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Safety of budesonide inhalation suspension in infants aged six to twelve months with mild to moderate persistent asthma or recurrent wheeze
SAFETY OF BUDESONIDE INHALATION SUSPENSION IN INFANTS AGED SIX TO TWELVE MONTHS WITH MILD TO MODERATE PERSISTENT ASTHMA OR RECURRENT WHEEZE WILLIAM E. BERGER, MD, PAUL Y. QAQUNDAH, MD, KATHRYN BLAKE, PHARMD, JOSE RODRIGUEZ-SANTANA, MD, ANNE-MARIE IRANI, MD, JOHN XU, PHD, AND MITCHELL GOLDMAN, MD, PHD
Objective To compare the safety of budesonide inhalation suspension (BIS) with placebo in infants 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze. Study design In this multicenter, randomized, double-blinded, parallel-group, placebo-controlled study, 141 patients received 0.5 mg BIS (n = 48), 1.0 mg BIS (n = 44), or placebo (n = 49) once daily for 12 weeks. The primary variable was adrenal function, based on cosyntropin-stimulated plasma cortisol levels. Spontaneous adverse events and clinical laboratory findings also were monitored. Results Overall, the types and frequencies of adverse events reported during the study were comparable across treatment groups. The response to cosyntropin stimulation was similar across treatment groups, with no significant difference between BIS treatment and placebo. Conclusions The safety profile of BIS was similar to that of placebo, with no suppressive effect on adrenal function in patients 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze. (J Pediatr 2005;146:91-5)
nhaled corticosteroids (ICS) are preferred for the long-term treatment of all severities of persistent asthma in children of all ages.1 Currently, budesonide inhalation suspension (BIS) (AstraZeneca LP, Wilmington, Del) is the only nebulized ICS approved by the US Food and Drug Administration (FDA) and the only ICS approved for use in asthmatic children as young as 12 months. No other ICS is approved for children younger than 4 years. Cromolyn sodium, the only other FDA-approved nebulized anti-inflammatory asthma medication, is approved for use in children 2 years of age and older. Cromolyn sodium is less efficacious than BIS2 and is not preferred for the long-term treatment of persistent asthma in children.1 In the United States, safety and efficacy of nebulized BIS have been demonstrated in three 12-week, randomized, double-blinded, placebo-controlled studies involving 1018 infants and young children 6 months to 8 years of age with mild to severe persistent asthma.3-5 Long-term (52-week) open-label extensions of these studies have shown that BIS treatment (median daily doses of 0.5 to 1.0 mg) is similarly well tolerated in children 8 months to 9 years of age.6,7 Controlled clinical studies addressing the safety and efficacy of ICS exclusively in infants are lacking; consequently, the FDA has requested that further safety and efficacy data be collected for the use of ICS in this patient population. The current study was conducted to assess the safety of once-daily administration of nebulized BIS in infants with
I
AE Adverse event ANCOVA Analysis of covariance BIS Budesonide inhalation suspension
FDA ICS
Food and Drug Administration Inhaled corticosteroid(s)
From Allergy and Asthma Associates of Southern California, Mission Viejo, California; Pediatric Care Medical Group, Inc, Huntington Beach, California; Nemours Children’s Clinic, Jacksonville, Florida; Pediatric Pulmonary Program of San Juan, San Juan, Puerto Rico; Virginia Commonwealth University, Richmond, Virginia; and AstraZeneca LP, Wilmington, Delaware. Supported by AstraZeneca LP, Wilmington, Delaware. Dr Berger receives research grants from AstraZeneca, GlaxoSmithKline, Aventis, and Schering-Plough; he is on the speaker’s bureau for AstraZeneca, GlaxoSmithKline, Aventis, and ScheringPlough. Dr Blake receives research grants from AstraZeneca, GlaxoSmith Kline, Merck, and Schering-Plough; she is on the speaker’s bureau for AstraZeneca, GlaxoSmithKline, and Merck. Dr Irani receives research grants from AstraZeneca; she is a paid consultant and on the speaker’s bureau for AstraZeneca. Dr Rodriguez-Santana has no inter-est or financial arrangement, includ-ing grants, advisory board memberships, or share holdings, with AstraZeneca. Dr Qaqundah has no potential, perceived, or real conflict of interest with the company that produces budesonide inhalation suspension (AstraZeneca). Each author contributed equally to the preparation and review of this manuscript. Submitted for publication Feb 19, 2004; last revision received Jun 30, 2004; accepted Aug 27, 2004. Reprint requests: William E. Berger, MD, Allergy and Asthma Associates of Southern California, 27800 Medical Center Road, Suite 244, Mission Viejo, CA 92691-6410. E-mail: Weberger@ uci.edu. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.08.060
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diagnosed mild to moderate persistent asthma or symptoms of recurrent wheeze. Adrenal function was the primary variable. Although the study was not powered to assess efficacy, asthma symptoms, global health status, treatment failures, and patient withdrawals were monitored.
METHODS Patients Enrolled patients were $6 but <12 months of age, with mild to moderate persistent asthma. Patients with $2 episodes of persistent or recurrent wheeze who might have benefited from inhaled anti-inflammatory treatment also were enrolled at the investigators’ discretion. Patients with severe asthma, a history of assisted ventilation (except at birth), or other severe chronic lung diseases were excluded. Exclusion criteria also included treatment with systemic corticosteroids within 4 weeks of study entry and treatment with oral corticosteroids or ICS, slow-release oral b2-adrenergic agonists, long-acting b2-adrenergic agonists, or 5-lipoxygenase and leukotriene antagonists within 2 weeks of random assignment. The study was performed according to the Declaration of Helsinki, and the institutional review board at each investigation site approved the study protocol. Each patient’s legal guardian provided informed consent.
