Effects of 2 Inhaled Corticosteroids on Growth
Results of a Randomized Controlled Trial
Fernando M. de Benedictis, MD; Alejandro Teper, MD; Robin J. Green, MD;
Attilio L. Boner, MD; Lisa Williams, MSc; Hilary Medley, DipClinSci; for the
International Study Group
Objective To compare the long-term effect of treatment with fluticasone
propionate or beclomethasone dipropionate on growth in asthmatic children.
Design Prospective, multicenter, randomized, double-blind, parallel-group
study.
Setting Children requiring regular treatment with inhaled corticosteroids
and with a sexual maturity rating of Tanner stage 1 (prepubertal).
Patients Three hundred forty-three children aged 4 to 11 years with asthma.
The growth population (excluding patients with protocol violations likely to
affect growth measurements) included 277 patients.
Interventions Fluticasone propionate or beclomethasone dipropionate, both at a
dosage of 200 µg administered twice daily via a dry powder inhaler (Diskhaler)
for 12 months.
Main Outcome
Measures Growth velocity, lung
function, and serum and urinary cortisol levels.
Results The adjusted mean growth velocity in the fluticasone group was
significantly greater than that in the beclomethasone group (5.01 [SE, 0.14] vs
4.10 [SE, 0.15] cm/y; difference, 0.91 cm; 95% confidence interval, 0.63-1.20
cm; P<.001). Both treatments
improved lung function, with significant differences in favor of fluticasone.
Adverse events were similar in both groups, and there were no significant
differences in effect on serum and urinary cortisol levels.
Conclusions The more favorable risk-benefit ratio of fluticasone indicates
that this agent is preferable to beclomethasone for the long-term treatment of
children with asthma, especially if moderate doses are required.
Arch Pediatr Adolesc Med.
2001;155:1248-1254
ASTHMA IS characterized by symptoms of wheeze,
cough, and tightness of the chest resulting from an inflammatory response in
the airways.1, 2 Anti-inflammatory drugs
such as inhaled corticosteroids are recommended in all age groups if inhaled,
short-acting -agonists are
required more than once a week.1 Beclomethasone
dipropionate and budesonide have similar efficacy profiles,3 but fluticasone
propionate is at least as effective and as well tolerated as beclomethasone and
budesonide at half the dose.4
Short-term studies have indicated that inhaled
beclomethasone dipropionate and budesonide (400
µg/d) can affect lower-leg growth rates in children,5-7 but these data do
not accurately predict long-term growth.8 One year of treatment
with beclomethasone dipropionate, 400 µg/d, has been shown to cause significant
slowing of growth, compared with placebo or noncorticosteroid control drug.9, 10 In contrast, a
12-month, placebo-controlled study showed that prepubescent children treated
with fluticasone propionate, 50 or 100 µg twice daily, grew at the expected
velocity for their age.11 Furthermore, a
significant difference in growth rate was found during a period of 20 months in
steroid-naive asthmatic children treated with fluticasone propionate, 200 µg/d
(5.75 cm/y), compared with beclomethasone dipropionate, 400 µg/d (4.94 cm/y).12
There are, however, limited data on the effect
of fluticasone propionate at dosages of greater than 200 µg/d on growth rates.
This study was therefore designed to compare the effects on growth of
fluticasone propionate with that of beclomethasone dipropionate, both at a
dosage of 400 µg/d administered via a dry powder inhaler (Diskhaler;
GlaxoSmithKline, Greenford, England) in children with a history of chronic
asthma. Lung function was also evaluated, to provide an indication of the
risk-benefit ratio of the treatments.
We conducted the study in Holland, Hungary,
Italy, Poland, Argentina, Chile, and South Africa under the conditions
described in the Declaration of Helsinki. Approval from the Ethics Committee of
each participating center and prior written informed consent from the
appropriate child, parent, and/or guardian were obtained.
STUDY POPULATION
Boys (aged 4-11 years) or girls (aged 4-9 years) with a sexual maturity rating
of Tanner stage 1 were eligible for entry into the study if they required
treatment with inhaled fluticasone propionate, 100 to 200 µg/d, or
beclomethasone dipropionate or budesonide, 200 to 500 µg/d, for at least the
previous 8 weeks, at a constant dosage for at least 4 weeks before the run-in
period. Patients with intermittent asthma or disorders that could affect
growth, patients receiving oral or parenteral steroids, and patients admitted
to a hospital with respiratory disease in the 4 weeks before the run-in period
were excluded from the study.
