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Efficacy and safety of high-dose inhaled steroids in children with asthma: A comparison of fluticasone propionate with budesonide
E
Efficacy and safety of high-dose inhaled steroids in children with asthma: A comparison of fluticasone propionate with budesonide
Alexander C. Ferguson, MD, Sheldon Spier, MD, Ahmed Manjra, MD, Florens G. A. Versteegh, MD, Stephen Mark, BSc, RT, and Paul Zhang, MSc Objective: To compare the efficacy and adverse effects of inhaled fluticasone propionate (FP), 400 µg/d, with those of budesonide (BUD), 800 µg/d, in children with moderate to severe asthma. Methods: Three hundred thirty-three children, ages 4 to 12 years, receiving inhaled corticosteroids were enrolled in a double-blind, double-dummy, randomized, parallel-group study. After a 2-week run-in phase, 166 children received FP and 167 received BUD for 20 weeks. The primary outcome variable was mean morning peak expiratory flow; the 2 treatments were to be regarded as equivalent if the 90% CI for the treatment difference was within ± 15 L/min. Pulmonary function, height, and diary cards were assessed at each visit; and morning serum cortisol levels were determined before and after treatment. Results: Baseline peak expiratory flow was similar, FP 236 ± 72 (SD) L/min and BUD 229 ± 74, increasing after treatment to 277 ± 41 and 257 ± 28, a difference between treatments of 12 L/min (90% CI 6-19 L/min; P = .002). Symptom control and use of rescue medication were the same. Cortisol levels after treatment were 199 nmol/L (FP) and 183 nmol/L (BUD) (treatment ratio = 1.09; 90% CI 0.98-1.21; P = .172). Linear growth was less in those receiving BUD (mean difference, 6.2 mm; 95% CI 2.9-9.6; P = .0003). Conclusion: FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms. Growth was reduced with BUD compared with FP, but there was no difference in serum cortisol suppression or hepatic or renal function. (J Pediatr 1999;134:422-7)
Inhaled corticosteroids have an important role in the treatment of chronic asthma in children.1 Despite the availability of several formulations, their ef-
ficacy relative to each other has not been widely studied, nor has the risk of long-term adverse effects, especially on growth and hypothalamo-pituitary-
From the B.C. Children’s Hospital, Vancouver, British Columbia, Canada; Alberta Children’s Hospital, Calgary, Alberta, Canada; Westville Hospital, Durban, South Africa; Groene Hart Ziekenhuis, Gouda, Netherlands; and Glaxo Wellcome Inc, Mississauga, Ontario, Canada.
Submitted for publication Aug 5, 1998; revision received Nov 16, 1998; accepted Dec 15, 1998. Reprint requests: Alexander C. Ferguson, MD, University of British Columbia, B.C. Children’s Hospital, 4480 Oak St, Vancouver, BC, V6H 3V4, Canada. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/96626
422
adrenocortical axis suppression in prepubertal children. Fluticasone propionate is a new ICS for the treatment of asthma. It has a potent glucocorticoid anti-inflammatory action with few systemic effects2 and is as efficacious as beclomethasone dipropionate, even when administered at half the dose.2-4 Studies in adults with the use of similar doses,5-7 and in children with mild asthma receiving 400 µg/d,8 comparing FP and BUD showed them to be equally effective. Differences in potency may be more important in children BDP BUD FEV1 FP ICS PEF
Beclomethasone dipropionate Budesonide Forced expiratory volume in 1 second Fluticasone propionate Inhaled corticosteroid Peak expiratory flow
with moderate to severe asthma requiring high doses of ICS in whom a lower effective dose might be associated with less likelihood of adverse effects. To determine whether FP in half the dose was as efficacious and as safe in controlling asthma as budesonide, we assessed the effects of these drugs in a group of prepubertal children with moderate to severe chronic asthma. The study was of randomized, doubleblind, double-placebo, parallel-group design comparing the clinical efficacy and safety/tolerability of daily FP, 400 µg, administered through a Diskus inhaler (GlaxoWellcome) with BUD, 800 µg, administered through a Turbuhaler inhaler (Astra Pharma Inc), both dry powder formulations.
