Download Hydrofluoroalkane-134a Beclomethasone

Hydrofluoroalkane-134a
Beclomethasone Dipropionate, 400 mg,
Is as Effective as Chlorofluorocarbon
Beclomethasone Dipropionate, 800 mg,
for the Treatment of Moderate Asthma*
Gary Gross, MD; Philip J. Thompson, MD, FCCP; Paul Chervinsky, MD;
Jennifer Vanden Burgt, BS, BA; and the Study Group†
Objective: The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate (CFC-BDP) suggests that lower doses of HFA-BDP may be required to provide
equivalent asthma control. The present study was undertaken to test this hypothesis.
Design: A 10- to 12-day run-in period confirmed that patients met established criteria of at least
moderate asthma and the asthma was inadequately controlled by current therapy (inhaled
b-agonist and CFC-BDP [< 400 mg/d]). A short course of oral prednisone, 30 mg/d for 7 to 12
days, was followed to establish the patients were steroid responsive and to provide an “in-study”
baseline of “optimal” asthma control.
Patients: A total of 347 patients were then randomized to HFA-BDP 400 mg/d, CFC-BDP 800
mg/d, or HFA-placebo for 12 weeks.
Results: Morning peak expiratory flow (AM PEF) measurements showed that HFA-BDP 400 mg/d
achieved equivalent control of asthma to CFC-BDP 800 mg/d at all time intervals after oral
steroid treatment. All other efficacy variables supported the AM PEF results and both active
treatments were more effective than placebo. The safety profile of HFA-BDP compared favorably
with that of CFC-BDP with no unexpected adverse events reported.
Conclusions: These findings demonstrate that HFA-BDP provides equivalent control of moderate
or moderately severe asthma as CFC-BDP in the population studied, but at half the total daily
dose.
(CHEST 1999; 115:343–351)
Key words: chlorofluorocarbon beclomethasone dipropionate; hydrofluoroalkane-134a beclomethasone dipropionate;
moderate asthma
Abbreviations: am PEF 5 morning peak expiratory flow; ANOVA 5 analysis of variance; BDP 5 beclomethasone
dipropionate; CFC 5 chlorofluorocarbon; CI 5 confidence interval; HFA 5 hydrofluoroalkane-134a; MDI 5 metereddose inhaler; pm PEF 5 evening peak expiratory flow
efficacy of inhaled corticosteroids for the
T hetreatment
of asthma is well recognized, with
both national and international treatment guidelines
recommending their use as first-line therapy for all
*From the Dallas Allergy and Asthma Center (Dr. Gross), Dallas,
TX; Asthma and Allergy Research Unit, Department of Medicine, University of Western Australia (Prof. Thompson), Perth,
Australia; New England Clinical Studies (Dr. Chervinsky),
North Dartmouth, MA; 3M Pharmaceuticals (Ms. Vanden
Burgt), St. Paul, MN.
This study was supported by a grant from 3M Pharmaceuticals.
†A complete list of Study Group participants is located in the
Appendix.
Manuscript received April 17, 1998; revision accepted August 12,
1998.
Correspondence to: Jennifer Vanden Burgt, 3M Pharmaceuticals,
3M Center, Building 270-3A-01, St. Paul, MN 55144-1000;
e-mail: [email protected]
patients, except those with very mild disease.1,2
However, successful clinical management depends
on achieving adequate delivery of the inhaled drug to
the lung.3,4 Targeting of anti-inflammatory agents,
such as corticosteroids, to the smaller airways appears to be the most promising treatment strategy of
For editorial comment see page 316
the future,5,6 especially since anti-inflammatory
drugs are thought to be most effective when deposited in the smaller airways.7
The mandatory replacement of chlorofluorocarbons (CFCs) in pressurized metered-dose inhalers
(MDIs) with non-ozone-depleting propellants such
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343
as hydrofluoroalkane-134a (HFA) has provided the
opportunity to significantly improve the delivery of
inhaled drugs to the respiratory tract.8,9 Beclomethasone dipropionate (BDP), an established corticosteroid for the treatment of asthma, has now been
reformulated using the new HFA propellant. In
contrast to current CFC-BDP products, this new
formulation is a solution, rather than a suspension, of
BDP in propellant,10 with the solution forming an
extrafine aerosol of small droplets as the propellant
evaporates.11 CFC preparations exhibit aerodynamic
particle sizes of between 3 to 4 mm, whereas this
HFA-BDP formulation has a mass median aerodynamic diameter of approximately 1.2 mm.8
Deposition studies have demonstrated that HFABDP extrafine aerosol changes the standard pattern
of drug deposition seen with CFC-BDP formulations, delivering most of the inhaled dose to the
airways and depositing a much smaller proportion in
the oropharynx.12 Results of direct radiolabeled deposition studies in both healthy volunteers and patients with asthma show ex-actuator lung deposition
to be 51 to 60% with HFA-BDP9 compared with
lung deposition of , 10% for CFC-BDP.13 The
extent of lung deposition is known to be a major
determinant of the therapeutic efficacy of inhaled
corticosteroids,3 so these improved delivery characteristics are likely to provide several important clinical benefits. In particular, the improved lung deposition of HFA-BDP extrafine aerosol compared with
CFC-BDP suggests that lower doses of HFA-BDP
may be needed to provide equivalent asthma control.
