-label studies designed to evaluate the long-term safety of a minimum effective dose of BIS compared with CAT; efficacy variables were also evaluated. There was no washout period between the doubleblind and open-label phases of the studies. At entry to the open-label phase, patients within each doubleblind treatment group were rerandomized in a 2:1 ratio to receive either BIS or CAT for 52 weeks. At the start of the open-label phase, BIS 0.5 mg was administered once or twice daily at the investigator’s discretion, and attempts were made at each clinic visit to titrate to the minimum effective dose. If possible, dose reductions were made to BIS 0.25 mg once or twice daily, BIS 0.25 mg every other day, or BIS discontinuation. Patients who discontinued BIS treatment were treated with CAT at the discretion of the investigator. Treatment with CAT was limited to 2-agonists (short-acting oral and inhaled), methylxanthines, or cromolyn sodium in the study by Kemp et al15; the studies by Shapiro et al16 and Baker et al14 also allowed ICSs as CAT. Any exacerbations of symptoms were managed by increasing the dose of breakthrough medications and/or BIS, or administering courses of oral prednisone, as judged necessary by the investigator. Long-acting inhaled 2-agonists, astemizole, and nonprescription asthma medications were not allowed during the open-label treatment phase. Statistical Methods The analysis of efficacy variables in the double-blind phase of each of the three studies has been described previously.14 –16 The evaluation of safety in both the 12-week, double-blind and 52-week, open-label phases of each study included evaluations of the incidence and severity of adverse events, changes in physical examinations, vital signs, and clinical laboratory tests, as well as measurements of cortisol concentrations in patients from approximately half the study sites. Baseline and posttreatment cortisol concentrations were required for inclusion in the
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HPA-axis analysis. Further, cortisol data were used in the analysis only if the blood sample was obtained before 9:30 AM on the day of the patient’s visit. In the 52-week open-label study phases, ACTH-stimulation data were summarized, as were the numbers and proportions of patients with HPA-axis suppression. Analysis of variance, adjusted for study center, was used to compare mean ACTH responses between active treatments and placebo. The double-blind studies were powered to demonstrate a response for the efficacy variables. Sample sizes for the open-label periods were not determined by any formal statistical criteria. RESULTS Patient Characteristics Double-blind phase. The studies by Kemp et al, Shapiro et al, and Baker et al included 359, 178, and 481 patients, respectively, who were assessable for safety after the 12-week, double-blind phase (Fig 1). Of these 1,018 patients, 185, 229, 327, and 45 patients were randomized to initial treatment with 0.25-, 0.5-, 1.0-, and 2.0-mg daily doses of BIS, respectively. Treatment groups were well balanced with regard to sex and race, but other characteristics reflected the higher minimum age (4 years) of patients enrolled in the
study by Shapiro et al; age, weight, height, and duration of asthma were higher in the group that received the highest BIS dose group. Baseline pulmonary function test results were similar for all treatment groups.14 –16 Open-label phase. The three openlabel extensions evaluated 670 patients for safety (447 randomized to BIS and 223 randomized to CAT; Fig 1). In the open-label extensions of the studies by Kemp et al, Shapiro et al, and Baker et al, 182, 61, and 204 patients, respectively, were randomized to BIS, and 90, 30, and 103 patients, respectively, were randomized to CAT. The overall mean duration of exposure to treatment was 342 ⫾ 83 days in patients who received BIS (n ⫽ 447) and 304 ⫾ 119 days for patients who received CAT (n ⫽ 223). The median length of treatment was 365 days for both groups. A total of 387 patients (87%) in the BIS treatment group and 160 patients (72%) in the CAT group completed open-label treatment (Fig 1). Median total daily doses of BIS were 0.5 mg, 0.8 to 1.0 mg (0.8 mg for weeks 1 to 36 and 1.0 mg for weeks 36 to 44⫹), and 0.5 mg in the studies by Kemp et al, Shapiro et al, and Baker et al, respectively. As with the 12-week doubleblind study periods, treatment groups in the 52-week, open-label study peri-
Figure 1. Disposition of patients: pooled by Kemp et al, Shapiro et al, and Baker et al. AE, adverse event; LT/DD, lack of therapeutic effect/disease deteriorated; NPM, nonprotocol use of medication; NC, noncompliance with study procedures; WC, withdrew consent; LFU, lost to followup. (Reproduced with permission from Leflein.29