FERGUSON ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 4
METHODS A cohort of 442 children, ages 4 to 12 years, with a history of moderate to severe asthma were recruited from 6 countries. All had a Sexual Maturity Rating of 1 (prepubertal) at the time of the initial clinic visit. Children with only seasonal or exercise-induced symptoms were excluded. All subjects required moderate to high doses of ICS to control symptoms, 400 to 800 µg of BDP or BUD or 200 to 400 µg of FP per day for at least 1 month preceding the start of the run-in period. All were using inhaled β-adrenergic medication for relief of symptoms when necessary and were able to demonstrate ability in using inhalation devices and peak flow meters and in completing diary cards with parental assistance. In the month preceding the study, none of the subjects had changed the dose of their inhaled or oral medications, and none had been admitted to the hospital for treatment of respiratory illness. Children who had received combination bronchodilators or systemic corticosteroids, had any sign of serious disease other than asthma, or had received any investigational drugs were excluded. Respective institutional ethics committee and regulatory agency approvals were received before commencing the study, and written informed consent was obtained from parents and, when appropriate, from children before entry into the study. During the 2-week run-in period, subjects discontinued the use of their usual inhaled β-adrenergic bronchodilator medication and replaced it with inhaled albuterol (Diskhaler [Glaxo Wellcome] or metered-dose inhaler), to be taken as required. All other asthma medications, including their usual ICS therapy, were continued at a constant dose and frequency. The use of long-acting β-adrenergic drugs, combination bronchodilators, or other corticosteroid formulations (except nasal sprays) was not permitted in the study. Subjects, with parental assistance if re-
Table I. Symptom scores
Symptoms Day None 1 short period 2 or more short periods Most of the day, activity not affected Most of the day, activity reduced Severe, unable to go to school Night None Wakened once Wakened 2 or more times Awake most of the night Severe, unable to sleep Total
quired, were instructed in the correct use of the Mini-Wright peak flow meter, the Diskus, and the Turbuhaler and were shown how to complete the daily diary cards. They were asked to measure and record the best of 3 maximal PEFs, morning and evening before administration of medication, and to record their symptom score and use of bronchodilator rescue medication twice daily, at bedtime and on rising (Table I). The peak flow meters were new and calibrated by the manufacturer. At the end of the run-in period, the subjects’ ICS treatment was randomized to FP, 400 µg, administered through Diskus (200 µg twice daily) or BUD, 800 µg, administered through Turbuhaler (400 µg twice daily) after the following inclusion criteria were satisfied: (1) daily symptom score of 1 or greater on at least 4 of the last 7 consecutive days before randomization and (2) a mean morning PEF, on 4 of the last 7 consecutive days of the run-in period, that was ≤85% of the postbronchodilator PEF at the randomization visit or PEF ≤85% of predicted value9 on at least 4 of the last 7 days before randomization or reversibility of 15% or greater of PEF or forced expiratory volume in 1 second in response to albuterol, 200 µg by metered-dose inhaler or 400 µg by Diskhaler, at the ini-
Score 0 1 2 3 4 5 0 1 2 3 4 0-9
tial or randomization clinic visit, albuterol having been withheld for at least the previous 4 hours. Treatment continued for 20 weeks, followed by a 2-week follow-up period during which treatment reverted to the patients’ usual therapy as designated by their physicians. Rescue therapy with albuterol from a metered-dose inhaler (100 µg per actuation) or Diskhaler (200 µg dry powder per blister) was available at all times. The use of a spacer device (Aero Chamber, Trudell Medical Group) was permitted, provided that this was constant throughout the study and documented. Concurrent asthma and non-asthma medications were permitted as long as the dose, frequency, and route remained fixed throughout the study. Children attended the clinic on 6 occasions: at the beginning and end of the run-in period; after 8, 16, and 20 weeks of treatment; and at the end of the 2-week follow-up period. At each of these visits, 3 measurements of PEF were obtained by using the child’s own Mini-Wright peak flow meter (Armstrong Industries Inc, Northbrook, Ill), and for those 6 years and older, spirometric assessment was performed (forced vital capacity, FEV1, and forced expiratory flow, midexpiratory phase). Children were instructed to withhold albuterol therapy for at 423
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THE JOURNAL OF PEDIATRICS APRIL 1999
Table II. Characteristics of the children studied
n Boys/girls Age (y, mean ± SD) Height (cm, mean ± SD) Duration of asthma (% of group) <1 y 1-5 y 6-10 y >10 y Unknown Presence of atopy (% of group)
FP group
BUD group
166 114/52 8.2 ± 2 131 ± 14
167 109/58 7.9 ± 2 129 ± 14
3 45 49 2 <1 88
2 57 40 <1 <1 86
least 4 hours before each clinic visit. Oropharyngeal swabs were obtained to determine the presence of Candida albicans if there was clinical evidence of infection on visual examination.
medication. Two courses of systemic corticosteroids, each of up to 2 weeks’ duration, were permitted during the study, but more than this prompted withdrawal of the child from the study.
Laboratory Evaluations
Analysis
Blood samples for complete blood count, hepatic and renal function, and serum cortisol determinations were obtained between 8:00 and 10:00 AM on 2 occasions—at baseline (pre-trial visit) and at the end of treatment. Samples were also obtained at the follow-up visit if any abnormal results had been noted at the end of treatment. Blood samples and urine (dipstick) were analyzed locally.
The primary outcome variable was mean morning PEF during the last 7 treatment days, obtained from the daily record cards assessed by analysis of covariance. Mean morning PEF during the run-in period as baseline was used as a covariate. The analysis incorporated adjustments for country, age, and sex. The treatment difference and the 90% CI of the treatment difference were computed. The mean evening PEF, mean morning and evening PEFs expressed as percent of predicted value for age, sex, and height, and mean diurnal variation in PEF were analyzed as for mean morning PEF. Predicted lung function values were calculated from subjects’ heights and sex by using standard formulas.9 The median day and night symptom scores, percentage of symptom-free nights, median number of albuterol doses per day and per night, and the percentage of days and nights during which albuterol was not required were analyzed to assess the difference between treatments by using the Wilcoxon rank-sum test. Changes from baseline height, baseline spi-
Adverse Events All adverse events were recorded. An asthma exacerbation was defined as a worsening of asthma symptoms requiring a change in or addition to a child’s asthma medication other than increased albuterol use. The occurrence of an exacerbation was not a withdrawal criterion, and a child could continue in the study at the physicians’ discretion. Those who experienced an exacerbation were instructed to use their inhaled bronchodilator and to report to the hospital clinic within 24 hours. The physician could decide to initiate a course of oral corticosteroid therapy in addition to the child’s study 424
rometric values, and serum cortisol levels (log-transformed) were assessed by analysis of covariance, adjusting for country, age, and sex. All statistical analyses were performed by using SAS version 6.12 (SAS Institute). The study was designed to show equivalence between FP and BUD. The results for the groups were to be taken as equivalent if the 90% CI for treatment difference in mean morning PEF was within ± 15 L/min. Assuming the standard deviation of mean PEF was 37 L/min as observed previously,3 the study would have approximately 97% power of declaring equivalence with 175 children per treatment group.