Study Design This randomized, double-blinded, placebo-controlled, parallel-group study was conducted at 55 US centers (AstraZeneca LP study SD-004-0732). During a 2- to 3-week run-in period, patients discontinued maintenance asthma therapies (except for anticholinergics and metaproterenol). Patients with asthma symptoms on $3 of the 7 days before random assignment and who provided basal morning and 1-hour postcosyntropin stimulation plasma specimens were randomly assigned 1:1:1 to receive 0.5 or 1.0 mg Pulmicort Respules (BIS) once daily or placebo. Random assignment was stratified according to patient age (6 months to <7 months, 7 months to <8 months, 8 months to <9 months, and 9 months to <12 months). Treatments were randomly assigned in blocks of 3 within each stratum. Study medications were administered by means of a Pari LC-Plus nebulizer connected to a Pari Master compressor (Pari Respiratory Equipment, Inc, Richmond, Va) with a face mask or mouthpiece. The first dose of study medication was administered at the clinic, and guardians were instructed on the proper method for subsequent medication administration. Patients returned to the clinic 4 times after random assignment (weeks 2, 4, 8, and 12) for evaluation and data collection. Adrenal function, the primary variable, was determined on the basis of mean changes from baseline to week 12 (or time of early discontinuation) in postcosyntropin-stimulated plasma cortisol levels. Basal plasma cortisol samples were obtained no later than 8:30 AM, when possible, and poststimulation samples were obtained 1 hour after a bolus injection of 0.125 mg cosyntropin (Cortrosyn; Organon Inc, West Orange, NJ). Subnormal adrenal function was defined as 92 Berger et al
a post–cosyntropin plasma cortisol value <500 nmol/L.8 Secondary safety variables included the incidence and severity of adverse events (AEs) and changes from baseline in vital signs, physical examination results, oropharyngeal and nasal fungal cultures, and clinical laboratory test results. Comprehensive physical examinations and laboratory and fungal culture assessments were performed at visit 1 and study end (week 12 or time of early discontinuation). Height was measured with the use of a tape measure while patients were in a supine position. Vital signs were monitored at each visit. Efficacy variables included asthma symptoms and breakthrough medication use (reported in patient diaries), percentage of symptom-free days, number of treatment failures and patient discontinuations, and global assessment of asthma status. Physicians compared global asthma status at study end or time of discontinuation with pretreatment status, based on a scale from 1 (a great deal better) to 5 (a great deal worse).
Concomitant Treatment Anticholinergics and metaproterenol were allowed during the run-in period if used on a regular basis. Shortacting b2-adrenergic agonists were allowed as rescue medication throughout the study. Oral prednisone or prednisolone was permitted after random assignment to treat asthma exacerbations, but use could not exceed 10 days. Other medications considered necessary for the patient’s welfare were given at the discretion of the investigator.
Statistical Analyses Sample size calculations for this study were not based on formal statistical calculations; the size and design of this study were based on guidance from the FDA. The difference between groups in the change from baseline to week 12 in cosyntropin-stimulated plasma cortisol levels was analyzed by means of analysis of covariance (ANCOVA), with treatment as the main effect and the baseline cosyntropin-stimulated value as a covariate. The Wilcoxon rank sum test also was used to analyze these data. A similar ANCOVA was used to analyze changes from baseline to the average over the 12-week treatment period in asthma symptom scores. The incidence of AEs and changes from baseline in physical and laboratory assessments were summarized descriptively. ANCOVA, with treatment as the main effect and baseline as the covariate, was used to analyze changes from baseline to the average over the 12-week, double-blinded treatment period in nighttime and daytime asthma symptom scores. The percentage of symptomfree days over the 12-week, double-blinded treatment period was analyzed by means of ANCOVA, with treatment as the main effect. Physicians’ global assessments at the last visit on treatment and the proportion of patients with treatment failures were analyzed by means of the Mantel-Haenszel test.
RESULTS Patient Demographic and Baseline Characteristics Of the 216 patients enrolled in the study, 141 were randomly assigned to treatment (Table I). Patient mean age The Journal of Pediatrics January 2005
Table I. Patient demographics and baseline characteristics Treatment group
Sex, n (%) Female Male Age, mo Mean ± SD Range Mean plasma cortisol ± SD, nmol/L Basal Cosyntropin-stimulated Age stratum, n (%) $6 to ,9 mo $9 to ,12 mo
0.5 mg BIS (n = 48)
1.0 mg BIS (n = 44)
Placebo (n = 49)
Total (N = 141)
16 (33.3) 32 (66.7)
18 (40.9) 26 (59.1)
20 (40.8) 29 (59.2)
54 (38.3) 87 (61.7)
8.3 ± 1.7 5-11
8.3 ± 1.8 6-12
8.6 ± 1.7 6-11
8.4 ± 1.7 5-12
245.5 ± 132.4 632.4 ± 179.2
240.2 ± 159.0 632.4 ± 168.4
247.8 ± 148.5 629.7 ± 184.2
244.7 ± 145.5 631.4 ± 176.4
26 (54.2) 22 (45.8)
25 (56.8) 19 (43.2)
25 (51.0) 24 (49.0)
76 (53.9) 65 (46.1)
was 8.4 months. With the exception of a higher percentage of boys than girls 9 to 12 months of age in the 0.5-mg BIS group (82% vs 18%, respectively), patient demographics were similar across treatment groups and age strata. Plasma cortisol levels were comparable across treatment groups (Table I) and age strata (data not shown). Of the 141 patients randomly assigned to treatment, 117 (83%) completed the study. The most common reasons for treatment discontinuation were loss of patient to follow-up and ‘‘other reasons’’ (such as noncompliance, physician’s choice, patient relocation, withdrawn consent). No patient discontinued the study because of treatment failure.