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ods were well balanced with regard to sex and race (Table 2). Among patients who were able to perform pulmonary function tests consistently (42%), these parameters were similar in the BIS and CAT groups (Table 2). HPA-Axis Function Double-blind phase. No clinically relevant differences in basal or ACTHstimulated plasma cortisol concentrations were observed between the placebo groups and any of the BIS treatment groups over the 12-week study period (Fig 2A). At the beginning and end of the 12-week, double-blind phase, mean
basal plasma cortisol concentrations for all treatment groups were within the normal range. Mean changes from baseline in ACTH-stimulated cortisol concentrations at the end of the 12-week, doubleblind phase are shown in Table 3. None of the differences observed between the BIS treatment groups and the placebo group were statistically significant (P ⱖ 0.07). The nearly statistically significant difference (P ⫽ 0.073) between the BIS 0.25-mg treatment group and the placebo group observed actually reflects a decline in ACTH-stimulated response observed in the placebo group (ie, pa-
Table 2. Patient Demographics and Baseline Asthma Characteristics From Analysis of 52-Week, Open-Label Studies: Pooled Data
Sex Male Female Race White Black Latino Asian Other Age (mo) Mean ⫾ SD Range Weight (kg) N Mean ⫾ SD Range Height (cm) N Mean ⫾ SD Range FEV1 (% predicted) N Mean ⫾ SD FVC (L) N Mean ⫾ SD Range FEF25%–75% (L/sec) N Mean ⫾ SD Range Morning PEFR (L/min) N Mean ⫾ SD Range
CAT (n ⴝ 223)
BIS (n ⴝ 447)
142 (63.7%) 81 (36.3%)
291 (65.1%) 156 (34.9%)
165 (74.0%) 35 (15.7%) 17 (7.6%) 0 (0%) 6 (2.7%)
357 (79.9%) 60 (13.4%) 21 (4.7%) 2 (0.4%) 7 (1.6%)
63.0 ⫾ 27.8 11–112
60.9 ⫾ 25.9 8–113
223 21.3 ⫾ 8.4 8.6–58.9
446 20.7 ⫾ 7.7 7.7–76.6
222 110.4 ⫾ 17.8 72.0–150.1
443 109.1 ⫾ 16.5 68.6–155.3
96 83.4 ⫾ 17.3
184 84.2 ⫾ 18.2
96 1.62 ⫾ 0.38 0.73–2.48
187 1.56 ⫾ 0.47 0.67–3.64
96 1.25 ⫾ 0.47 0.40–2.61
187 1.21 ⫾ 0.52 0.23–3.06
107 166.9 ⫾ 45.7 80.0–285.3
213 169.4 ⫾ 55.6 56.3–461.4
FEV1 ⫽ forced expiratory volume in 1 second; FVC ⫽ forced vital capacity; FEF25%–75% ⫽ forced expiratory flow during the middle half of the forced vital capacity; PEFR ⫽ peak expiratory flow rate.
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tients in the BIS 0.25-mg group actually had a more favorable ACTH response than patients in the placebo group). The percentage of patients shifting from “normal” to “abnormal” ACTH-stimulated response at week 12 were similar between the placebo and BIS treatment groups (Table 4). Open-label phase. Long-term safety of BIS treatment was evaluated in 670 children. Basal plasma cortisol concentrations were measured in 189 patients, and ACTH-stimulated cortisol concentrations were measured in 180 patients (Fig 2B). No clinically significant differences in basal or ACTHstimulated cortisol concentrations were observed between the BIS and the CAT group over the 52-week treatment period (P ⫽ 0.312; Table 2). Further, the proportions of patients with shifts in response from “normal” to “abnormal” at week 52 in ACTHstimulated cortisol concentrations were not different between the BIS and the CAT groups (24% of patients in the BIS treatment group and 21% of patients in the CAT group). DISCUSSION Many short- and long-term studies have shown ICSs to be of benefit in children with asthma. However, most efficacy and safety studies in asthmatic children have been limited to children ⬎6 years old. In addition, comparable data in this age group using a nebulized delivery for ICSs are limited. Therefore, three 12-week, placebocontrolled studies evaluating BIS in infants and young children aged 6 months to 8 years were continued as 52-week, open-label extension studies to provide additional information on the safety of nebulized budesonide in this age group. No clinically relevant or statistically significant differences in basal or ACTH-stimulated cortisol concentrations were detected between the BIS and placebo groups in the controlled studies, nor between the BIS and CAT groups in the open-label studies. These results are consistent with those of a previous study in which no detectable adrenal suppression (as evaluated by measurement of over-
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Figure 2. Mean basal and ACTH-stimulated plasma cortisol concentrations at baseline and week 12 of the double-blind study period (A) and at baseline and week 52 of the open-label treatment period (B).
