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ARTICLE IN PRESS
Respiratory Medicine (2007) 101, 1585–1593
Beclometasone dipropionate extrafine aerosol versus
fluticasone propionate in children with asthma
W.M.C. van Aalderena,, D. Priceb, F.M. De Baetsc, J. Priced
a
Emma Children’s Hospital AMC, Amsterdam, The Netherlands
Aberdeen University Foresterhill Health Centre, Aberdeen, UK
c
University Hospital, Gent, Belgium
d
King’s College London School of Medicine, King’s College Hospital, Denmark Hill, London, UK
b
Received 18 October 2006; accepted 24 November 2006
Available online 24 January 2007
KEYWORDS
Asthma;
Beclometasone
diproprionate;
Children;
HFA 134a;
Extrafine aerosol;
Administration
inhalation
Summary
Beclometasone dipropionate (BDP) extrafine is a hydrofluoroalkane-based, chlorofluorocarbon (CFC)-free inhalation aerosol. This study was conducted to determine whether
BDP extrafine and CFC-fluticasone proprionate (FP) aerosols were equivalent in terms of
efficacy and tolerability in children with symptomatic mild-to-moderate asthma.
Male and female patients (aged 5–12 yr) with an asthma diagnosis for X3 months, peak
expiratory flow (PEF) X60% of predicted normal and suboptimal asthma control were
randomised to double-blind treatment with BDP extrafine 200 mg day1 (n ¼ 139) or CFC-FP
200 mg day1 (n ¼ 141) for up to 18 weeks. After 6 and 12 weeks, study medication was
‘stepped down’ to 100 and 50 mg day1, respectively, if patients had achieved good asthma
control. Patients with poor asthma control discontinued from the study and those with
intermediate control continued in the study but did not undergo a dose reduction.
The estimated treatment difference in morning PEF% predicted at 6 weeks was 1.9% (90%
CI 4.9, 1.0). There was a trend towards a greater increase in forced vital capacity
(% predicted) in the BDP extrafine group (5.3 versus 0.4%; p ¼ 0.084). A ‘step-down’ in
therapy to 100 mg day1 was possible in 36% and 42% of patients in the BDP extrafine and
CFC-FP groups, respectively, at 6 weeks. Both drugs were well tolerated.
BDP extrafine and CFC-FP aerosols were equally effective at improving asthma control in
children with mild-to-moderate asthma at the same daily dose.
& 2006 Elsevier Ltd. All rights reserved.
Introduction
Corresponding author. Tel.: +31 20 5662851; fax: +31 20 6917735.
E-mail address: [email protected]
(W.M.C. van Aalderen).
0954-6111/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2006.11.020
In accordance with the Montreal Protocol, chlorofluorocarbons (CFCs), which have traditionally been used as
propellants in inhaled corticosteroid (ICS) asthma inhalers,
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are being phased out.1 Beclometasone dipropionate (BDP)
extrafine aerosol (QVARTM; IVAX Pharmaceuticals) is a CFCfree formulation that uses a hydrofluoroalkane (HFA)
propellant. Unlike traditional CFC-based inhalers, the ICS
particles in BDP extrafine aerosol are held in a solution,
rather than a suspension of propellant. In addition, the
average particle size of BDP extrafine aerosol is smaller, the
velocity of the particles leaving the inhaler on actuation is
slower, the duration of the spray is longer and the
temperature of the spray is warmer compared with that of
traditional inhalers.2 As a result, a softer more gentle spray
is produced, fewer BDP particles impact on the oropharynx
and more drug reaches the lung, particularly the small
airways.2,3 These improved delivery characteristics of BDP
extrafine aerosol may be particularly relevant for young
children in whom a greater proportion of airways are
classified as small (i.e. o2 mm in diameter)4 and airways
resistance is low.
In studies of both adults and children with asthma, BDP
extrafine aerosol produced equivalent asthma control at
approximately half the daily dose compared with CFC-based
BDP inhalers and the budesonide Turbohalers/metered-dose
inhaler.5–11 The approximate 2:1 dosing ratio of BDP
extrafine aerosol to CFC-BDP is likely to be attributed to
the greater fine particle fraction and increased lung
deposition of BDP. When compared with a more potent ICS
in adults with mild-to-moderate asthma, BDP extrafine
aerosol provided equivalent asthma control to CFC-based
fluticasone propionate (FP) at approximately the same
dose.12,13
The aim of this study was to determine whether BDP
extrafine aerosol was equivalent to CFC-FP in terms of
efficacy and safety in children with mild-to-moderate
asthma. Although equivalence between BDP extrafine
aerosol and CFC-FP has been demonstrated previously in
adults,12,13 this is the first study to compare these
treatments in children with asthma. A ‘step down’ approach
was also incorporated in the study design to enable
estimation of the lowest dose of study medication at which
effective control of asthma could be maintained.