During the 2-week run-in period, patients continued
to receive their existing inhaled corticosteroid treatment and albuterol
sulfate from a metered-dose or dry-powder inhaler on an as-needed basis.
Patients were randomized to treatment if they demonstrated a mean morning peak
expiratory flow (PEF) during the last 7 days of the run-in period of no greater
than 85% of their maximum achievable response after inhalation of albuterol
sulfate, 400 µg, via a metered dose inhaler. Patients also had to have an
asthma symptom score of at least 1 or require albuterol at least once daily on
at least 4 of the last 7 days of the run-in period.
Patients were permitted to continue with the
following antiasthma treatments, providing that the dose remained constant
during the course of the study: cromolyn sodium, nedocromil sodium,
methylxanthines, ketotifen fumarate, anticholinergics, and oral or long-acting -agonists. In
addition, the following treatments were permitted for use as needed: oral
corticosteroids for asthma exacerbations, intranasal corticosteroids,
decongestants, antihistamines, and antibiotics.
STUDY DESIGN
The study was a prospective, multicenter, randomized, double-blind,
parallel-group design. The 2-week run-in period was followed by 52 weeks of
treatment with fluticasone propionate or beclomethasone dipropionate, both
administered at a dosage of 200 µg twice daily using a dry powder inhaler
(Diskhaler). No specific instructions were given with respect to mouth rinsing.
This was left to the investigators' discretion, according to local practice.
Both formulations looked the same because of the predominance of lactose in the
formulation, and any taste associated with the products would be attributable
to the lactose. Treatment randomization was generated by computer using a
validated computer program (Patient Allocation for Clinical Trials;
GlaxoSmithKline). Each investigator was given a block of treatment (minimum
block size, 4 treatments) and provided with individually sealed envelopes
containing details of the medication that corresponded to each patient's
treatment number. Treatment was assigned in ascending order, starting with the
lowest number.
Patients visited the clinic after 2 and 4 weeks
of treatment, and then at 12-week intervals for the next 48 weeks. A follow-up
visit was arranged at 2 weeks after completion of treatment. No detailed
assessments of compliance were made during the study. Although compliance with
inhaled corticosteroid therapy is generally considered to be poor, the purpose
of this study was to compare 2 inhaled corticosteroids for which it was assumed
that compliance rates would be similar. However, investigators were asked to
confirm whether patients were taking their medication correctly at each clinic
visit.
OUTCOME MEASURES
The primary end point was growth velocity, measured by means of stadiometry
during the 52-week treatment. Secondary end points included asthma symptom
scores, -agonist use,
asthma exacerbation rate, and lung function measurements.
The study was powered to detect a difference in
growth of 1 cm/y between the treatments. Based on data from a previous study,13 if the SD of growth
velocity was 2.7 cm/y, it would be necessary to recruit 240 patients, ie, 120
per treatment group, to ensure a power of 80% to detect a difference of 1 cm/y
at the 5% significance level.
On a daily basis, each patient recorded their
daytime and nighttime asthma symptom score (0 indicates no symptoms; 1, mild;
2, moderate; and 3, severe), morning and evening PEF, the number of doses of
as-needed albuterol administered, and concurrent medication on a diary card.
This information was entered throughout the run-in period and the first 4 weeks
of treatment, and on the 14 days before subsequent clinic visits.
Height and lung function were recorded at each clinic
visit. Height was measured on a standard calibrated, wall-mounted stadiometer
(Harpenden; Holtain Ltd, Crymych, Wales) that was supplied to each
participating center. Staff were trained in its use to ensure standardization
of the measuring technique. The same operator collected all height measurements
in triplicate at the same time (4 hours) for
an individual subject throughout the study. The PEF was measured using a
mini–Wright peak flowmeter (Clement Clark International Ltd, Harlow, England).