Concomitant Treatment Concomitant asthma medications were used during the study by 19% and 25% of patients receiving 0.5 and 1.0 mg BIS, respectively, and 31% of patients receiving placebo. Oral corticosteroids were the most common concomitant asthma medications and were used by 7 (15%), 9 (21%), and 11 (22%) patients in the 0.5-mg BIS, 1.0-mg BIS, and placebo groups, respectively.
Safety ADRENAL FUNCTION. Some patients in the intention-totreat population did not have sufficient treatment duration or adrenal function data to meet the specifications set forth in the FDA’s written request. Thus, adrenal function was assessed in a subset of 76 patients who provided both basal and stimulated plasma cortisol samples at baseline and end of treatment and who remained in the study for $78 days after random assignment (evaluable population). Cosyntropin stimulation at baseline and week 12 resulted in increased mean plasma cortisol levels in all treatment groups. Mean poststimulation plasma cortisol levels at week 12 were 674, 661, and 650 nmol/L in the 0.5-mg BIS, 1.0-mg BIS, and placebo treatment groups, respectively. Changes from baseline in poststimulated plasma cortisol levels were similar for both
Table II. Shift from baseline to week 12 in cosyntropin-stimulated plasma cortisol values (nmol/L) Treatment group Baseline value 0.5 mg BIS $500 ,500 Total 1.0 mg BIS $500 ,500 Total Placebo $500 ,500 Total
Week 12 $500, n (%)
<500, n (%)
21 (75.0) 2 (7.1) 23 (82.1)
4 (14.3) 1 (3.6) 5 (17.9)
12 (70.6) 3 (17.6) 15 (88.2)
2 (11.8) 0 (0.0) 2 (11.8)
24 (77.4) 3 (9.7) 27 (87.1)
1 (3.2) 3 (9.7) 4 (12.9)
active treatment groups and placebo (ANCOVA, P > .58; Wilcoxon rank sum test, P > .89). Shifts in cosyntropin-stimulated plasma cortisol levels from baseline to week 12 are summarized in Table II for the evaluable population. Shifts from normal baseline ($500 nmol/L) to subnormal on-treatment levels (<500 nmol/L)8 were observed in 4 (14.3%), 2 (11.8%), and 1 (3.2%) of the patients in the 0.5-mg BIS, 1.0-mg BIS, and placebo groups, respectively. Of these 7 patients, only 1 received treatment with an oral corticosteroid during the study (days 63 to 68). Shifts from subnormal at baseline to normal on treatment were observed in 2 (7.1%), 3 (17.6%), and 3 (9.7%) patients in the 0.5-mg BIS, 1.0 mg-BIS, and placebo groups, respectively. Results of adrenal function analyses using the intentionto-treat patient population (ie, all randomly assigned patients who received $1 dose of study medication and who had $1
Safety Of Budesonide Inhalation Suspension In Infants Aged Six To Twelve Months With Mild To Moderate Persistent Asthma Or Recurrent Wheeze
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Table III. Adverse events reported by $10% of patients in any treatment group Adverse event
0.5 mg BIS (n = 48)
Respiratory infection Otitis media Fever Rhinitis Vomiting Aggravated asthma Diarrhea Tooth disorder Sinusitis Coughing Rash Conjunctivitis Pharyngitis Rhonchi
1.0 mg BIS (n = 44)
22 (45.8) 23 (47.9) 12 (25.0) 10 (20.8) 5 (10.4) 4 (8.3) 4 (8.3) 6 (12.5) 4 (8.3) 4 (8.3) 5 (10.4) 7 (14.6) 7 (14.6) 1 (2.1)
22 12 10 12 7 4 5 7 6 2 4 0 0 1
(50.0) (27.3) (22.7) (27.3) (15.9) (9.1) (11.4) (15.9) (13.6) (4.5) (9.1) (0.0) (0.0) (2.3)
Placebo (n = 49) 23 20 17 10 5 8 6 2 4 6 3 4 2 6
(46.9) (40.8) (34.7) (20.4) (10.2) (16.3) (12.2) (4.1) (8.2) (12.2) (6.1) (8.2) (4.1) (12.2)
Total (N = 141) 67 (47.5) 55 (39.0) 39 (27.7) 32 (22.7) 17 (12.1) 16 (11.3) 15 (10.6) 15 (10.6) 14 (9.9) 12 (8.5) 12 (8.5) 11 (7.8) 9 (6.4) 8 (5.7)
Values shown are number (%) of patients.
observation taken while receiving study medication; N = 141) were consistent with those presented for the evaluable population. Also, no differences were noted between the BIS groups and placebo group in the change from baseline in plasma cortisol values within either of the 2 age strata: 6 to <9 months or 9 to <12 months (data not shown). ADVERSE EVENTS. One hundred twenty-nine of 141 patients (91.5%) had $1 AE while receiving treatment. Approximately 90%, 98%, and 88% of patients in the 0.5-mg BIS, 1.0-mg BIS, and placebo groups, respectively, reported $1 AE. The most commonly reported AEs are shown in Table III. Overall, the types and frequencies of AEs reported during the study were comparable across treatment groups. Tooth disorder (eg, teething, teething pain, teething syndrome), reported at a higher frequency with BIS treatment, was considered by the study investigator to be unrelated to study medication in each case. The frequency of AEs did not differ appreciably as a function of age strata, except in the case of rhinitis. Rhinitis was reported by about twice as many patients 6 to 9 months of age compared with patients 9 to 12 months of age in both the 0.5-mg BIS (27% vs 14%) and placebo (28% vs 13%) groups. Discontinuations caused by AEs were limited to 1 patient in the 0.5-mg BIS group who discontinued treatment early after a treatment-related rash on the face and neck and 2 patients in the 1.0-mg BIS group after serious AEs requiring hospitalization (asthma [n = 1] and pneumonia [n = 1]). Serious AEs were reported in 3 patients in the 0.5-mg BIS group (asthma, respiratory infection, viral infection) and 2 patients in the 1.0-mg BIS group (asthma, pneumonia). All of the serious AEs occurred in children 9 to <12 months of age, and none were considered related to treatment. OTHER SAFETY ASSESSMENTS. Mean and median changes in vital signs from baseline to each visit were small, with no 94 Berger et al
clinically meaningful differences between the treatment groups. Mean height increased from baseline to week 12 in all treatment groups and in both age strata. Compared with placebo, mean differences in change in height from baseline of 0.2 cm (95% CI, 20.6 to 1.0) and 0.6 cm (95% CI, 20.2 to 1.4) were observed in the 0.5-mg BIS and 1.0-mg BIS groups, respectively. Positive fungal nasal cultures were rare, and there were no significant differences between the treatment groups with respect to fungal cultures at week 12 when adjusted for baseline culture results. Mean and median changes in hematology and clinical chemistry values were generally comparable among the 3 treatment groups.