RESULTS A total of 442 children were enrolled in the study, of whom 333 proceeded to randomized treatment and qualified for the primary population of analysis, the intent-to-treat population. There were 166 subjects who received FP, 200 µg twice daily, and 167 subjects who received BUD, 400 µg twice daily. Twenty-five subjects (7.5%) were ultimately excluded from analysis because of protocol violations (15 receiving FP and 10 receiving BUD); protocol violations were incorrect dose of ICS or inadequate symptom scores to fulfill the entry criteria. Children in both treatment groups were similar in terms of baseline PEF and clinical characteristics (Table II). Compliance was calculated as the number of days or nights when each study medication was used, divided by the number of days of recorded data, multiplied by 100. There was no significant difference between treatment groups (P = .977). The compliance rate was almost 100% for both FP and BUD groups. Fiftynine subjects in the FP group received nasal corticosteroids during the study period (33 FP, 12 BUD, 8 triamcinolone, 5 BDP, 1 flunisolide) compared with 45 in the BUD group (24
FERGUSON ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 4 FP, 10 BUD, 4 flunisolide, 4 BDP, and 3 triamcinolone).
Efficacy Baseline mean morning PEF for the FP group was 236 ± 72 (SD) L/min, and for the BUD group, 229 ± 74 L/min, not significantly different. After treatment, the adjusted mean morning PEFs, measured over the last 7 treatment days, were 271 ± 82 and 259 ± 75 L/min, respectively (Fig 1). The difference in means was 12 L/min (90% CI 619 L/min, P = .002). There were no significant interactions of treatment by country of study, sex, or baseline PEF, but there was a significant interaction by age. For the purpose of the study, the 2 treatment regimens, FP and BUD, were to be considered equivalent if the 90% CI for the difference in the mean morning PEFs for the last 7 days of the 20-week treatment period was within ± 15 L/min. The 90% lower and upper confidence limits for the treatment difference were 6 and 19 L/min, respectively, indicating that the treatments were not equivalent, with FP being superior. The improvements were reflected in mean morning PEF at clinic visits (Fig 2). Morning PEF (measured at home over the last 7 treatment days), expressed as percent of predicted value, improved slightly more with FP; adjusted mean was 106% compared with BUD 102% (P = .027), as did mean evening PEF, 271 and 259 L/min (P = .002), and evening PEF as percent of predicted value, 106% and 102% (P = .037), respectively. There were no differences between treatment groups for improvement in daytime symptom scores (P = .729), nighttime symptom scores (P = .34), or percentage of days with symptom scores <2 (P = .107). Nighttime symptom scores were equally reduced in both groups (P = .958). Similarly, the need for rescue medication was similar in the 2 groups during the treatment phase for daytime (P = .181) and nighttime (P = .59) albuterol use and for ability to completely withdraw albuterol,
Fig 1. Mean morning PEF at the end of treatment week. Differences were: after 20 weeks, 12 L/min (90% CI 6-19 L/min, P = .002); at week 5, 6 L/min (P = .096); at week 10, 5 L/min (P = .286); and at week 15, 8 L/min (P = .043).
Fig 2. Mean PEF at clinic visits.Visit 1 is start of run-in period, visit 2 start of treatment, and visit 5 end of treatment.
Table III. Height of study subjects in response to treatment, measured by stadiometry
FP group n Mean height (cm) Visit 2 Visit 5 Adjusted mean growth (cm)
76 129.6 133.0 3.31*
BUD group 78 130.2 132.2 1.99*
*Difference in adjusted mean increase in height was 1.32 cm (95% CI 0.48-2.17; P = .002).
day (P = .134) or night (P = .507). In children who were able to perform pulmonary function maneuvers in the clinic, there was a comparable improvement from baseline to end of treatment in forced vital capacity (P = .244), PEF (P = .096), FEV1 (P = .183), and forced expiratory flow, midexpiratory phase (P = .081) in both treatment groups.
Safety There was no significant difference in the number of children who experienced an adverse event in the 2 treatment groups. The most common adverse event was “upper respiratory tract infection,” reported with a similar incidence—28% of children in the FP group and 32% in the BUD group. There were no differences in the incidence of other predictable adverse
events, the most common being headache and throat irritation. During the study, 4 subjects (2%) in the FP group and 10 (6%) in the BUD group reported a serious adverse event during treatment. These included asthma exacerbations (2 in the FP group and 8 in the BUD group), respiratory tract infections, fractured bones, seizure disorders, gastroenteritis, appendicitis, and viral meningitis. Only one of these patients, with an exacerbation of asthma in the BUD group, was withdrawn from the study at treatment week 19. The results of clinical examinations in both groups were similar, and none of the children had oropharyngeal candidiasis. No clinically significant abnormalities were detected in blood counts or tests of hepatic or renal function. Baseline geometric mean serum cor425
FERGUSON ET AL
tisol levels were 227.6 ± 63 (SD) nmol/L for FP and 203 ± 74 nmol/L for BUD. The adjusted geometric means at end of treatment were 199 nmol/L and 183 nmol/L, respectively (treatment ratio = 1.09; 90% CI 0.98-1.21; P = .172). Thus in terms of morning serum cortisol levels, there was no difference between the 2 treatment groups. Linear growth velocity was greater in those receiving FP who had an adjusted mean increase in height of 2.51 cm compared with 1.89 for those receiving BUD. The difference was 6.2 mm (95% CI 2.9-9.6, P = .0003). The study was not designed to critically assess growth as an outcome factor; measurement of height was done primarily to calculate predicted values for spirometry. To further test the validity of the growth effect, we evaluated a subgroup of 154 children whose heights had been measured by stadiometry. The difference in adjusted mean increase in height was 13.2 mm (P = .0024, Table III).