Optional spirometer measurements of forced expiratory volume in 1 second (FEV1),
forced vital capacity (FVC), and forced expiratory flow from 25% to 75% of the
FVC measurement (FEF25%-75%) were also obtained. Patients were asked
to stop -agonist use (4
hours for short-acting and 12 hours for long-acting agents) before the
spirometry measurements.
Adverse events, including exacerbations of
asthma, were recorded at each clinic visit. An asthma exacerbation was
predefined as any worsening of asthma symptoms requiring a change or addition
to the patient's asthma medications, other than an increased use of as-needed
albuterol.
Nonfasting venous blood samples were taken at
the start and the end of the treatment period for determination of standard
hematologic and biochemical variables. Urine and blood samples were collected
at the start of treatment and after 16 and 52 weeks for the measurement of
morning serum cortisol level and overnight 12-hour urinary cortisol excretion.
Samples were analyzed using a fluorescent polarization antibody technique.
STATISTICAL ANALYSIS
Thirty-two centers from 7 countries were involved in the study, and all centers
within a country constituted a single subgroup for the purposes of statistical
analysis. All analyses were performed on the intent-to-treat population except
growth velocity, which was performed on the growth population. Treatment
differences were tested using a 2-sided significance test at the 5% level.
Growth velocity was calculated for each patient
during the 52-week study using linear regression of all the available clinic
visit means of the triplicate height measurements. Only patients with at least
2 data points, one at randomization and the other on or after 16 weeks of
treatment, were included in the growth population. Tanner staging assessments
were performed by a physician at each visit, and patients were excluded from
the growth population if they reached a Tanner stage of 2 or more at any time
during the study. Patients were also excluded from the growth population if
there were other factors likely to affect the measurement of growth (such as
poor compliance or use of systemic corticosteroids). Growth velocity was
investigated using analysis of covariance, with the patient's height and age at
randomization, country grouping, sex, and ethnic origin taken as covariates in
the model. The difference between treatment groups was tested, and the
associated P value and 95%
confidence interval (CI) were produced. The primary end point (growth velocity)
was also analyzed for the intent-to-treat population, excluding only those
patients with no height measurements at baseline and/or during treatment.
Individual country-specific growth charts were
not available for this international multicenter study conducted in 7 countries.
However, we compared individual patients' growth velocities against the North
American growth charts14 to calculate the
number of patients with a growth velocity below the 3rd, 10th, 25th, and 50th
percentiles. Percentiles were determined using the mean age for the time in
which the patient was in the study. We compared the proportion of patients in
each treatment group below the specified percentile using the Fisher exact
test.
Clinic lung function variables (PEF, FEV1,
FVC, and FEF25%-75%) were also analyzed using an analysis of
covariance with pretreatment lung function, age, sex, and country grouping
included as covariates.
Diary card lung function variables (morning and
evening PEF) were investigated using a similar method to that used for clinic
lung function variables, with baseline taken as the mean of the last 7 days of
the run-in period. Diary-card symptom data were analyzed using the van Elteren
extension to the Wilcoxon rank sum test, which allowed possible imbalances
between countries to be taken into account in the analysis.
The frequency of asthma exacerbations for each
patient was also analyzed using the van Elteren extension to the Wilcoxon rank
sum test.15 The number of
patients with exacerbations in each treatment group were compared using the
Fisher exact test.
Logarithm-transformed serum and urinary cortisol
measurements were analyzed using an analysis of covariance similar to that used
for clinic lung function variables. The difference between treatments was
expressed as a ratio, and the corresponding P
value and 95% CI for this ratio were calculated.
Of the 403 enrolled patients, 343 were
randomized to treatment (170 to fluticasone and 173 to beclomethasone)
(intent-to-treat population). The treatment groups were generally balanced with
respect to age, sex, race, duration and severity of asthma, and use of
corticosteroids before the study (Table 1).
For the analyses of growth velocity, the intent-to-treat population excluded 3
patients treated with fluticasone and 4 patients treated with beclomethasone
for whom there were insufficient height measurements. Sixty-six patients were
excluded from the growth population, which therefore consisted of 277 patients
(137 in the fluticasone group and 140 in the beclomethasone group) (Figure 1).
Eight patients (3 receiving fluticasone and 5 receiving beclomethasone)
required oral corticosteroid treatment and were excluded from the growth
population.