Efficacy Compared with patients receiving placebo, the mean percentage of symptom-free days was numerically greater for patients receiving 0.5 and 1.0 mg BIS (37.5%, 48.8%, and 43.4%, respectively). Treatment-related differences in physicians’ global assessments of patient health status did not reach statistical significance, but physicians rated 90% and 85% of patients in the 0.5-mg BIS and 1.0-mg BIS groups, respectively, a ‘‘great deal better’’ or ‘‘somewhat better’’ compared with 67% of patients in the placebo group. BIS treatment resulted in a greater reduction in daytime and nighttime symptoms compared with placebo.
DISCUSSION The primary purpose of this 12-week study was to collect additional safety data for nebulized BIS in a patient population that is underrepresented in clinical trials of ICS. Adrenal function, the primary variable, was assessed in children with asthma 6 to 12 months of age, based on changes in cosyntropinstimulated plasma cortisol levels. The cosyntropin-stimulation test is considered an adequate measure of adrenal function.9 The Journal of Pediatrics January 2005
Consistent with previously reported studies showing no effect of short-term (12 weeks) or long-term (52 weeks) BIS treatment on adrenal function in children 6 months to 8 years of age,3-5,7 the current study demonstrated no suppression of adrenal function with once-daily BIS treatment in infants 6 to 12 months of age. Compared with placebo, treatment with BIS was not associated with a difference in response to cosyntropin stimulation. The safety of BIS, based on other safety variables (ie, AEs, study discontinuations, and clinical laboratory test results), was similar to that of placebo and consistent with that in children older than 12 months.3-5 The most frequently reported AEs were those common to children with asthma (respiratory infection, otitis media, fever, rhinitis). The frequency of conjunctivitis, the most commonly reported ocular AE, was low. A review of BIS safety that included studies enrolling children as young as 6 months similarly reports a low frequency of ocular AEs with BIS.10 In general, proper administration of nebulized treatments should limit ocular deposition and any potential for ocular AEs. As in previous short-term growth studies of ICS use in children, patients receiving BIS demonstrated reduced growth velocity compared with those receiving placebo. However, changes in growth velocity are more adequately addressed in long-term studies. Long-term studies with inhaled budesonide have shown that initial reductions in growth velocity are transient11 and that expected final adult height can be achieved with long-term treatment.12 Assessing treatment efficacy in infants is difficult because data (eg, symptoms) are reported indirectly by the parent or guardian, and it is difficult to obtain objective lung function measurements.13 Moreover, the current study was not powered to address efficacy. Nevertheless, asthma symptom control and global health status were somewhat improved in patients treated with BIS versus placebo. Adrenal function was assessed only in a subset of patients who provided appropriate plasma cortisol samples and remained in the study for $78 days after random assignment, so additional data should be sought for this patient population despite the difficulties involved. In conclusion, this study provides additional safety data for BIS in an understudied patient population. The results of this 12-week study, conducted exclusively in infants 6 to 12 months of age, indicate that once-daily administration of BIS,
0.5 or 1.0 mg, is safe and well-tolerated in infants with mild to moderate persistent asthma or recurrent wheeze.
REFERENCES 1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics: 2002. J Allergy Clin Immunol 2002;110(Suppl 5): S141-219. 2. Leflein JG, Szefler SJ, Murphy KR, Fitzpatrick S, Cruz-Rivera M, Miller CJ, et al. Nebulized budesonide inhalation suspension compared with cromolyn sodium nebulizer solution for asthma in young children: results of a randomized outcomes trial. Pediatrics 2002;109:866-72. 3. Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M, WaltonBowen K, Smith JA. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998;102:789-96. 4. Kemp JP, Skoner DP, Szefler SJ, Walton-Bowen K, Cruz-Rivera M, Smith JA. Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999;83:231-9. 5. Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, WaltonBowen K. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103:414-21. 6. Leflein JG, Gawchik SM, Galant SP, Lyzell E, Young M, Cruz-Rivera M, 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;22:359-66. 7. Irani A-M, Cruz-Rivera M, Fitzpatrick S, Hoag J, Smith JA. Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal–axis function in infants and young children with persistent asthma. Ann Allergy Asthma Immunol 2002;88:306-12. 8. Grinspoon SK, Biller BMK. Clinical review 62: laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923-31. 9. Chrousos GP, Harris AG. Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy, I: general principles. Neuroimmunomodulation 1998;5:277-87. 10. Szefler SJ, Lyzell E, Fitzpatrick S, Cruz-Rivera M. Safety profile of budesonide inhalation suspension in the pediatric population: worldwide experience. Ann Allergy Asthma Immunol 2004;93:83-90. 11. The Childhood Asthma Management Program Research Group. Longterm effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-63. 12. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343: 1064-9. 13. Kemp JP. Study designs and challenges in clinical studies conducted in infants and children with asthma. J Allergy Clin Immunol 1999;104: S184-90.