Methods
Patients
Male and female patients (aged 5–12 yr) with an asthma
diagnosis for at least 3 months, peak expiratory flow (PEF)
X60% of predicted normal (after withholding b2-agonist
therapy for X4 h), suboptimal asthma control requiring the
initiation of, or an increase in current ICS therapy (CFC-BDP
200 mg day1 or equivalent), currently using a short-acting
b2-agonist on an as-required basis, and able to use a miniWright PEF meter correctly, were eligible for study entry.
Patients were excluded from the study if they had an acute
upper respiratory tract infection within 2 weeks or a lower
respiratory tract infection within 4 weeks of the screening
visit or during the run-in period, or if they had other
unstable or untreated chronic conditions.
The use of sodium chromones, theophylline, anticholinergics, long-acting b2-agonists (salmeterol and formoterol), leukotriene antagonists and 5-lipoxygenase inhibitors
W.M.C. van Aalderen et al.
was not permitted in the 2 weeks before the screening visit,
during the run-in period or during the double-blind treatment period. Medications, such as oral or parenteral
steroids, salmeterol in combination with fluticasone propionate (SeretideTM), monoamine oxidase inhibitors, tricyclic
antidepressants, b-blockers (including eye drops) and oral
b2-agonists within 4 weeks of the screening visit or during
the run-in period were also prohibited. Nasal steroid therapy
(equivalent to X400 mg day1 BDP), provided that the dose
remained constant for 4 weeks before study entry and
throughout the study, and oral antihistamines (excluding
astemizole) were permitted.
Study design
This was an 18-week, randomised, double-blind, doubledummy, parallel-group, multinational study conducted at 46
sites in Belgium, The Netherlands and the UK. The trial was
conducted in accordance with the ethical principles in the
Declaration of Helsinki, the International Conference on
Harmonisation Good Clinical Practice Guidelines, and
appropriate regulatory requirements. The study protocol
was also approved by the appropriate Independent Ethics
Committees. Written informed consent was provided by the
parent/guardian of all participants and, if possible, also by
the patients themselves. The study design, conduct of the
trial and management and analysis of the data were
overseen by an independent steering committee, which
comprised the authors of this paper.
After an initial screening visit, patients underwent a
2-week run-in period, during which they continued on their
current asthma therapy, followed by three 6-week treatment periods (Fig. 1). After the run-in period, patients were
randomised to treatment with either BDP extrafine aerosol
200 mg day1 plus the AeroChamber Pluss holding chamber,
or CFC-FP 200 mg day1 (Flixotides; GlaxoSmithKline) plus
the VolumaticTM spacer. During weeks 7–12 and 13–18, study
medication was ‘stepped down’ to 100 and 50 mg day1,
respectively, if patients had achieved good asthma control.
Patients with poor asthma control were discontinued from
the study. Those with intermediate control continued in the
study but did not undergo a dose reduction. If a patient had
intermediate asthma control at the end of week 6, remained
on a dose of 200 mg day1 during weeks 7–12, and then had
good control at the end of week 12, their dose was only
reduced to 100 mg day1 and not to 50 mg day1. The ‘step
down’ design enabled assessment of the minimal effective
dose for each patient.
Inhaled b2-agonist therapy was continued throughout the
study on an as-required basis, but was withheld for at least
4 h before each clinic visit.
Assessments
The highest of three measurements for morning (AM) and
evening (PM) PEF, measured by the patient/carer using a
mini-Wright peak flow meter, were recorded daily on a diary
card. A diary card was also used to record daily daytime
asthma symptoms, sleep disturbance, and use of b2agonists. Daytime asthma symptoms, including wheeze,
shortness of breath, chest tightness and cough, were
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BDP extrafine aerosol in children with asthma
Screening
1587
Run-in Wk 1–6
(2wks
Asthma control Wk 7–12 Asthma control Wk 13–18
achieved
achieved
Good
Good
100 μg • day-1
50 μg • day-1
Intermediate 100 μg • day-1
Poor Discontinued
before wk 13–18
Patients’
current
asthma
-1
therapy 200 μg • day
Intermediate
Poor
200 μg • day-1
Discontinued
before wk 7–12
Good
100 μg
μ • day-1
Intermediate
200 μg • day-1
Poor
Discontinued
before wk 13–18
Figure 1 Study design. All doses given are for beclometasone dipropionate extrafine aerosol and chlorofluorocarbon-free
fluticasone propionate.