The mean (SD) baseline height in both treatment
groups for the growth population was comparable (fluticasone group, 123.8 [9.7]
cm; beclomethasone group, 124.3 [10.8] cm), and there was a gradual increase in
height over time in both groups (Figure 2).
Adjusted mean (SE) growth velocity was significantly greater in the fluticasone
than in the beclomethasone group (5.01 [0.14] vs 4.10 [0.15] cm/y; difference,
0.91 cm; 95% CI, 0.63-1.20 cm; P<.001).
The growth velocity frequency distribution for both treatment groups is
displayed in Figure 3.
The results of the analyses for the intent-to-treat population were similar.
The adjusted mean growth velocity was greater in the fluticasone group than in
the beclomethasone group (4.76 [0.28] vs 4.06 [0.29] cm/y; difference, 0.70 cm;
95% CI, 0.13-1.26 cm; P<.02).
The SEs for the intent-to-treat population analyses (0.28 and 0.29), however,
were nearly twice those for the growth population analyses (0.14 and 0.15),
indicating that the patients removed from the analyses were contributing to a
large proportion of the variation. The difference in growth velocity between
the fluticasone group (n = 127; adjusted mean, 5.04 [SE, 0.15] cm/y) and the
beclomethasone group (n = 135; adjusted mean, 4.05 [SE, 0.16] cm/y) remained
significant (P<.001) when
excluding those patients who received intranasal corticosteroids during the
study.
Table 2
shows the number of patients with a growth velocity below the specified North
American standard percentiles. As expected from the study population, most patients
in each treatment group were below the 50th percentile. However, there was a
significant difference between treatment groups, whereby patients treated with
beclomethasone were more likely to be below a specific percentile than patients
treated with fluticasone (P<.001).
The mean change from baseline in morning
percentage of predicted PEF was higher at all weekly time points for patients
receiving fluticasone than those receiving beclomethasone (Figure 4).
During the 52-week treatment, the adjusted mean morning PEF was significantly
higher in the fluticasone group (percentage of predicted, 105.6% vs 102.0%;
difference, 3.6%; 95% CI, 1.2%-6.0%; P
= .003) (mean PEF, 251.3 vs 242.8 L/min; difference, 8.5 L/min; 95% CI,
2.8-14.2 L/min; P = .004).
Results for evening PEF were similar, with a higher mean value in the
fluticasone group during the entire treatment period (255.1 vs 246.5 L/min;
difference, 8.6 L/min; 95% CI, 3.0-14.1 L/min; P
= .003). Both treatments produced significant improvements from baseline in
clinic lung function assessments, with a significantly greater benefit in the
fluticasone group compared with the beclomethasone group for all measured variables
at week 52 (adjusted mean PEF, 282.5 vs 267.3 L/min [P<.001]; FEV1, 1.8 vs 1.6 L [P<.001]; FVC, 2.0 vs 1.9 L [P = .008]; FEF25%-75%, 2.2 vs
2.0 L/s [P = .02]).
There were no significant differences between
treatment groups for any assessment period with respect to diary-card symptoms
or the as-needed use of albuterol. There was no significant difference between
treatments in the total number of exacerbations (47 in the fluticasone group vs
52 in the beclomethasone group) and the percentage of patients who experienced
at least 1 exacerbation (16% of patients in the fluticasone group vs 19% of
patients in the beclomethasone group). The incidence of exacerbations was
similar in the small group of patients (n = 55) who were previously receiving a
daily dose of inhaled corticosteroids greater than 400 µg/d (11% of the
fluticasone group vs 18% of the beclomethasone group).
Both treatments were well tolerated, and the
numbers and types of adverse events were similar in both treatment groups (Table 3).
During the treatment period, there were no
significant changes from baseline in morning serum cortisol levels in either
treatment group, despite a trend toward reduced levels in both groups. A
significant reduction from baseline in overnight urinary cortisol levels was
found in the beclomethasone group; however, the differences between treatments
were not statistically significant (Table 4).
The primary purpose of this study was to compare
the effect of fluticasone and beclomethasone on the growth of children with a
history of chronic asthma requiring treatment with inhaled corticosteroids. To
overcome any influence of the pubertal growth spurt, the analysis of growth
velocity excluded patients with a sexual maturity rating of greater than Tanner
stage 1 at any time during the study. The growth rate of children treated with
fluticasone was significantly greater than that of children treated with
beclomethasone.