DISCUSSION The results of our study are consistent with previous reports of similar clinical efficacy when comparing FP (200 µg) and BDP (400 µg) per day in children with mild to moderate asthma2,3 and when comparing FP at half the daily dose with BUD in adult asthmatic subjects.4-7 A study in children with mild to moderate asthma, in which FP and BUD (both 400 µg/d) were compared, showed a similar effect in control of asthma symptoms.8 Our findings of equivalence or superior clinical effect with half the nominal dose of FP compared with BUD are consistent with the much longer elimination half-life,10 longer glucocorticoid receptor-binding half-life,11 and lipophilicity10 of FP. There was no difference in morning serum cortisol levels in those receiving FP compared with those receiving BUD, and neither drug resulted in a significant suppression from baseline. The children had 426
THE JOURNAL OF PEDIATRICS APRIL 1999 previously been receiving moderate to high doses of inhaled steroids, which might have already influenced hypothalamo-pituitary-adrenocortical axis function,12 but the values we found were not reduced (normal >170 nmol/L). This group of children with moderate to severe asthma may be more resistant to the effect of corticosteroids than others with mild to moderate disease, and more sensitive measures of adrenal function may be required to assess adrenal suppression in these children. With evidence of greater pharmacologic potency for FP, it is both surprising and of great interest that it had less effect on linear growth than BUD. The findings are not conclusive because the study was not designed to focus on growth. Assessment of height was not standardized, other than by stadiometry in less than half of the children; the follow-up period was only 20 weeks; and we could not include a placebo control group in our study because we were treating children with moderate to severe asthma, so the full effect of FP and BUD on growth velocity is unclear. Short-term studies in mild asthma show that, in daily doses of 400 µg, both FP and BUD suppress lower leg growth compared with placebo, although the relevance of this to longterm growth is unclear.13 BDP at 400 µg/d can suppress linear growth when given over 12 months in children with mild to moderate asthma,14 and there may be differential susceptibility to the adverse effects of ICSs on growth and adrenal function. Inhalation of BDP, 400 µg/d, for 7 months resulted in adrenal function being unaffected, as assessed by morning serum cortisol levels, whereas growth velocity was impaired.15 Dose responsiveness may also be different in children with mild compared with severe asthma, with growth velocity in the latter being more resistant to glucocorticoid effects. The comparability of growth suppression with available ICSs requires further evaluation by prospec-
tive randomized studies in various age groups of children with differing degrees of asthma. We conclude that over a 20-week study period FP in half the dose of BUD (400 µg and 800 µg, respectively) was superior in improving PEF and as effective in controlling symptoms and reducing the need for rescue therapy in children with moderate to severe asthma. Children treated with FP appeared to have better linear growth than those who received BUD. There was no suppression of morning serum cortisol by either drug. The following physicians kindly allowed their patients to participate in this study. Canada: B. Lyttle, P. Patel, S. Mehra, P. Zuberbuhler, D. Hughes, B. Muram, D. Hummel, L. Charette, J. Bouchard, D. Wong, W. Arkinstall, and T. Kovesi. Denmark: K. Ibsen and J. Henricksen. Finland: A. Koivikki. Netherlands: J. Pilon, J. Hoekx, W. den Ouden, R. Roorda, and J. Gosen. Indonesia: N. Rahayoe. Poland: J. Pietrzyk, A. Emeryk, and T. Malaczynska. South Africa: G. BreretonStiles, M. Ossip, M. Laher, and M. Bailey.
REFERENCES 1. The British Guidelines on Asthma Management. Thorax 1997;52(suppl): S1-S21. 2. Fuller R, Johnson M, Bye A. Fluticasone propionate: an update on preclinical and clinical experience. Respir Med 1995;89:3-18. 3. Gustafsson P, Tsanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma. Arch Dis Child 1993;69:206-11. 4. Barnes NC, Hollett C, Harris TA. Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respir Med 1998;92:95-104. 5. Langdon CG, Thompson J. A multicentre study to compare the efficacy and safety of inhaled fluticasone propionate and budesonide via metered dose inhalers with mild to moderate asthma. Br J Clin Res 1994;5:73-84.
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 4 6. Langdon CG, Capsey LJ. Fluticasone propionate and budesonide in adult asthmatics: a comparison using dry powder inhaler devices. Br J Clin Res 1994;5:85-99. 7. Ayres JG, Bateman ED, Lundback B, Harris TAJ. High dose fluticasone propionate 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily in patients with chronic severe asthma. Eur Respir J 1995;8:579-86. 8. Hoekx JCM, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J. Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dose of 400 µg · day-1. Eur Respir J 1996;9:2263-72.
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9. Polgar G, Promadhat V. Pulmonary function testing in children. Techniques and standards. Philadelphia: WB Saunders Co, 1971. 10. Thorsson L, Dahlstrom K, Edsbacker S, Callen A, Poulson G, Wiren G. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997;43:155-61. 11. Hogger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994;59:597-602. 12. Lipworth BJ, Clark DJ, McFarlane LC. Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to
asthmatic school children. Thorax 1997;52:686-9. 13. Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study. Eur Respir J 1997;10:1507-12. 14. Simons FER, the Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol and placebo in children with asthma. N Engl J Med 1997;337:1659-65. 15. Doull OJM, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 1995;151: 1715-9.