night urinary free cortisol excretion) was observed with administration of budesonide at doses up to 1,250 g daily in asthmatic children.19 The systemic effects of ICSs are dependent on many factors, including delivery device used, pharmacokinetic properties of the drug, site and degree of drug deposition, delivered dose, concurrent medications, and individual patient responses.20 Budesonide has several unique features that may have contributed to the study results. First, the bioavailability of nebulized budes-
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onide in children is the lowest of all currently approved ICSs at 6% of the nominal dose. The low bioavailability of budesonide in children is attributable, in part, to relatively low delivery to the lungs, as well as high (85 to 95%) first-pass hepatic metabolism of swallowed drug.8,12 This low bioavailability alone would predict minimal HPA-axis suppression at the doses studied. Budesonide clearance in children is 30 mL/minute/kg2, approximately 50% faster than in adults. Finally, BIS is effective in many children
with once-daily dosing,15 which may contribute to minimizing the effect on the diurnally sensitive HPA axis. Fundamental differences between corticosteroids are also apparent. Studies comparing the effects of different ICSs on the HPA axis have been reviewed and include evaluations of beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolide, and triamcinolone acetonide,20 with differences in the risk for HPA-axis effects demonstrated in studies of both asthmatic adults and children.21 Budesonide seems to suppress HPA-axis function to a lesser extent than either beclomethasone dipropionate or fluticasone propionate at comparable doses,20 –25 although some dependence on specific inhaler devices used is evident in the available data. In an evaluation of beclomethasone and budesonide for asthmatic children, a greater effect on the HPA axis was observed for beclomethasone than budesonide.24 In a study of 10 children, single-dose inhaled fluticasone resulted in greater adrenal suppression than inhaled budesonide.19 The short ACTH test as the standard evaluation of HPA-axis function is not without controversy, and the optimal dose of ACTH is controversial as well. In some studies, lowdose ACTH (0.5 g/1.73 m2 body surface) was used to identify individuals with mild adrenal insufficiency not identified with standard-dose ACTH stimulation.26,27 However, a recent trial comparing low- and standard-dose ACTH stimulation with the insulin tolerance test for HPA-axis evaluation in children with idiopathic multiple pituitary hormone deficiencies demonstrated a similar high sensitivity and specificity in detecting secondary adrenal insufficiency with both lowand standard-dose ACTH stimulation tests,28 supporting use of standarddose ACTH testing in this open-label safety program. Many open-label safety studies evaluate safety in patient groups without a positive control, often after FDA approval. Thus, these safety studies can be affected by patient selection or prior treatment biases. The BIS open-label
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Table 3. Changes in Basal and ACTH-Stimulated Plasma Cortisol Levels by Total Daily Dose of BIS (Pooled Data) Basal (nmol/L) Total daily dose (mg/day)
12-week, double-blind phase Placebo BIS 0.25 BIS 0.5 BIS 1.0 52-week, open-label phase BIS CAT
ACTH-stimulated (nmol/L)
N
Baseline (mean)
End (mean)
N
Baseline (mean)
End (mean)
Adjusted change*
64 56 69 91
300 288 312 301
290 296 293 298
61 58 66 92
669 652 675 658
635 662 671 647
⫺27.9 22.5 ⫺2.8 ⫺2.3
132 57
294 296
280 296
125 55
654 621
563 570
⫺98.4 ⫺67.7
95% CI on adjusted change ⫺69, ⫺21, ⫺44, ⫺37,
14 66 38 32
P Value
0.073 vs placebo 0.355 vs placebo 0.313 vs placebo
⫺140, ⫺57 ⫺124, ⫺12
0.312 vs CAT
* Mean change from baseline in ACTH-stimulated cortisol level from ANOVA. Table 4. Shifts in ACTH-Stimulation Test from Baseline to End of Double-Blind Phase (Week 12) by Total Daily Dose
Baseline
Abnormal (%) Normal (%)
Placebo (n ⴝ 61)
BIS total daily dose 0.25 mg (n ⴝ 55)
0.5 mg (n ⴝ 64)
1.0 mg (n ⴝ 90)
2.0 mg (n ⴝ 13)
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal
1 (13%) 8 (15%)
7 (88%) 45 (85%)
1 (25%) 6 (12%)
3 (75%) 45 (88%)
1 (11%) 7 (13%)
8 (89%) 48 (87%)
3 (38%) 8 (10%)
5 (63%) 74 (90%)
— 1 (9%)
2 (100%) 10 (91%)
extension program was designed to randomly assign patients to either BIS or CAT to provide safety data on BIS in the context of current pediatric asthma management and to ensure that patient demographics were comparable between active treatment groups. However, because study medications were not blinded in the open-label phase of this study, and because only a subset of study sites evaluated HPAaxis function, bias in patient selection or study conduct can not be ruled out. CONCLUSION BIS is a valuable therapeutic option for administration of ICSs to infants and young children with asthma who may lack the understanding or coordination necessary to use pressurized metereddose or dry-powder inhalers. The 52week extension studies suggest that BIS causes no clinically significant suppression of HPA-axis function, as reflected by both basal plasma cortisol concentrations and ACTH-stimulated cortisol response.