Analysis of growth velocity using SD scores was
considered, to compare the results with the equivalent healthy population.
However, this comparison would not have been conclusive for 2 main reasons.
First, children with moderate to severe asthma have been shown to have slower
growth rates and later onset of puberty than nonasthmatic children.16 Thus, the differences
between the growth rates measured in this study from reference values could be
attributable to the treatment used or to the patients' asthma. Second,
reference growth values are not available for all the countries where this
study was conducted, and comparison with data from England or the United States
could be confounded by factors such as nutritional or ethnic differences.14, 17 This problem might
have been avoided if a control group had been included in the study, but the
use of placebo would not be ethical in a population with asthma requiring
long-term therapy. Inclusion of a control group taking active, nonsteroidal
therapy would have caused problems with multinational approval and would also
have led to difficulties with treatment blinding.
The comparison of the data against North
American percentiles clearly illustrates these problems. Most patients in both
treatment groups had a growth velocity below the 50th percentile. This could be
attributable to the influence of asthma, the influence of treatment, and/or the
inapplicability of the North American standards.14 Nevertheless, in the
comparison of both treatment groups, which was the objective of the study, the
results of this analysis were entirely consistent with primary outcome data.
Patients treated with beclomethasone were significantly more likely to have a
growth velocity below a specified percentile than were patients treated with
fluticasone.
A potential criticism of this study design is
that intranasal corticosteroids were permitted for use as required. There is
evidence that intranasal beclomethasone can affect growth in children,18 but other intranasal
corticosteroids have lower systemic bioavailabilities and so may not have the
same effect on growth. There was, however, no change in the outcome of this
study when excluding those patients who received treatment with an intranasal
corticosteroid during the course of the study.
To our knowledge, this is the first large,
prospective, long-term study on the comparative effects of 2 inhaled corticosteroids
on growth of asthmatic children. In a recent study of 333 children with
moderate to severe asthma, Ferguson et al19 demonstrated a
significant difference in growth rate in favor of fluticasone propionate (400
µg/d) compared with budesonide (800 µg/d) during a 20-week period. However,
that study was not specifically designed to critically assess growth as an
outcome factor, and height was measured by means of stadiometry only in a
subgroup of patients.
The finding that children treated with
fluticasone propionate, 200 µg twice daily, grew at a faster rate than those
treated with beclomethasone dipropionate, 200 µg twice daily, was unexpected.
The dose of fluticasone was twice the therapeutic equivalent dose of
beclomethasone,4 and it could therefore
be predicted that the systemic effects of the drugs would be similar.
Although the mean growth velocity in the
fluticasone group was significantly greater than that in the beclomethasone
group, an effect on growth velocity with fluticasone cannot be excluded.
Although the growth velocity of prepubertal children treated with fluticasone
propionate at doses of 100 and 200 µg/d for 1 year was not different from that
of children treated with placebo,11 a trend for slower
growth velocity compared with children treated with placebo was evident.
Furthermore, an effect of budesonide on growth velocity in children has been
observed.20, 21 However, it has been
demonstrated recently that these initial reductions in growth velocity are not
correlated with attained adult height.22 Indeed, the
difference between attained adult height and target adult height after
treatment with budesonide (mean dose, 412 µg/d for a mean of 9.2 years) was not
different from that of children with asthma not receiving inhaled
corticosteroids or that of healthy siblings of the budesonide-treated children.
Fluticasone and beclomethasone improved lung
function, but there was a significantly greater improvement with fluticasone in
all efficacy assessments, both in morning and evening PEF and in results of
clinic visit spirometry. This finding is not surprising considering the at
least 2-fold greater clinical potency of fluticasone compared with
beclomethasone, and is in keeping with other studies of inhaled corticosteroids
in asthmatic children4, 23 and adults.4, 24
There was no difference between treatment groups
for morning serum and overnight urinary cortisol levels, although there were
trends toward greater reductions in the beclomethasone group. This does not
contradict the results of previous studies, which showed that fluticasone is
much less likely to produce endogenous cortisol suppression than is
beclomethasone at equipotent doses.4, 23, 25-27 Finally, both
drugs were well tolerated. The incidence of rhinitis was lower in the
beclomethasone group than in the fluticasone group. This may reflect a
beneficial effect on rhinitis through the more systemically active
beclomethasone.