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427
Efficacy and safety of high-dose inhaled steroids in children with asthma: A comparison of fluticasone propionate with budesonide
Alexander C. Ferguson, MD, Sheldon Spier, MD, Ahmed Manjra, MD, Florens G. A. Versteegh, MD, Stephen Mark, BSc, RT, and Paul Zhang, MSc Objective: To compare the efficacy and adverse effects of inhaled fluticasone propionate (FP), 400 µg/d, with those of budesonide (BUD), 800 µg/d, in children with moderate to severe asthma. Methods: Three hundred thirty-three children, ages 4 to 12 years, receiving inhaled corticosteroids were enrolled in a double-blind, double-dummy, randomized, parallel-group study. After a 2-week run-in phase, 166 children received FP and 167 received BUD for 20 weeks. The primary outcome variable was mean morning peak expiratory flow; the 2 treatments were to be regarded as equivalent if the 90% CI for the treatment difference was within ± 15 L/min. Pulmonary function, height, and diary cards were assessed at each visit; and morning serum cortisol levels were determined before and after treatment. Results: Baseline peak expiratory flow was similar, FP 236 ± 72 (SD) L/min and BUD 229 ± 74, increasing after treatment to 277 ± 41 and 257 ± 28, a difference between treatments of 12 L/min (90% CI 6-19 L/min; P = .002). Symptom control and use of rescue medication were the same. Cortisol levels after treatment were 199 nmol/L (FP) and 183 nmol/L (BUD) (treatment ratio = 1.09; 90% CI 0.98-1.21; P = .172). Linear growth was less in those receiving BUD (mean difference, 6.2 mm; 95% CI 2.9-9.6; P = .0003). Conclusion: FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms. Growth was reduced with BUD compared with FP, but there was no difference in serum cortisol suppression or hepatic or renal function. (J Pediatr 1999;134:422-7)
Inhaled corticosteroids have an important role in the treatment of chronic asthma in children.1 Despite the availability of several formulations, their ef-
ficacy relative to each other has not been widely studied, nor has the risk of long-term adverse effects, especially on growth and hypothalamo-pituitary-
From the B.C. Children’s Hospital, Vancouver, British Columbia, Canada; Alberta Children’s Hospital, Calgary, Alberta, Canada; Westville Hospital, Durban, South Africa; Groene Hart Ziekenhuis, Gouda, Netherlands; and Glaxo Wellcome Inc, Mississauga, Ontario, Canada.
Submitted for publication Aug 5, 1998; revision received Nov 16, 1998; accepted Dec 15, 1998. Reprint requests: Alexander C. Ferguson, MD, University of British Columbia, B.C. Children’s Hospital, 4480 Oak St, Vancouver, BC, V6H 3V4, Canada. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/96626
422
adrenocortical axis suppression in prepubertal children. Fluticasone propionate is a new ICS for the treatment of asthma. It has a potent glucocorticoid anti-inflammatory action with few systemic effects2 and is as efficacious as beclomethasone dipropionate, even when administered at half the dose.2-4 Studies in adults with the use of similar doses,5-7 and in children with mild asthma receiving 400 µg/d,8 comparing FP and BUD showed them to be equally effective. Differences in potency may be more important in children BDP BUD FEV1 FP ICS PEF
Beclomethasone dipropionate Budesonide Forced expiratory volume in 1 second Fluticasone propionate Inhaled corticosteroid Peak expiratory flow
with moderate to severe asthma requiring high doses of ICS in whom a lower effective dose might be associated with less likelihood of adverse effects. To determine whether FP in half the dose was as efficacious and as safe in controlling asthma as budesonide, we assessed the effects of these drugs in a group of prepubertal children with moderate to severe chronic asthma. The study was of randomized, doubleblind, double-placebo, parallel-group design comparing the clinical efficacy and safety/tolerability of daily FP, 400 µg, administered through a Diskus inhaler (GlaxoWellcome) with BUD, 800 µg, administered through a Turbuhaler inhaler (Astra Pharma Inc), both dry powder formulations.