assessed before the evening dose of medication using a scale
of 0–3 (0 ¼ no symptoms; 3 ¼ severe symptoms preventing
normal daily activities). Sleep disturbance caused by asthma
was assessed before the morning dose of medication using a
scale of 0–3 (0 ¼ slept through the night; 3 ¼ asthma
symptoms causing wakefulness most of the night).
Pulmonary function (forced expiratory volume in 1 s
(FEV1); forced vital capacity (FVC); and forced expiratory
flow at between 25% and 75% (FEF25–75%) of the FVC) was
measured using a Vitalographs alpha spirometer every 3
weeks at each clinic visit.
Asthma control was defined as good, intermediate, or
poor if the following criteria were met during the last 14
days of treatment in each 6-week treatment period: good:
symptoms on p2 days and a PEF X80% of the predicted at
baseline; intermediate: symptoms on 3–6 days and a PEF
X80% of the predicted at baseline; poor: symptoms on X7
days or a PEF o80% of the predicted at baseline. Symptoms
were defined as a score of X1 for any daytime symptom or
sleep disturbance in a 24-h period.
The minimal effective dose was also determined for each
patient during the study. This was defined as the dose of
study medication taken before that causing loss of asthma
control or the dose providing intermediate control.
Quality of life (QoL) was assessed at the end of the run-in
period and at the end of weeks 6, 12 and 18. The Paediatric
Asthma Quality of Life Questionnaire (PAQLQ) was used for
children aged X7 yr14 and the Paediatric Asthma Caregiver’s
Quality of Life Questionnaire (PACQLQ)15 for children
aged o7 yr.
Routine physical examinations were performed and vital
signs were monitored at the screening visit, at the end of
week 18 and as part of the end of study procedures if a
patient discontinued the study. Adverse events were
assessed every 3 weeks and were categorised as mild,
moderate or severe according to the following definitions:
mild, the patient was aware of the signs and symptoms, but
they were easily tolerated; moderate, the signs and
symptoms were sufficient to restrict, but did not prevent
the patient’s usual daily activity; severe, the patient was
unable to perform their usual daily activities. Urinary freecortisol was measured at the end of the run-in period and
after 6 weeks of treatment in patients recruited in The
Netherlands only; patients receiving nasal steroid therapy
were excluded.
Treatment compliance was assessed before and after each
6-week treatment period based on the weight difference
between used and unused inhaler canisters of active study
medication; this was then converted into the number of
actuations. A patient was considered compliant if his/her
total number of calculated actuations was between 470%
and o130% of the predicted.
Statistical analyses
Efficacy analyses were performed on the intent-to-treat
population (ITT), which comprised all patients who received
at least one dose of study medication. The primary efficacy
endpoint was the change in mean AM PEF, as a percentage of
the predicted value (% predicted), from baseline to weeks
5–6. A 90% CI was constructed; the null hypothesis of
inferiority being rejected if the lower limit of the interval
was 45% of predicted PEF. Based on a SD of 15% for the
change from baseline in AM PEF as a percentage of predicted
at the end of 6 weeks of treatment,16 it was estimated that
a sample size of 224 patients would provide at least 80%
power to test the null hypothesis at the p ¼ 0.05 level.
Allowing for a 19% dropout rate, a minimum of 138 patients
were required to be recruited to each treatment group.
Secondary efficacy endpoints included PM PEF, daytime
symptom scores, sleep disturbance scores, and b2-agonist
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W.M.C. van Aalderen et al.
use recorded on the daily diary cards; clinic FVC, FEV1, and
FEF25–75%; proportion of patients achieving good, intermediate or poor asthma control; and patient and caregiver QoL.
An analysis of variance (ANOVA), with treatment and
centre terms in the model, was used to determine the
difference between treatment groups for primary and
secondary efficacy variables, with the exception of QoL,
minimal effective dose, and asthma control, which used a
Fisher’s Exact Test. Formal statistical tests were not
performed on efficacy data from weeks 7–12 and 13–18
because of insufficient power for efficacy analyses.