2.
3.
4.
5.
6.
REFERENCES 1. National Heart, Lung, and Blood Institute/National Institutes of Health.
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7.
National Asthma Education Program Expert Panel Report. Guidelines for the diagnosis and management of asthma. Expert panel report no. 2. Bethesda, MD: National Institutes of Health, 1997. Publication no 97– 4051. Haahtela T, Ja¨rvinen M, Kava T, et al. Comparison of a 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388 –392. Juniper EF, Kline PA, Vanzieleghem MA, et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142:832– 836. Pedersen S, Hansen OR. Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol 1995; 95:29 –33. Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148: S1–S26. Chrousos GP, Harris AG. Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 1. General principles. Neuroimmunomodulation 1998;5:277–287. Clissold SP, Heel RC. Budesonide. A preliminary review of its pharmacody-
8.
9.
10.
11.
12.
13.
14.
namic properties and therapeutic efficacy in asthma and rhinitis. Drugs 1984;28:485–518. Agertoft L, Andersen A, Weibull E, Pedersen S. Systemic availability and pharmacokinetics of nebulised budesonide in preschool children. Arch Dis Child 1999;80:241–247. Bisgaard H, Pedersen S, Damkjær Nielsen M, Østerballe O. Adrenal function in asthmatic children treated with inhaled budesonide. Acta Pædiatr Scand 1991;80:213–217. Lipworth BJ, Seckl JR. Measures for detecting systemic bioactivity with inhaled and intranasal corticosteroids. Thorax 1997;52:476 – 482. Pulmicort Turbuhaler 200 g (budesonide inhalation powder) product information. AstraZeneca LP. Physicians’ Desk Reference, 55th edition. Montvale, NJ: Medical Economics Company, 2001:591–595. Szefler SJ. Pharmacodynamics and pharmacokinetics of budesonide: a new nebulized corticosteroid. J Allergy Clin Immunol 1999;104: S175–S183. Mannino D, Homa DM, Pertowski CA, et al. Surveillance for asthma–United States, 1960 –1995. Mor Mortal Wkly Rep CDC Surveill Summ 1998:47:1–27. Baker JW, Mellon M, Wald J, et al. A multiple-dosing, placebo-controlled
311
15.
16.
17.
18.
19.
312
study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103:414 – 421. Kemp J, Skoner D, Szefler SJ, et al. Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999; 83:231–239. Shapiro G, Mendelson L, Kraemer MJ, et al. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998; 102:789 –796. Scott MB, Skoner DP. Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999;104: 200 –209. van den Berg JH, Mol CR, Deelder RS, Thijssen JH. A quantitative assay of cortisol in human plasma by high performance liquid chromatography using a selective chemically bonded stationary phase. Clin Chim Acta 1977;78:165–172. Clark DJ, Clark RA, Lipworth BJ. Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic
children. Thorax 1996;51:941–943. 20. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998;157:S1–S53. 21. O’Byrne PM, Pedersen S. Measuring efficacy and safety of different inhaled corticosteroid preparations. J Allergy Clin Immunol 1998;102:879 – 886. 22. Bisgaard H, Damkjær Nielsen M, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J Allergy Clin Immunol 1988;81:1088 –1095. 23. Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55–58. 24. 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: 433– 435. 25. Wilson AM, Clark DJ, Devlin MM, et al. Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults. Eur J Clin Pharmacol 1998;53:317–320. 26. Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in pa-
tients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995;80: 1243–1246. 27. Crowley S, Hindmarsh PC, Honour JW, Brook CG. Assessment of cortisol secretion in children with asthma treated with inhaled steroids. Pediatr Res 1993;33:S13. 28. Weintrob N, Sprecher E, Josefsberg Z, et al. Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitary-adrenal axis in children with idiopathic multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 1998;83:88 –92. 29. Leflein JG, Gawchik SM, Galant SP, et al. Safety of budesonide inhalation suspension (Pulmicort Respules) after up to 52 weeks of treatment in infants and young children with persistent asthma. Allergy Asthma Proc 2001;22: 359 –366.
Requests for reprints should be addressed to: Anne-Marie Irani, MD Department of Pediatrics/Allergy, Immunology & Rheumatology Virginia Commonwealth University MCV Station, Box 980 –225 Richmond, VA 23298-0225 E-mail: [email protected]
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