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 4
METHODS A cohort of 442 children, ages 4 to 12 years, with a history of moderate to severe asthma were recruited from 6 countries. All had a Sexual Maturity Rating of 1 (prepubertal) at the time of the initial clinic visit. Children with only seasonal or exercise-induced symptoms were excluded. All subjects required moderate to high doses of ICS to control symptoms, 400 to 800 µg of BDP or BUD or 200 to 400 µg of FP per day for at least 1 month preceding the start of the run-in period. All were using inhaled β-adrenergic medication for relief of symptoms when necessary and were able to demonstrate ability in using inhalation devices and peak flow meters and in completing diary cards with parental assistance. In the month preceding the study, none of the subjects had changed the dose of their inhaled or oral medications, and none had been admitted to the hospital for treatment of respiratory illness. Children who had received combination bronchodilators or systemic corticosteroids, had any sign of serious disease other than asthma, or had received any investigational drugs were excluded. Respective institutional ethics committee and regulatory agency approvals were received before commencing the study, and written informed consent was obtained from parents and, when appropriate, from children before entry into the study. During the 2-week run-in period, subjects discontinued the use of their usual inhaled β-adrenergic bronchodilator medication and replaced it with inhaled albuterol (Diskhaler [Glaxo Wellcome] or metered-dose inhaler), to be taken as required. All other asthma medications, including their usual ICS therapy, were continued at a constant dose and frequency. The use of long-acting β-adrenergic drugs, combination bronchodilators, or other corticosteroid formulations (except nasal sprays) was not permitted in the study. Subjects, with parental assistance if re-
Table I. Symptom scores
Symptoms Day None 1 short period 2 or more short periods Most of the day, activity not affected Most of the day, activity reduced Severe, unable to go to school Night None Wakened once Wakened 2 or more times Awake most of the night Severe, unable to sleep Total
quired, were instructed in the correct use of the Mini-Wright peak flow meter, the Diskus, and the Turbuhaler and were shown how to complete the daily diary cards. They were asked to measure and record the best of 3 maximal PEFs, morning and evening before administration of medication, and to record their symptom score and use of bronchodilator rescue medication twice daily, at bedtime and on rising (Table I). The peak flow meters were new and calibrated by the manufacturer. At the end of the run-in period, the subjects’ ICS treatment was randomized to FP, 400 µg, administered through Diskus (200 µg twice daily) or BUD, 800 µg, administered through Turbuhaler (400 µg twice daily) after the following inclusion criteria were satisfied: (1) daily symptom score of 1 or greater on at least 4 of the last 7 consecutive days before randomization and (2) a mean morning PEF, on 4 of the last 7 consecutive days of the run-in period, that was ≤85% of the postbronchodilator PEF at the randomization visit or PEF ≤85% of predicted value9 on at least 4 of the last 7 days before randomization or reversibility of 15% or greater of PEF or forced expiratory volume in 1 second in response to albuterol, 200 µg by metered-dose inhaler or 400 µg by Diskhaler, at the ini-
Score 0 1 2 3 4 5 0 1 2 3 4 0-9
tial or randomization clinic visit, albuterol having been withheld for at least the previous 4 hours. Treatment continued for 20 weeks, followed by a 2-week follow-up period during which treatment reverted to the patients’ usual therapy as designated by their physicians. Rescue therapy with albuterol from a metered-dose inhaler (100 µg per actuation) or Diskhaler (200 µg dry powder per blister) was available at all times. The use of a spacer device (Aero Chamber, Trudell Medical Group) was permitted, provided that this was constant throughout the study and documented. Concurrent asthma and non-asthma medications were permitted as long as the dose, frequency, and route remained fixed throughout the study. Children attended the clinic on 6 occasions: at the beginning and end of the run-in period; after 8, 16, and 20 weeks of treatment; and at the end of the 2-week follow-up period. At each of these visits, 3 measurements of PEF were obtained by using the child’s own Mini-Wright peak flow meter (Armstrong Industries Inc, Northbrook, Ill), and for those 6 years and older, spirometric assessment was performed (forced vital capacity, FEV1, and forced expiratory flow, midexpiratory phase). Children were instructed to withhold albuterol therapy for at 423
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Table II. Characteristics of the children studied
n Boys/girls Age (y, mean ± SD) Height (cm, mean ± SD) Duration of asthma (% of group) <1 y 1-5 y 6-10 y >10 y Unknown Presence of atopy (% of group)
FP group
BUD group
166 114/52 8.2 ± 2 131 ± 14
167 109/58 7.9 ± 2 129 ± 14
3 45 49 2 <1 88
2 57 40 <1 <1 86
least 4 hours before each clinic visit. Oropharyngeal swabs were obtained to determine the presence of Candida albicans if there was clinical evidence of infection on visual examination.
medication. Two courses of systemic corticosteroids, each of up to 2 weeks’ duration, were permitted during the study, but more than this prompted withdrawal of the child from the study.
Laboratory Evaluations
Analysis
Blood samples for complete blood count, hepatic and renal function, and serum cortisol determinations were obtained between 8:00 and 10:00 AM on 2 occasions—at baseline (pre-trial visit) and at the end of treatment. Samples were also obtained at the follow-up visit if any abnormal results had been noted at the end of treatment. Blood samples and urine (dipstick) were analyzed locally.
The primary outcome variable was mean morning PEF during the last 7 treatment days, obtained from the daily record cards assessed by analysis of covariance. Mean morning PEF during the run-in period as baseline was used as a covariate. The analysis incorporated adjustments for country, age, and sex. The treatment difference and the 90% CI of the treatment difference were computed. The mean evening PEF, mean morning and evening PEFs expressed as percent of predicted value for age, sex, and height, and mean diurnal variation in PEF were analyzed as for mean morning PEF. Predicted lung function values were calculated from subjects’ heights and sex by using standard formulas.9 The median day and night symptom scores, percentage of symptom-free nights, median number of albuterol doses per day and per night, and the percentage of days and nights during which albuterol was not required were analyzed to assess the difference between treatments by using the Wilcoxon rank-sum test. Changes from baseline height, baseline spi-
Adverse Events All adverse events were recorded. An asthma exacerbation was defined as a worsening of asthma symptoms requiring a change in or addition to a child’s asthma medication other than increased albuterol use. The occurrence of an exacerbation was not a withdrawal criterion, and a child could continue in the study at the physicians’ discretion. Those who experienced an exacerbation were instructed to use their inhaled bronchodilator and to report to the hospital clinic within 24 hours. The physician could decide to initiate a course of oral corticosteroid therapy in addition to the child’s study 424
rometric values, and serum cortisol levels (log-transformed) were assessed by analysis of covariance, adjusting for country, age, and sex. All statistical analyses were performed by using SAS version 6.12 (SAS Institute). The study was designed to show equivalence between FP and BUD. The results for the groups were to be taken as equivalent if the 90% CI for treatment difference in mean morning PEF was within ± 15 L/min. Assuming the standard deviation of mean PEF was 37 L/min as observed previously,3 the study would have approximately 97% power of declaring equivalence with 175 children per treatment group.