Safety Of Budesonide Inhalation Suspension In Infants Aged Six To Twelve Months With Mild To Moderate Persistent Asthma Or Recurrent Wheeze
95
Objective To compare the safety of budesonide inhalation suspension (BIS) with placebo in infants 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze. Study design In this multicenter, randomized, double-blinded, parallel-group, placebo-controlled study, 141 patients received 0.5 mg BIS (n = 48), 1.0 mg BIS (n = 44), or placebo (n = 49) once daily for 12 weeks. The primary variable was adrenal function, based on cosyntropin-stimulated plasma cortisol levels. Spontaneous adverse events and clinical laboratory findings also were monitored. Results Overall, the types and frequencies of adverse events reported during the study were comparable across treatment groups. The response to cosyntropin stimulation was similar across treatment groups, with no significant difference between BIS treatment and placebo. Conclusions The safety profile of BIS was similar to that of placebo, with no suppressive effect on adrenal function in patients 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze. (J Pediatr 2005;146:91-5)
nhaled corticosteroids (ICS) are preferred for the long-term treatment of all severities of persistent asthma in children of all ages.1 Currently, budesonide inhalation suspension (BIS) (AstraZeneca LP, Wilmington, Del) is the only nebulized ICS approved by the US Food and Drug Administration (FDA) and the only ICS approved for use in asthmatic children as young as 12 months. No other ICS is approved for children younger than 4 years. Cromolyn sodium, the only other FDA-approved nebulized anti-inflammatory asthma medication, is approved for use in children 2 years of age and older. Cromolyn sodium is less efficacious than BIS2 and is not preferred for the long-term treatment of persistent asthma in children.1 In the United States, safety and efficacy of nebulized BIS have been demonstrated in three 12-week, randomized, double-blinded, placebo-controlled studies involving 1018 infants and young children 6 months to 8 years of age with mild to severe persistent asthma.3-5 Long-term (52-week) open-label extensions of these studies have shown that BIS treatment (median daily doses of 0.5 to 1.0 mg) is similarly well tolerated in children 8 months to 9 years of age.6,7 Controlled clinical studies addressing the safety and efficacy of ICS exclusively in infants are lacking; consequently, the FDA has requested that further safety and efficacy data be collected for the use of ICS in this patient population. The current study was conducted to assess the safety of once-daily administration of nebulized BIS in infants with
I
AE Adverse event ANCOVA Analysis of covariance BIS Budesonide inhalation suspension
FDA ICS
Food and Drug Administration Inhaled corticosteroid(s)
From Allergy and Asthma Associates of Southern California, Mission Viejo, California; Pediatric Care Medical Group, Inc, Huntington Beach, California; Nemours Children’s Clinic, Jacksonville, Florida; Pediatric Pulmonary Program of San Juan, San Juan, Puerto Rico; Virginia Commonwealth University, Richmond, Virginia; and AstraZeneca LP, Wilmington, Delaware. Supported by AstraZeneca LP, Wilmington, Delaware. Dr Berger receives research grants from AstraZeneca, GlaxoSmithKline, Aventis, and Schering-Plough; he is on the speaker’s bureau for AstraZeneca, GlaxoSmithKline, Aventis, and ScheringPlough. Dr Blake receives research grants from AstraZeneca, GlaxoSmith Kline, Merck, and Schering-Plough; she is on the speaker’s bureau for AstraZeneca, GlaxoSmithKline, and Merck. Dr Irani receives research grants from AstraZeneca; she is a paid consultant and on the speaker’s bureau for AstraZeneca. Dr Rodriguez-Santana has no inter-est or financial arrangement, includ-ing grants, advisory board memberships, or share holdings, with AstraZeneca. Dr Qaqundah has no potential, perceived, or real conflict of interest with the company that produces budesonide inhalation suspension (AstraZeneca). Each author contributed equally to the preparation and review of this manuscript. Submitted for publication Feb 19, 2004; last revision received Jun 30, 2004; accepted Aug 27, 2004. Reprint requests: William E. Berger, MD, Allergy and Asthma Associates of Southern California, 27800 Medical Center Road, Suite 244, Mission Viejo, CA 92691-6410. E-mail: Weberger@ uci.edu. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.08.060
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diagnosed mild to moderate persistent asthma or symptoms of recurrent wheeze. Adrenal function was the primary variable. Although the study was not powered to assess efficacy, asthma symptoms, global health status, treatment failures, and patient withdrawals were monitored.
METHODS Patients Enrolled patients were $6 but <12 months of age, with mild to moderate persistent asthma. Patients with $2 episodes of persistent or recurrent wheeze who might have benefited from inhaled anti-inflammatory treatment also were enrolled at the investigators’ discretion. Patients with severe asthma, a history of assisted ventilation (except at birth), or other severe chronic lung diseases were excluded. Exclusion criteria also included treatment with systemic corticosteroids within 4 weeks of study entry and treatment with oral corticosteroids or ICS, slow-release oral b2-adrenergic agonists, long-acting b2-adrenergic agonists, or 5-lipoxygenase and leukotriene antagonists within 2 weeks of random assignment. The study was performed according to the Declaration of Helsinki, and the institutional review board at each investigation site approved the study protocol. Each patient’s legal guardian provided informed consent.