The safety analysis was performed on the ITT population.
The incidence of adverse events was assessed using a twosided Fisher’s Exact Test, and urinary free-cortisol and vital
signs were analysed using an ANOVA model. Kaplan–Meier
estimates of time until first exacerbation were compared
between the two treatment groups using a Wilcoxon test.
Results
Study population
A total of 139 patients were randomised to BDP extrafine
aerosol and 141 to CFC-FP. One patient in the CFC-FP group
failed to take any study medication and was consequently
excluded from the ITT population (n ¼ 279). The two groups
were well matched in terms of baseline characteristics
(Table 1). Eleven patients receiving BDP extrafine aerosol
and eight patients receiving CFC-FP discontinued during
weeks 1–6. The main reasons for withdrawal included
withdrawal of consent, inadequate response, and violation
Table 1 Patient baseline characteristics (intent-totreat population).
Mean (SD) age (yr)
Mean (SD) weight (kg)
Female (%)
Duration of asthma (%)
o1 yr
1–5 yr
45 yr
AM PEF (SD) (%
predicted)
FEV1 (SD) (% predicted)
FEF25–75% (% predicted)
FVC (% predicted)
BDP extrafine
aerosol
(n ¼ 139)
CFC-FP
(n ¼ 141)
8.3 (2.0)
32.1 (10.1)
45
8.6 (2.2)
33.5 (13.4)
38
7
52
41
94.7 (19.6)
6
52
41
95.7 (18.1)
86.0 (13.4)
76.5 (26.6)
96.3 (18.5)
88.0 (13.7)
77.9 (27.9)
97.1 (15.9)
AM PEF: morning peak expiratory flow; BDP: beclometasone
dipropionate; CFC-FP: fluticasone propionate formulated
with chlorofluorocarbon propellant; FEV1: forced expiratory
volume in 1 s; FEV25–75%: forced expiratory flow at between
25% and 75% of the FVC; FVC: forced vital capacity; SD:
standard deviation.
Includes one patient who did not take any study
medication.
of entry criteria. Figure 2 shows patient disposition during
the 18-week treatment period.
Mean compliance in the ITT population during weeks 1–6
was 81.6% in the BDP extrafine aerosol group and 73.8% in
the CFC-FP group. During the entire study period, compliance was 79.5% and 73.2%, respectively.
Efficacy
Pulmonary function
In the ITT population, AM PEF% predicted improved in both
treatment groups at week 6. The mean (SD) change from
baseline in AM PEF% predicted was 5.7% (13.9) in the BDP
extrafine aerosol group and 7.3% (13.9) in the CFC-FP group;
the treatment difference was 1.9 (90% CI: 4.9, 1.0).
Improvements in AM PEF% predicted achieved at week 6
increased or were maintained at weeks 12 and 18 (Table 2).
Similar small improvements in PM PEF, FEV1, and FEF25–75%
(all % predicted) were reported at week 6 in both treatment
groups (Table 3). These improvements generally increased
or were maintained at weeks 12 and 18. There was a
significantly greater increase in FEF25–75% from baseline at
week 6 in the CFC-FP compared with the BDP extrafine
aerosol group (0.7 versus 4.8%; p ¼ 0.027); however, there
was a trend towards a greater increase from baseline in
FVC% predicted in patients receiving BDP extrafine aerosol
compared with patients receiving CFC-FP (5.3 versus 0.4%;
p ¼ 0.084).
Asthma symptoms
Similar improvements were reported in the percentage of
symptom-free days, nights without sleep disturbance, and
use of as-required b2-agonist therapy in both treatment
groups at week 6. The percentage change from baseline in
symptom-free days was 35.2% in both the BDP extrafine
aerosol and CFC-FP groups (p ¼ 0.897). The corresponding
change in nights without sleep disturbance was 17.5% and
20.8%, respectively (p ¼ 0.561). The mean number of puffs
of b2-agonist inhaler decreased from 1.59 to 0.73 puffs
day1 in the BDP extrafine aerosol group and from 1.40 to
0.69 puffs day1 in the CFC-FP group (p ¼ 0.505). Further
improvements in symptom control were reported in both
treatment groups at weeks 12 and 18.