This study was undertaken to test this hypothesis.
The primary objective was to determine whether a
total daily dose of 400 mg HFA-BDP extrafine
aerosol would provide equivalent control of moderate or moderately severe asthma to that of 800 mg of
CFC-BDP.
Materials and Methods
Study Design and Population
This was a 12-week, placebo-controlled, parallel-group, randomized, blinded, multicenter study. The study population included nonsmoking adults, aged 18 to 65 years, with at least
moderate asthma who were symptomatic despite current treatment with bronchodilators and inhaled steroid of 0 to 400 mg/d
(Table 1). Additional qualification criteria were concurrent use of
b-agonists for symptom relief and reversibility of FEV1 of $ 15%
in response to pirbuterol (400 mg). Eligible patients entered a 10to 12-day run-in period that established the presence of symptoms, lung function parameters, and bronchodilator usage consistent with a Global Initiative for Asthma classification of at least
moderate severity asthma.1 During the run-in period, patients
continued to take their b-agonist and their previously prescribed
inhaled corticosteroid if any. Patients were required to show signs
and symptoms of active asthma during the last 5 days of run-in to
be eligible to continue in the trial. This was defined as a mean
morning peak expiratory flow (am PEF) of between 50% and
80% of the predicted normal value plus one or more of the
following: sleep disturbance on $ 1 nights (recorded using a
recognized rating scale, see assessments section); presence of
asthma symptoms on $ 3 days; or use of a b-agonist inhaler on
average at least twice daily to relieve symptoms. A 7- to 12-day
course of oral steroid treatment (prednisone, 30 mg/d) followed.
Patients were required to have an improvement in am PEF of at
least 15% (average of am PEF readings taken over the last 3 days)
at the end of the oral steroid treatment period.
Patients meeting these criteria and demonstrating a satisfactory
technique in using an MDI were randomized to inhaled treatment with HFA-BDP (QVAR; 3M Pharmaceuticals; St. Paul,
MN; 400 mg/d [4 3 50 mg ex-valve twice daily]), CFC-BDP
(Beclovent; GlaxoWellcome; Research Triangle Park, NC; 800
mg/d [8 3 50 mg twice daily]), HFA-placebo (four puffs twice
daily), or HFA-placebo (eight puffs twice daily) for 12 weeks.
Patients were instructed to take their assigned study treatment in
the morning and evening, at about the same time each day. To
ensure blinding to active treatments, patients were randomly
assigned either a white study inhaler (HFA-BDP or HFAplacebo) or a cream-colored inhaler (CFC-BDP or HFA-placebo) and instructed to take four or eight puffs, respectively.
Thus, patients knew to take either four or eight puffs twice daily
but did not know if they were randomized to active treatment.
Table 1—Randomized Patients: Characteristics and Pulmonary Function at Screening
Characteristic
HFA-BDP, 400 mg/d
CFC-BDP, 800 mg/d
HFA-Placebo
No. of patients
Sex, No. (%)
Female
Male
Age, yr; mean (SD)
Asthma . 5 yr; No. (%)
Taking inhaled steroids; No. (%)
am PEF
Actual, L/min; mean (SD)
% predicted; mean (SD)
FEV1
Actual, L; mean (SD)
% predicted; mean (SD)
% reversibility to pirbuterol; mean (SD)
113
117
117
Overall p Value
67 (59.3)
46 (40.7)
32.5 (9.96)
102 (90.3)
35 (31.0)
63 (53.8)
54 (46.2)
34.8 (11.91)
96 (82.1)
46 (39.3)
55 (47.0)
62 (53.0)
34.6 (9.42)
103 (88.0)
48 (41.0)
0.190
380.1 (72.11)
71.0 (9.93)
389.7 (80.20)
71.1 (9.95)
386.0 (84.13)
69.1 (10.89)
0.704
0.319
2.36 (0.70)
67.4 (16.05)
31.9 (22.10)
2.40 (0.67)
66.7 (12.66)
31.5 (15.68)
2.41 (0.71)
67.2 (16.07)
30.0 (17.61)
0.871
0.957
0.774
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0.235
0.175
0.837
Clinical Investigations
This could lead to potential bias since patients may be more
compliant with a regimen with fewer inhalations required. A
double-blind, double-dummy study design was not used for
several reasons: (1) there was a desire not to expose a patient to
both propellants at a dosing session as this would make interpretation of possible inhalation effects difficult; (2) it was not
possible to use a CFC propellant in a canister designed for the
HFA propellant; (3) a patient would be taking a large number of
inhalations in one day; and (4) there would be potential for a
patient to take the wrong number of inhalations from the active
canister.