Study Design This randomized, double-blinded, placebo-controlled, parallel-group study was conducted at 55 US centers (AstraZeneca LP study SD-004-0732). During a 2- to 3-week run-in period, patients discontinued maintenance asthma therapies (except for anticholinergics and metaproterenol). Patients with asthma symptoms on $3 of the 7 days before random assignment and who provided basal morning and 1-hour postcosyntropin stimulation plasma specimens were randomly assigned 1:1:1 to receive 0.5 or 1.0 mg Pulmicort Respules (BIS) once daily or placebo. Random assignment was stratified according to patient age (6 months to <7 months, 7 months to <8 months, 8 months to <9 months, and 9 months to <12 months). Treatments were randomly assigned in blocks of 3 within each stratum. Study medications were administered by means of a Pari LC-Plus nebulizer connected to a Pari Master compressor (Pari Respiratory Equipment, Inc, Richmond, Va) with a face mask or mouthpiece. The first dose of study medication was administered at the clinic, and guardians were instructed on the proper method for subsequent medication administration. Patients returned to the clinic 4 times after random assignment (weeks 2, 4, 8, and 12) for evaluation and data collection. Adrenal function, the primary variable, was determined on the basis of mean changes from baseline to week 12 (or time of early discontinuation) in postcosyntropin-stimulated plasma cortisol levels. Basal plasma cortisol samples were obtained no later than 8:30 AM, when possible, and poststimulation samples were obtained 1 hour after a bolus injection of 0.125 mg cosyntropin (Cortrosyn; Organon Inc, West Orange, NJ). Subnormal adrenal function was defined as 92 Berger et al
a post–cosyntropin plasma cortisol value <500 nmol/L.8 Secondary safety variables included the incidence and severity of adverse events (AEs) and changes from baseline in vital signs, physical examination results, oropharyngeal and nasal fungal cultures, and clinical laboratory test results. Comprehensive physical examinations and laboratory and fungal culture assessments were performed at visit 1 and study end (week 12 or time of early discontinuation). Height was measured with the use of a tape measure while patients were in a supine position. Vital signs were monitored at each visit. Efficacy variables included asthma symptoms and breakthrough medication use (reported in patient diaries), percentage of symptom-free days, number of treatment failures and patient discontinuations, and global assessment of asthma status. Physicians compared global asthma status at study end or time of discontinuation with pretreatment status, based on a scale from 1 (a great deal better) to 5 (a great deal worse).
Concomitant Treatment Anticholinergics and metaproterenol were allowed during the run-in period if used on a regular basis. Shortacting b2-adrenergic agonists were allowed as rescue medication throughout the study. Oral prednisone or prednisolone was permitted after random assignment to treat asthma exacerbations, but use could not exceed 10 days. Other medications considered necessary for the patient’s welfare were given at the discretion of the investigator.
Statistical Analyses Sample size calculations for this study were not based on formal statistical calculations; the size and design of this study were based on guidance from the FDA. The difference between groups in the change from baseline to week 12 in cosyntropin-stimulated plasma cortisol levels was analyzed by means of analysis of covariance (ANCOVA), with treatment as the main effect and the baseline cosyntropin-stimulated value as a covariate. The Wilcoxon rank sum test also was used to analyze these data. A similar ANCOVA was used to analyze changes from baseline to the average over the 12-week treatment period in asthma symptom scores. The incidence of AEs and changes from baseline in physical and laboratory assessments were summarized descriptively. ANCOVA, with treatment as the main effect and baseline as the covariate, was used to analyze changes from baseline to the average over the 12-week, double-blinded treatment period in nighttime and daytime asthma symptom scores. The percentage of symptomfree days over the 12-week, double-blinded treatment period was analyzed by means of ANCOVA, with treatment as the main effect. Physicians’ global assessments at the last visit on treatment and the proportion of patients with treatment failures were analyzed by means of the Mantel-Haenszel test.
RESULTS Patient Demographic and Baseline Characteristics Of the 216 patients enrolled in the study, 141 were randomly assigned to treatment (Table I). Patient mean age The Journal of Pediatrics January 2005
Table I. Patient demographics and baseline characteristics Treatment group
Sex, n (%) Female Male Age, mo Mean ± SD Range Mean plasma cortisol ± SD, nmol/L Basal Cosyntropin-stimulated Age stratum, n (%) $6 to ,9 mo $9 to ,12 mo
0.5 mg BIS (n = 48)
1.0 mg BIS (n = 44)
Placebo (n = 49)
Total (N = 141)
16 (33.3) 32 (66.7)
18 (40.9) 26 (59.1)
20 (40.8) 29 (59.2)
54 (38.3) 87 (61.7)
8.3 ± 1.7 5-11
8.3 ± 1.8 6-12
8.6 ± 1.7 6-11
8.4 ± 1.7 5-12
245.5 ± 132.4 632.4 ± 179.2
240.2 ± 159.0 632.4 ± 168.4
247.8 ± 148.5 629.7 ± 184.2
244.7 ± 145.5 631.4 ± 176.4
26 (54.2) 22 (45.8)
25 (56.8) 19 (43.2)
25 (51.0) 24 (49.0)
76 (53.9) 65 (46.1)
was 8.4 months. With the exception of a higher percentage of boys than girls 9 to 12 months of age in the 0.5-mg BIS group (82% vs 18%, respectively), patient demographics were similar across treatment groups and age strata. Plasma cortisol levels were comparable across treatment groups (Table I) and age strata (data not shown). Of the 141 patients randomly assigned to treatment, 117 (83%) completed the study. The most common reasons for treatment discontinuation were loss of patient to follow-up and ‘‘other reasons’’ (such as noncompliance, physician’s choice, patient relocation, withdrawn consent). No patient discontinued the study because of treatment failure.
Concomitant Treatment Concomitant asthma medications were used during the study by 19% and 25% of patients receiving 0.5 and 1.0 mg BIS, respectively, and 31% of patients receiving placebo. Oral corticosteroids were the most common concomitant asthma medications and were used by 7 (15%), 9 (21%), and 11 (22%) patients in the 0.5-mg BIS, 1.0-mg BIS, and placebo groups, respectively.