Asthma control
The proportions of patients achieving asthma control in the
BDP extrafine aerosol and CFC-FP groups were similar. As the
study progressed, proportionally more patients in each
subsequent part of the study achieved or maintained good
asthma control, despite a lowering of the dose (Fig. 3). At
week 6, 36% of patients (50/139) receiving BDP extrafine
aerosol and 42% of patients (59/141) receiving CFC-FP had
good asthma control and were able to ‘step down’ their dose
of study medication to 100 mg day1. At week 12, another
‘step down’ in therapy to 50 mg day1 was possible in 66% of
patients (46/70) in the BDP extrafine aerosol group and 61%
of patients (47/77) in the CFC-FP group.
The minimal effective dose over the 18-week study period
was 200, 100 and 50 mg day1 for 24%, 31% and 7% of
patients, respectively, in the BDP-extrafine aerosol group
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BDP extrafine aerosol in children with asthma
Treatment group
Randomised
Discontinued
during wk 1–6
1589
BDP extrafine
139
CFC-FP
141
Total
11
Inadequate response 1
Total
8
Inadequate response 2
Completed wk 1–6 128
Discontinued
at end of wk 6
133
Total
58
Inadequate response 41
70
Entered wk 7
Discontinued
during wk 7–12
Total
56
Inadequate response 45
77
Total
7
Inadequate response 3
Total
7
Inadequate response 4
Completed wk 7–1
63
Discontinued
at end of wk 12
70
Total
8
Inadequate response 6
55
Entered wk 13
Discontinued
at end of wk 18
Total
12
Inadequate response 8
58
Total
2
Inadequate response 0
Completed wk 13–18
53
Total
0
Inadequate response 0
58
Figure 2 Flow chart of patient disposition. BDP: beclometasone dipropionate; CFC-FP: fluticasone propionate formulated with
chlorofluorocarbon propellant.
Table 2
Improvement in pulmonary function during weeks 1–6, 7–12 and 13–18 (intent-to-treat population).
Variable (mean, SD)
BDP extrafine aerosol
Baseline
6 weeks
CFC-FP
Change
AM PEF (% predicted)y
Weeks 1–6
94.7 (19.6) 100.3 (19.6) 5.7 (13.9)
Weeks 7–12
102.8 (19.8) 103.6 (19.9)
Weeks 13–18
103.6 (18.6) 104.2 (16.8)
Baseline
6 weeks
Change
95.7 (18.1) 103.3 (17.9) 7.3 (13.9)
107.7 (16.7) 106.0 (16.7)
107.5 (15.4) 108.1 (18.2)
Estimate of
treatment
difference
(90% CI)
1.9 (4.9, 1.0)
AM PEF: morning peak expiratory flow; BDP: beclometasone dipropionate; CFC-FP: fluticasone propionate formulated with
chlorofluorocarbon propellant; CI: confidence interval; SD: standard deviation.
Change from baseline.
y
Statistical analyses were only conducted on week 1–6 data.
(based on 126 evaluable patients). In the CFC-FP group
(n ¼ 132), the minimal effective dose was 200, 100 and
50 mg day1 for 32%, 27% and 10% of patients, respectively.
Quality of life
The proportion of patients experiencing a clinically
significant improvement in asthma QoL during the
initial 6-week treatment period was similar in the BDP
extrafine aerosol and CFC-FP treatment groups (PAQLQ: BDP
extrafine aerosol 68% versus CFC-FP 50%, p ¼ 1.00; PACQLQ:
BDP extrafine aerosol 44% versus CFC-FP 42%, p ¼ 0.369)
(Fig. 4). There were no statistically significant differences
between the two treatment groups with respect to
improvement in overall QoL score or for the individual
domains.
Safety and tolerability
There was no statistically significant difference in the
proportion of patients experiencing adverse events in the
BDP extrafine aerosol and CFC-FP treatment groups (47%
versus 49%, respectively). The most frequently reported
adverse event was upper respiratory tract infection, which
occurred in 19% of patients receiving BDP extrafine aerosol
and 21% of patients receiving CFC-FP. All but two adverse
events were of mild-to-moderate intensity. Severe adverse
events occurred in two patients (1%) receiving BDP extrafine
aerosol: one case of severe stomatitis and another of severe
accidental fracture of the arm. Neither event was considered to be treatment-related. Indeed, only two adverse
events were considered to be probably treatment-related:
one case of dysphonia in the BDP extrafine aerosol group and
one case of coughing in the CFC-FP group.
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Table 3
W.M.C. van Aalderen et al.
Improvement in pulmonary function during weeks 1–6, 7–12 and 13–18 (intent-to-treat population).