RESULTS A total of 442 children were enrolled in the study, of whom 333 proceeded to randomized treatment and qualified for the primary population of analysis, the intent-to-treat population. There were 166 subjects who received FP, 200 µg twice daily, and 167 subjects who received BUD, 400 µg twice daily. Twenty-five subjects (7.5%) were ultimately excluded from analysis because of protocol violations (15 receiving FP and 10 receiving BUD); protocol violations were incorrect dose of ICS or inadequate symptom scores to fulfill the entry criteria. Children in both treatment groups were similar in terms of baseline PEF and clinical characteristics (Table II). Compliance was calculated as the number of days or nights when each study medication was used, divided by the number of days of recorded data, multiplied by 100. There was no significant difference between treatment groups (P = .977). The compliance rate was almost 100% for both FP and BUD groups. Fiftynine subjects in the FP group received nasal corticosteroids during the study period (33 FP, 12 BUD, 8 triamcinolone, 5 BDP, 1 flunisolide) compared with 45 in the BUD group (24
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 4 FP, 10 BUD, 4 flunisolide, 4 BDP, and 3 triamcinolone).
Efficacy Baseline mean morning PEF for the FP group was 236 ± 72 (SD) L/min, and for the BUD group, 229 ± 74 L/min, not significantly different. After treatment, the adjusted mean morning PEFs, measured over the last 7 treatment days, were 271 ± 82 and 259 ± 75 L/min, respectively (Fig 1). The difference in means was 12 L/min (90% CI 619 L/min, P = .002). There were no significant interactions of treatment by country of study, sex, or baseline PEF, but there was a significant interaction by age. For the purpose of the study, the 2 treatment regimens, FP and BUD, were to be considered equivalent if the 90% CI for the difference in the mean morning PEFs for the last 7 days of the 20-week treatment period was within ± 15 L/min. The 90% lower and upper confidence limits for the treatment difference were 6 and 19 L/min, respectively, indicating that the treatments were not equivalent, with FP being superior. The improvements were reflected in mean morning PEF at clinic visits (Fig 2). Morning PEF (measured at home over the last 7 treatment days), expressed as percent of predicted value, improved slightly more with FP; adjusted mean was 106% compared with BUD 102% (P = .027), as did mean evening PEF, 271 and 259 L/min (P = .002), and evening PEF as percent of predicted value, 106% and 102% (P = .037), respectively. There were no differences between treatment groups for improvement in daytime symptom scores (P = .729), nighttime symptom scores (P = .34), or percentage of days with symptom scores <2 (P = .107). Nighttime symptom scores were equally reduced in both groups (P = .958). Similarly, the need for rescue medication was similar in the 2 groups during the treatment phase for daytime (P = .181) and nighttime (P = .59) albuterol use and for ability to completely withdraw albuterol,
Fig 1. Mean morning PEF at the end of treatment week. Differences were: after 20 weeks, 12 L/min (90% CI 6-19 L/min, P = .002); at week 5, 6 L/min (P = .096); at week 10, 5 L/min (P = .286); and at week 15, 8 L/min (P = .043).
Fig 2. Mean PEF at clinic visits.Visit 1 is start of run-in period, visit 2 start of treatment, and visit 5 end of treatment.
Table III. Height of study subjects in response to treatment, measured by stadiometry
FP group n Mean height (cm) Visit 2 Visit 5 Adjusted mean growth (cm)
76 129.6 133.0 3.31*
BUD group 78 130.2 132.2 1.99*
*Difference in adjusted mean increase in height was 1.32 cm (95% CI 0.48-2.17; P = .002).
day (P = .134) or night (P = .507). In children who were able to perform pulmonary function maneuvers in the clinic, there was a comparable improvement from baseline to end of treatment in forced vital capacity (P = .244), PEF (P = .096), FEV1 (P = .183), and forced expiratory flow, midexpiratory phase (P = .081) in both treatment groups.
Safety There was no significant difference in the number of children who experienced an adverse event in the 2 treatment groups. The most common adverse event was “upper respiratory tract infection,” reported with a similar incidence—28% of children in the FP group and 32% in the BUD group. There were no differences in the incidence of other predictable adverse
events, the most common being headache and throat irritation. During the study, 4 subjects (2%) in the FP group and 10 (6%) in the BUD group reported a serious adverse event during treatment. These included asthma exacerbations (2 in the FP group and 8 in the BUD group), respiratory tract infections, fractured bones, seizure disorders, gastroenteritis, appendicitis, and viral meningitis. Only one of these patients, with an exacerbation of asthma in the BUD group, was withdrawn from the study at treatment week 19. The results of clinical examinations in both groups were similar, and none of the children had oropharyngeal candidiasis. No clinically significant abnormalities were detected in blood counts or tests of hepatic or renal function. Baseline geometric mean serum cor425
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tisol levels were 227.6 ± 63 (SD) nmol/L for FP and 203 ± 74 nmol/L for BUD. The adjusted geometric means at end of treatment were 199 nmol/L and 183 nmol/L, respectively (treatment ratio = 1.09; 90% CI 0.98-1.21; P = .172). Thus in terms of morning serum cortisol levels, there was no difference between the 2 treatment groups. Linear growth velocity was greater in those receiving FP who had an adjusted mean increase in height of 2.51 cm compared with 1.89 for those receiving BUD. The difference was 6.2 mm (95% CI 2.9-9.6, P = .0003). The study was not designed to critically assess growth as an outcome factor; measurement of height was done primarily to calculate predicted values for spirometry. To further test the validity of the growth effect, we evaluated a subgroup of 154 children whose heights had been measured by stadiometry. The difference in adjusted mean increase in height was 13.2 mm (P = .0024, Table III).