The results of this study are not necessarily
transferable to all formulations of fluticasone and beclomethasone. The
systemic bioavailability of inhaled corticosteroids in adults is known to
depend on the inhalation device. For fluticasone, the systemic bioavailability
via the Diskus (GlaxoSmithKline) and Diskhaler dry powder inhalers is 16.6% and
11.9%, respectively, in healthy volunteers,28 and for the
metered-dose inhaler containing a chlorofluorocarbon or hydrofluoroalkane
propellant, the corresponding values are 26.4% and 28.6%, respectively.29 Together with the
elimination of the traditional coordination problems associated with
metered-dose inhalers, this finding provides further evidence that a powder
inhaler may be more appropriate for use in children with asthma than a
metered-dose inhaler.
The 12-month growth rate of children treated
with fluticasone propionate, 200 µg twice daily, was greater compared with that
for children treated with beclomethasone dipropionate, 200 µg twice daily. Lung
function was improved to a significantly greater extent with fluticasone than
with beclomethasone. On the grounds of this study, fluticasone should be chosen
in preference to beclomethasone for children with asthma, especially if
moderate doses are required.
Author/Article Information
From the Pediatric Division, University of Perugia, Perugia, Italy (Dr de
Benedictis); Hospital de Niños "R. Gutiérrez," Buenos Aires,
Argentina (Dr Teper); Sunninghill Hospital, Johannesburg, South Africa (Dr
Green); the Pediatric Division, University of Verona, Verona, Italy (Dr Boner);
and GlaxoSmithKline, Uxbridge, England (Mss Williams and Medley).
Corresponding author and reprints: Fernando M. de Benedictis, MD, Clinica
Pediatrica, Policlinico Monteluce, 06100 Perugia, Italy (e-mail: [log in to unmask]).
Accepted for publication May 25, 2001.
This study was funded by grant FLTB 3015 from
GlaxoSmithKline, Uxbridge, England.
The results of this study were presented at the
European Respiratory Society 8th Annual Congress, Geneva, Switzerland,
September 19-23, 1998.
The International Study Group includes the
following participants: J. L. Lanoel, MD, and A. M. Teper, MD (Argentina); E.
Ceruti, MD, and G. Giraldi, MD (Chile); A. C. H. van Kessel, MD, G. H. van Leeuwen,
MD, J. C. M. Hoekx, MD, J. H. Scheewe, MD, M. C. Kuthe, MD, N. Sorgedrager, MD,
and R. Schornagel, MD (Holland); B. Nagy, MD, I. Bittera, MD, L. Kosa, MD, and
M. Adonyi, MD (Hungary); A. Battistini, MD, A. L. Boner, MD, E. Baraldi, MD, F.
M. de Benedictis, MD, M. Giovannini, MD, M. La Rosa, MD, and M. Miraglia del
Giudice, MD (Italy); D. Chmielewska, MD, J. Alkiewicz, MD, and M. Migdat, MD
(Poland); and C. Bester, MD, G. Brereton-Stiles, MD, J. Vermeulen, MD, K. H. E.
von Delft, MD, N. J. T. de Villiers, MD, and R. J. Green, MD (South Africa).
What
This Study Adds Inhaled corticosteroids are recommended for
the treatment of asthma in all age groups if inhaled, short-acting -agonists are
required more than once a week, but little is known about the comparative
effects of inhaled corticosteroids on growth rates. This 12-month study was
therefore designed to compare the effects on growth and comparative
risk-benefit ratio of 2 inhaled corticosteroids, fluticasone propionate, 400
µg/d, and beclomethasone dipropionate, 400 µg/d, in children with a history
of chronic asthma. The adjusted mean growth velocity in the
fluticasone group was significantly greater than that in the beclomethasone
group. Both treatments improved lung function, with significant differences
in favor of fluticasone. The more favorable risk-benefit ratio of fluticasone
indicates that this agent is preferable to beclomethasone for the long-term
treatment of children with asthma, especially if moderate doses are required. |
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.