Variable (mean, SD) BDP extrafine aerosol
Baseline
6 weeks
PM PEF (% predicted)y
Weeks 1–6
95.8 (19.0) 101.9 (19.6)
Weeks 7–12
104.8 (19.8) 105.4 (18.7)
Weeks 13–18
105.2 (17.6) 105.7 (17.8)
FEV1 (% predicted)y
Weeks 1–6
Weeks 7–12
Weeks 13–18
FVC (% predicted)y
Weeks 1–6
Weeks 7–12
Weeks 13–18
86.0 (13.4)
89.0 (11.1)
90.9 (12.8)
88.5 (12.7)
90.3 (12.7)
91.1 (14.1)
96.3 (18.5) 101.6 (26.4)
101.0 (20.7) 102.0 (18.3)
102.3 (17.9) 104.6 (19.5)
FEF25–75% (% predicted)y
Weeks 1–6
76.5 (26.6)
Weeks 7–12
77.8 (27.3)
Weeks 13–18
78.2 (27.1)
CFC-FP
Change
5.9 (13.3)
Baseline
Change
97.0 (18.1) 104.4 (19.3) 7.3 (15.1) 1.5 (4.6, 1.6)
108.9 (18.6) 107.3 (17.0)
108.6 (15.7) 111.0 (17.3)
3.0 (9.2)
5.3 (23.7)
6 weeks
Estimate of
treatment
difference
(90% CI)
88.0 (13.7)
91.1 (13.7)
93.5 (14.0)
p-Value
0.415
89.0 (14.6) 0.6 (13.5) 1.6
93.3 (13.5)
92.9 (14.6)
0.335
97.1 (15.9) 98.2 (14.2) 0.4 (13.4) 4.6
99.7 (13.2) 100.1 (13.0)
100.3 (13.2) 102.0 (15.7)
0.084
76.1 (26.2) 0.7 (21.3)
76.6 (26.3)
75.8 (24.7)
77.9 (27.9)
87.7 (26.9)
88.3 (29.7)
83.8 (26.8) 4.8 (23.1) 6.9
88.1 (28.8)
84.9 (29.6)
0.027
BDP: beclometasone dipropionate; CFC-FP: fluticasone propionate formulated with chlorofluorocarbon propellant; CI: confidence
interval; FEV1: forced expiratory volume in 1 s; FEF25–75%: forced expiratory flow at between 25% and 75% of the FVC; FVC: forced vital
capacity; PM PEF: evening peak expiratory flow; SD: standard deviation.
Change from baseline.
y
Statistical analyses were only conducted on week 1–6 data.
100
Good control
Intermediate control
Poor control
90
80
Patients (%)
70
60
50
40
30
20
10
0
BDP extrafine CFC-FP BDP extrafine CFC-FP BDP extrafine CFC-FP
n=78
n=87
n=47
n=74
n=40
n=36
Part 1
Part 2
Part 3
Figure 3 Asthma control during weeks 1–6, 7–12 and 13–18 (intent-to-treat population). aGood control: symptoms on p2 days and a
PEF X80% of the predicted at baseline; intermediate control: symptoms on 3–6 days and a PEF X80% of the predicted at baseline;
poor control: symptoms on X7 days or a PEF o80% of the predicted at baseline. Symptoms were defined as a score of X1 for any
daytime symptom or sleep disturbance in a 24-h period. BDP: beclometasone dipropionate; CFC-FP: fluticasone propionate
formulated with chlorofluorocarbon propellant.
Five patients (4%) randomised to BDP extrafine aerosol
discontinued treatment as a result of adverse events: four
cases of asthma exacerbation and one case of dizziness after
inhalation from the AeroChamber Pluss. Treatment was
discontinued in one patient (1%) randomised to CFC-FP
because of pallor, hyperactivity and inattentiveness at
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BDP extrafine aerosol in children with asthma
59%
1591
43%
Net % pts improveda
100
Improved
(change ≥ 0.5)
80
50%
68%
Patients (%)
60
Maintained
(change > -0.5 to < 0.5)
40
Deteriorated
(change ≤ –0.5)
20
42%
23%
0
9%
20
BDP extrafine
(n=139)
8%
FP
(n=141)
40
Figure 4 Percentage of patients with a clinically significant improvement in asthma quality of life during the initial 6-week
treatment period. aPercentage of patients with clinical improvement minus percentage of patients with clinically significant
worsening. BDP: beclometasone dipropionate; CFC-FP: fluticasone propionate formulated with chlorofluorocarbon propellant.
school. Two serious adverse events (not considered to be
treatment-related) were reported in the BDP extrafine
aerosol group (one case of hospitalisation for a tonsillectomy, and an arm fracture due to a fall).