Safety ADRENAL FUNCTION. Some patients in the intention-totreat population did not have sufficient treatment duration or adrenal function data to meet the specifications set forth in the FDA’s written request. Thus, adrenal function was assessed in a subset of 76 patients who provided both basal and stimulated plasma cortisol samples at baseline and end of treatment and who remained in the study for $78 days after random assignment (evaluable population). Cosyntropin stimulation at baseline and week 12 resulted in increased mean plasma cortisol levels in all treatment groups. Mean poststimulation plasma cortisol levels at week 12 were 674, 661, and 650 nmol/L in the 0.5-mg BIS, 1.0-mg BIS, and placebo treatment groups, respectively. Changes from baseline in poststimulated plasma cortisol levels were similar for both
Table II. Shift from baseline to week 12 in cosyntropin-stimulated plasma cortisol values (nmol/L) Treatment group Baseline value 0.5 mg BIS $500 ,500 Total 1.0 mg BIS $500 ,500 Total Placebo $500 ,500 Total
Week 12 $500, n (%)
<500, n (%)
21 (75.0) 2 (7.1) 23 (82.1)
4 (14.3) 1 (3.6) 5 (17.9)
12 (70.6) 3 (17.6) 15 (88.2)
2 (11.8) 0 (0.0) 2 (11.8)
24 (77.4) 3 (9.7) 27 (87.1)
1 (3.2) 3 (9.7) 4 (12.9)
active treatment groups and placebo (ANCOVA, P > .58; Wilcoxon rank sum test, P > .89). Shifts in cosyntropin-stimulated plasma cortisol levels from baseline to week 12 are summarized in Table II for the evaluable population. Shifts from normal baseline ($500 nmol/L) to subnormal on-treatment levels (<500 nmol/L)8 were observed in 4 (14.3%), 2 (11.8%), and 1 (3.2%) of the patients in the 0.5-mg BIS, 1.0-mg BIS, and placebo groups, respectively. Of these 7 patients, only 1 received treatment with an oral corticosteroid during the study (days 63 to 68). Shifts from subnormal at baseline to normal on treatment were observed in 2 (7.1%), 3 (17.6%), and 3 (9.7%) patients in the 0.5-mg BIS, 1.0 mg-BIS, and placebo groups, respectively. Results of adrenal function analyses using the intentionto-treat patient population (ie, all randomly assigned patients who received $1 dose of study medication and who had $1
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Table III. Adverse events reported by $10% of patients in any treatment group Adverse event
0.5 mg BIS (n = 48)
Respiratory infection Otitis media Fever Rhinitis Vomiting Aggravated asthma Diarrhea Tooth disorder Sinusitis Coughing Rash Conjunctivitis Pharyngitis Rhonchi
1.0 mg BIS (n = 44)
22 (45.8) 23 (47.9) 12 (25.0) 10 (20.8) 5 (10.4) 4 (8.3) 4 (8.3) 6 (12.5) 4 (8.3) 4 (8.3) 5 (10.4) 7 (14.6) 7 (14.6) 1 (2.1)
22 12 10 12 7 4 5 7 6 2 4 0 0 1
(50.0) (27.3) (22.7) (27.3) (15.9) (9.1) (11.4) (15.9) (13.6) (4.5) (9.1) (0.0) (0.0) (2.3)
Placebo (n = 49) 23 20 17 10 5 8 6 2 4 6 3 4 2 6
(46.9) (40.8) (34.7) (20.4) (10.2) (16.3) (12.2) (4.1) (8.2) (12.2) (6.1) (8.2) (4.1) (12.2)
Total (N = 141) 67 (47.5) 55 (39.0) 39 (27.7) 32 (22.7) 17 (12.1) 16 (11.3) 15 (10.6) 15 (10.6) 14 (9.9) 12 (8.5) 12 (8.5) 11 (7.8) 9 (6.4) 8 (5.7)
Values shown are number (%) of patients.
observation taken while receiving study medication; N = 141) were consistent with those presented for the evaluable population. Also, no differences were noted between the BIS groups and placebo group in the change from baseline in plasma cortisol values within either of the 2 age strata: 6 to <9 months or 9 to <12 months (data not shown). ADVERSE EVENTS. One hundred twenty-nine of 141 patients (91.5%) had $1 AE while receiving treatment. Approximately 90%, 98%, and 88% of patients in the 0.5-mg BIS, 1.0-mg BIS, and placebo groups, respectively, reported $1 AE. The most commonly reported AEs are shown in Table III. Overall, the types and frequencies of AEs reported during the study were comparable across treatment groups. Tooth disorder (eg, teething, teething pain, teething syndrome), reported at a higher frequency with BIS treatment, was considered by the study investigator to be unrelated to study medication in each case. The frequency of AEs did not differ appreciably as a function of age strata, except in the case of rhinitis. Rhinitis was reported by about twice as many patients 6 to 9 months of age compared with patients 9 to 12 months of age in both the 0.5-mg BIS (27% vs 14%) and placebo (28% vs 13%) groups. Discontinuations caused by AEs were limited to 1 patient in the 0.5-mg BIS group who discontinued treatment early after a treatment-related rash on the face and neck and 2 patients in the 1.0-mg BIS group after serious AEs requiring hospitalization (asthma [n = 1] and pneumonia [n = 1]). Serious AEs were reported in 3 patients in the 0.5-mg BIS group (asthma, respiratory infection, viral infection) and 2 patients in the 1.0-mg BIS group (asthma, pneumonia). All of the serious AEs occurred in children 9 to <12 months of age, and none were considered related to treatment. OTHER SAFETY ASSESSMENTS. Mean and median changes in vital signs from baseline to each visit were small, with no 94 Berger et al
clinically meaningful differences between the treatment groups. Mean height increased from baseline to week 12 in all treatment groups and in both age strata. Compared with placebo, mean differences in change in height from baseline of 0.2 cm (95% CI, 20.6 to 1.0) and 0.6 cm (95% CI, 20.2 to 1.4) were observed in the 0.5-mg BIS and 1.0-mg BIS groups, respectively. Positive fungal nasal cultures were rare, and there were no significant differences between the treatment groups with respect to fungal cultures at week 12 when adjusted for baseline culture results. Mean and median changes in hematology and clinical chemistry values were generally comparable among the 3 treatment groups.