DISCUSSION The results of our study are consistent with previous reports of similar clinical efficacy when comparing FP (200 µg) and BDP (400 µg) per day in children with mild to moderate asthma2,3 and when comparing FP at half the daily dose with BUD in adult asthmatic subjects.4-7 A study in children with mild to moderate asthma, in which FP and BUD (both 400 µg/d) were compared, showed a similar effect in control of asthma symptoms.8 Our findings of equivalence or superior clinical effect with half the nominal dose of FP compared with BUD are consistent with the much longer elimination half-life,10 longer glucocorticoid receptor-binding half-life,11 and lipophilicity10 of FP. There was no difference in morning serum cortisol levels in those receiving FP compared with those receiving BUD, and neither drug resulted in a significant suppression from baseline. The children had 426
THE JOURNAL OF PEDIATRICS APRIL 1999 previously been receiving moderate to high doses of inhaled steroids, which might have already influenced hypothalamo-pituitary-adrenocortical axis function,12 but the values we found were not reduced (normal >170 nmol/L). This group of children with moderate to severe asthma may be more resistant to the effect of corticosteroids than others with mild to moderate disease, and more sensitive measures of adrenal function may be required to assess adrenal suppression in these children. With evidence of greater pharmacologic potency for FP, it is both surprising and of great interest that it had less effect on linear growth than BUD. The findings are not conclusive because the study was not designed to focus on growth. Assessment of height was not standardized, other than by stadiometry in less than half of the children; the follow-up period was only 20 weeks; and we could not include a placebo control group in our study because we were treating children with moderate to severe asthma, so the full effect of FP and BUD on growth velocity is unclear. Short-term studies in mild asthma show that, in daily doses of 400 µg, both FP and BUD suppress lower leg growth compared with placebo, although the relevance of this to longterm growth is unclear.13 BDP at 400 µg/d can suppress linear growth when given over 12 months in children with mild to moderate asthma,14 and there may be differential susceptibility to the adverse effects of ICSs on growth and adrenal function. Inhalation of BDP, 400 µg/d, for 7 months resulted in adrenal function being unaffected, as assessed by morning serum cortisol levels, whereas growth velocity was impaired.15 Dose responsiveness may also be different in children with mild compared with severe asthma, with growth velocity in the latter being more resistant to glucocorticoid effects. The comparability of growth suppression with available ICSs requires further evaluation by prospec-
tive randomized studies in various age groups of children with differing degrees of asthma. We conclude that over a 20-week study period FP in half the dose of BUD (400 µg and 800 µg, respectively) was superior in improving PEF and as effective in controlling symptoms and reducing the need for rescue therapy in children with moderate to severe asthma. Children treated with FP appeared to have better linear growth than those who received BUD. There was no suppression of morning serum cortisol by either drug. The following physicians kindly allowed their patients to participate in this study. Canada: B. Lyttle, P. Patel, S. Mehra, P. Zuberbuhler, D. Hughes, B. Muram, D. Hummel, L. Charette, J. Bouchard, D. Wong, W. Arkinstall, and T. Kovesi. Denmark: K. Ibsen and J. Henricksen. Finland: A. Koivikki. Netherlands: J. Pilon, J. Hoekx, W. den Ouden, R. Roorda, and J. Gosen. Indonesia: N. Rahayoe. Poland: J. Pietrzyk, A. Emeryk, and T. Malaczynska. South Africa: G. BreretonStiles, M. Ossip, M. Laher, and M. Bailey.
REFERENCES 1. The British Guidelines on Asthma Management. Thorax 1997;52(suppl): S1-S21. 2. Fuller R, Johnson M, Bye A. Fluticasone propionate: an update on preclinical and clinical experience. Respir Med 1995;89:3-18. 3. Gustafsson P, Tsanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma. Arch Dis Child 1993;69:206-11. 4. Barnes NC, Hollett C, Harris TA. Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respir Med 1998;92:95-104. 5. Langdon CG, Thompson J. A multicentre study to compare the efficacy and safety of inhaled fluticasone propionate and budesonide via metered dose inhalers with mild to moderate asthma. Br J Clin Res 1994;5:73-84.
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 4 6. Langdon CG, Capsey LJ. Fluticasone propionate and budesonide in adult asthmatics: a comparison using dry powder inhaler devices. Br J Clin Res 1994;5:85-99. 7. Ayres JG, Bateman ED, Lundback B, Harris TAJ. High dose fluticasone propionate 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily in patients with chronic severe asthma. Eur Respir J 1995;8:579-86. 8. Hoekx JCM, Hedlin G, Pedersen W, Sorva R, Hollingworth K, Efthimiou J. Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dose of 400 µg · day-1. Eur Respir J 1996;9:2263-72.
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9. Polgar G, Promadhat V. Pulmonary function testing in children. Techniques and standards. Philadelphia: WB Saunders Co, 1971. 10. Thorsson L, Dahlstrom K, Edsbacker S, Callen A, Poulson G, Wiren G. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997;43:155-61. 11. Hogger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994;59:597-602. 12. Lipworth BJ, Clark DJ, McFarlane LC. Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to
asthmatic school children. Thorax 1997;52:686-9. 13. Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose response study. Eur Respir J 1997;10:1507-12. 14. Simons FER, the Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol and placebo in children with asthma. N Engl J Med 1997;337:1659-65. 15. Doull OJM, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 1995;151: 1715-9.
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