There were no clinically relevant trends in urinary freecortisol levels (measured in 59 patients in The Netherlands),
vital signs, or use of concomitant medication, and no
clinically relevant changes were noted on physical examination. The percentage of patients experiencing an asthma
exacerbation during the study was low and similar in the two
treatment groups (BDP extrafine aerosol: nine patients (6%);
CFC-FP: eight patients (6%)).
Discussion
The results of this study show that BDP extrafine aerosol, in
combination with the AeroChamber Pluss holding chamber
was as effective as CFC-FP plus the VolumaticTM spacer at
improving pulmonary function, asthma control and QoL in
children aged 5–12 yr with symptomatic mild-to-moderate
asthma.
The therapeutic equivalence of BDP extrafine aerosol and
CFC-FP has previously been demonstrated in adults with
asthma12,13; however, this is the first study to compare these
agents in children. In our study, the ITT population results
for the mean change in AM PEF% predicted showed that the
lower limit of the CI for the mean difference (1.9)
between the two treatment groups was 4.9 at week 6
(i.e. greater than the designated 5.0 limit) indicating that
BDP extrafine aerosol is as effective as CFC-FP at improving
asthma control in children. The use of a ‘step down’
approach in this study allowed determination of true
equivalence as opposed to equivalence in over treatment.
The difficulties associated with establishing the true
therapeutic equivalence of inhaled asthma therapies are
well documented; in particular defining the appropriate
limits of equivalence can be problematic, and should include
both upper and lower limits to capture the profile of the
drug in terms of efficacy and safety. The limits of
equivalence of the drug should also be smaller than the
beneficial effects of the drug and should be applied to
defined groups of patients only.
A significantly greater improvement in FEF25–75% from
baseline at week 6 was reported in the CFC-FP compared
with the BDP extrafine aerosol group. The trend towards a
greater improvement in FVC with BDP extrafine aerosol
compared with CFC-FP reported in this study is consistent
with a greater reduction in air trapping and small airways
obstruction. Reduced air trapping has been reported
previously with BDP extrafine aerosol compared with CFCBDP17 and it has been hypothesised that this may be
associated with more effective suppression of small airways
inflammation, and consequently greater peripheral airways
patency. Achievement of this is particularly important in
children as it allows the whole bronchial tree to be treated
from a young age, thus reducing the likelihood of airway
remodelling and pathological changes.
The manufacture of CFC-FP was discontinued during
the course of this study and CFC-FP has since been
wholly replaced by HFA-FP. Data suggest that HFA-FP and
CFC-FP have equivalent efficacy at the same dose in
children.18 However, we used the CFC formulation of FP as
comparator because, at the time the study was conducted, an equivalent dose-strength HFA-FP inhaler was not
available.
Compliance with study medication is seldom assessed in
studies of children with asthma; however, the overall mean
percentage compliance with study medication in our study
(79.5% and 73.2% in the BDP extrafine aerosol and CFC-FP
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1592
groups, respectively) was comparable with that reported in
three other studies conducted in children with asthma.19,20
The importance of gaining early control of asthma as
quickly as possible is highlighted in current asthma treatment guidelines.21,22 Once control of asthma has been
achieved, the aim is to gradually reduce the daily dose of ICS
therapy to the lowest dose required to maintain good
control of asthma (‘step down’ approach). Treatment with
the lowest possible dose of ICS is particularly important in
children, as they are more susceptible than adults to the
adverse systemic effects associated with the use of
unnecessarily high doses of ICS. The aim of the first 6-week
treatment period in this study was to examine the early
control of symptomatic asthma with BDP extrafine aerosol
and CFC-FP 200 mg day1 over 6 weeks. A ‘step down’
approach was used during weeks 7–12 and 13–18. At week 6,
eligible patients had their dose of medication reduced to
100 mg day1 for 6 weeks and, if appropriate, the dose
halved again at week 12–50 mg day1 for a further 6 weeks.
In total, 36% of patients in the BDP extrafine aerosol group
and 42% of patients in the CFC-FP group were eligible for
‘step down’ therapy after just 6 weeks, and 66% and 61%,
respectively, were eligible for ‘step down’ after 12 weeks.