Efficacy Compared with patients receiving placebo, the mean percentage of symptom-free days was numerically greater for patients receiving 0.5 and 1.0 mg BIS (37.5%, 48.8%, and 43.4%, respectively). Treatment-related differences in physicians’ global assessments of patient health status did not reach statistical significance, but physicians rated 90% and 85% of patients in the 0.5-mg BIS and 1.0-mg BIS groups, respectively, a ‘‘great deal better’’ or ‘‘somewhat better’’ compared with 67% of patients in the placebo group. BIS treatment resulted in a greater reduction in daytime and nighttime symptoms compared with placebo.
DISCUSSION The primary purpose of this 12-week study was to collect additional safety data for nebulized BIS in a patient population that is underrepresented in clinical trials of ICS. Adrenal function, the primary variable, was assessed in children with asthma 6 to 12 months of age, based on changes in cosyntropinstimulated plasma cortisol levels. The cosyntropin-stimulation test is considered an adequate measure of adrenal function.9 The Journal of Pediatrics January 2005
Consistent with previously reported studies showing no effect of short-term (12 weeks) or long-term (52 weeks) BIS treatment on adrenal function in children 6 months to 8 years of age,3-5,7 the current study demonstrated no suppression of adrenal function with once-daily BIS treatment in infants 6 to 12 months of age. Compared with placebo, treatment with BIS was not associated with a difference in response to cosyntropin stimulation. The safety of BIS, based on other safety variables (ie, AEs, study discontinuations, and clinical laboratory test results), was similar to that of placebo and consistent with that in children older than 12 months.3-5 The most frequently reported AEs were those common to children with asthma (respiratory infection, otitis media, fever, rhinitis). The frequency of conjunctivitis, the most commonly reported ocular AE, was low. A review of BIS safety that included studies enrolling children as young as 6 months similarly reports a low frequency of ocular AEs with BIS.10 In general, proper administration of nebulized treatments should limit ocular deposition and any potential for ocular AEs. As in previous short-term growth studies of ICS use in children, patients receiving BIS demonstrated reduced growth velocity compared with those receiving placebo. However, changes in growth velocity are more adequately addressed in long-term studies. Long-term studies with inhaled budesonide have shown that initial reductions in growth velocity are transient11 and that expected final adult height can be achieved with long-term treatment.12 Assessing treatment efficacy in infants is difficult because data (eg, symptoms) are reported indirectly by the parent or guardian, and it is difficult to obtain objective lung function measurements.13 Moreover, the current study was not powered to address efficacy. Nevertheless, asthma symptom control and global health status were somewhat improved in patients treated with BIS versus placebo. Adrenal function was assessed only in a subset of patients who provided appropriate plasma cortisol samples and remained in the study for $78 days after random assignment, so additional data should be sought for this patient population despite the difficulties involved. In conclusion, this study provides additional safety data for BIS in an understudied patient population. The results of this 12-week study, conducted exclusively in infants 6 to 12 months of age, indicate that once-daily administration of BIS,
0.5 or 1.0 mg, is safe and well-tolerated in infants with mild to moderate persistent asthma or recurrent wheeze.
REFERENCES 1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics: 2002. J Allergy Clin Immunol 2002;110(Suppl 5): S141-219. 2. Leflein JG, Szefler SJ, Murphy KR, Fitzpatrick S, Cruz-Rivera M, Miller CJ, et al. Nebulized budesonide inhalation suspension compared with cromolyn sodium nebulizer solution for asthma in young children: results of a randomized outcomes trial. Pediatrics 2002;109:866-72. 3. Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M, WaltonBowen K, Smith JA. Efficacy and safety of budesonide inhalation suspension (Pulmicort Respules) in young children with inhaled steroid-dependent, persistent asthma. J Allergy Clin Immunol 1998;102:789-96. 4. Kemp JP, Skoner DP, Szefler SJ, Walton-Bowen K, Cruz-Rivera M, Smith JA. Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999;83:231-9. 5. Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, WaltonBowen K. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103:414-21. 6. Leflein JG, Gawchik SM, Galant SP, Lyzell E, Young M, Cruz-Rivera M, 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;22:359-66. 7. Irani A-M, Cruz-Rivera M, Fitzpatrick S, Hoag J, Smith JA. Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal–axis function in infants and young children with persistent asthma. Ann Allergy Asthma Immunol 2002;88:306-12. 8. Grinspoon SK, Biller BMK. Clinical review 62: laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923-31. 9. Chrousos GP, Harris AG. Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy, I: general principles. Neuroimmunomodulation 1998;5:277-87. 10. Szefler SJ, Lyzell E, Fitzpatrick S, Cruz-Rivera M. Safety profile of budesonide inhalation suspension in the pediatric population: worldwide experience. Ann Allergy Asthma Immunol 2004;93:83-90. 11. The Childhood Asthma Management Program Research Group. Longterm effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-63. 12. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343: 1064-9. 13. Kemp JP. Study designs and challenges in clinical studies conducted in infants and children with asthma. J Allergy Clin Immunol 1999;104: S184-90.
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