As the study proceeded, proportionally more patients
achieved asthma control despite an overall reduction (‘step
down’) in the dose of study medication, which suggests that
adopting this relatively rapid ‘step down’ approach did not
result in the loss of asthma control. ‘Stepping down’ therapy
once initial control has been achieved therefore appears to
be a sensible approach in children with mild-to-moderate
asthma. The ‘step down’ approach also allowed estimation
of the lowest dose at which effective control of asthma was
maintained. A similar proportion of patients in the BDPextrafine aerosol and CFC-FP groups had a minimal effective
dose of 200, 100 and 50 mg day1.
The double-blind, double-dummy design of this study
prevented identification of the active inhaler in each
treatment group. This was necessary because the BDP
extrafine aerosol and CFC-FP inhalers and spacers did not
have the same appearance and the different propellants
may have led patients to notice a difference in the taste and
feel of the study medications. BDP extrafine aerosol is
currently indicated for the prophylactic treatment of adults
with asthma in Europe and is licensed for use in children in
several European countries. The starting dose of 200 mg
day1 BDP extrafine aerosol selected for this study is the
maximum recommended dose for the treatment of children
with asthma in The Netherlands.23,24
The safety profile of BDP extrafine aerosol compared
favourably with that of CFC-FP, and the overall pattern and
incidence of adverse events was not unexpected in this
study population. This is particularly important given that
the increased deposition of ICS to the lungs with BDP
extrafine aerosol could lead to greater systemic availability.
In addition, the ability to ‘step down’ the dose of treatment
during the study ensured the best possible safety profile for
both drugs. As expected, the most frequently reported
adverse events were related to the respiratory system and
included respiratory tract infection, cough, and pharyngitis.
No cases of oropharyngeal candidiasis were reported. The
incidence of adverse events considered to be treatmentrelated was also low. Our findings confirm the general
W.M.C. van Aalderen et al.
consensus that ICS therapy is well tolerated in children;
however, concern has been raised regarding its effect at
high doses on adrenal function, and bone formation and
resorption.25 Our study reported no clinically relevant effect
on adrenal function with BDP extrafine aerosol, as measured
by urinary free-cortisol, which is in accordance with findings
from earlier studies.26,27 Although, the relatively short
duration of our study precluded an assessment of the effect
of BDP extrafine aerosol on childhood growth, results from a
study conducted by Pedersen et al.27 indicated that BDP
extrafine aerosol had no effect when used at recommended
doses of 100–200 mg day1.
Conclusions
BDP extrafine aerosol was as effective as CFC-FP at
improving asthma control in children aged 5–12 yr with
symptomatic mild-to-moderate asthma. This finding supports the hypothesis that reformulation of BDP as a CFC-free
extrafine aerosol provides comparable symptom control to
CFC-FP at the same daily dose. The observed trend towards
greater improvement in FVC with BDP extrafine aerosol
compared with CFC-FP may suggest more effective suppression of inflammation in the small airways, which is
particularly important in children.
Acknowledgements
We would like to thank the following investigators for their
participation in the study; The Netherlands: M. Affourtit,
I.G.C.M. Bierens, P.L.P. Brand, P.D.M. Coenen, J. de Jong,
J.J.E.M. De Nef, H. Ferguson, C.A.C. Hugen, Q. Jobsis, J.M.
Kouwenberg, I.R. Ong, G.H.P.R. Slabbers, M.J. SpaanGroenemeijer, G.J.M. van Doesburg, J. Veerman, K. Vieira,
W.B. Vreede.
Belgium: Casimir, G. De Bilderling, J. Foucart, K. Ladha.
United Kingdom: R. Addlestone, M.D. Blagdon, Bowen,
Brown, P. Buck, D. Burwood, M. Clamp, R. Cook, G.
Derbyshire, D.A. Dutchman, M. Fahmy, C.P. Fletcher, D.
Freeman, S. Holgate, A.P. Jackson, C. Langdon, A. Marshall,
A.P.M. Matthews, A. Middleton, P. Mooney, M. Mutch, N.H.
Patel, B. Penney, Rotheray, S. Rowland, D. Ryan, J. Ryan, G.
Sado, I. Serrell, B.D. Silvert, G. Singh, G. Spence, M.
Spencer, M. Thomas, E. White, M.A. Whitehead, Young.
Medical writing support was provided by Julie Adkins at
Prime Medica during the preparation of this paper, supported
by IVAX Pharmaceuticals. Responsibility for opinions, conclusions and interpretation of the data lies with the author.
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