Exclusion criteria included any clinically significant abnormality or disease, and acute upper or lower respiratory tract infection
within 4 weeks before the start of the trial or during the run-in
period. Patients who received any other medication were not
selected for enrollment. However, the use of an inhaled b-agonist
bronchodilator was permitted throughout the study to relieve
symptoms of asthma on an “as needed” basis.
Ethical Considerations
The study was performed in accordance with the Declaration
of Helsinki. A central or local institutional review board for each
study site approved the study, and all patients gave written
informed consent.
As part of the study design, withdrawal criteria were established so that if a patient’s asthma deteriorated by a predetermined level during the run-in or study periods, the patient was
withdrawn from the study and appropriate treatment given if
deemed necessary by the investigator.
Statistical Methods
The intent-to-treat population was used for all analyses. The
mean change following cessation of oral steroid treatment for the
primary efficacy variable of am PEF, over weeks 1 to 3, 4 to 6, 7
to 9, and 10 to 12 was compared between treatment groups using
an analysis of variance (ANOVA) with treatment, center, and
treatment-by-center interaction terms. The standard method for
testing for equivalence, the two one-sided test method, was used
to demonstrate equivalence of the active treatments. This
method is tantamount to the use of 90% confidence intervals
(CIs) for assessing equivalence. The mean change in am PEF and
pm PEF following cessation of oral steroid treatment in the
patients who received HFA-BDP was considered to be equivalent to the mean for the patients receiving CFC-BDP if the 90%
CI for the mean difference between the active treatments was
within 6 25 L/min using the two one-sided test method.15,16 For
FEV1, a difference between active treatments in mean change
from oral steroid therapy within 6 0.2 L was defined as equivalent. Comparisons of each active treatment with placebo were
also made.
ANOVAs for the secondary efficacy variables were performed
and 90% CIs were constructed. Time to withdrawal because of
asthma symptoms was compared among treatment groups using
a Wilcoxon test, and intergroup differences in the incidence of
adverse events were compared using Fisher’s Exact Test.
The last nonmissing values were carried forward to each
successive time point for patients who prematurely withdrew
from the trial in the intent-to-treat analysis. Bonferroni adjustments were made to account for multiple comparisons.
Assessments
PEF, asthma symptoms, and bronchodilator use were assessed
on a daily basis by the patients and recorded on a diary card.
Morning (am) and evening (pm) PEF measurements were taken
using a mini-Wright peak flow meter (Clement Clarke; Columbus, OH), before use of b-agonist or study medication. Daytime
symptoms of wheezing, shortness of breath, chest tightness, and
cough were rated on a scale of 0 to 5 (0 5 not present, 5 5 so
severe that the patient could not attend work or carry out normal
daily activities) and nighttime symptoms were assessed on a scale
of 0 to 4 (0 5 no asthma symptoms during the night, 4 5 asthma
symptoms so severe that the patient did not fall asleep at all).
Spirometry was performed to determine FEV1 and forced expiratory flow over 25 to 75% of the full FVC in accordance with
American Thoracic Society criteria at the screening visit, at the
end of the run-in and oral steroid treatment periods, and at clinic
visits every 3 weeks.14
Adverse events were assessed throughout the study. Any
patient reporting an oropharyngeal adverse event was examined
by the investigator and had mouth or throat swabs taken for
Candida culture if clinical signs were present. Standard clinical
chemistry assessments, physical examination, and ECG were
recorded prestudy and poststudy, and vital signs were monitored
at all visits.
Plasma cortisol level was measured at the end of the run-in
period, following the course of oral steroids and after 12 weeks of
inhaled treatment. For all patients, the first measurement was
taken in a window between 6:30 am and 9:30 am and, for each
individual, the subsequent measurements were taken within 30
min of the time of their first determination.
Compliance was assessed by comparing the weights of all study
inhaler canisters before dispensing with the weights of returned
canisters and converting predicted and actual inhaler weights to
number of administered doses.
Results
Demographics
A total of 347 patients were entered into this
study, of whom 113 received HFA-BDP, 117 received CFC-BDP, and 117 received HFA-placebo.
The three treatment groups were similar in all
baseline patient characteristics, including lung function (Table 1). The use of inhaled steroids and the
proportions of steroid-naive patients before randomization were also comparable between treatment
groups.
Sixty-one patients (17.6%) withdrew prematurely
from the study, with a total of 286 patients completing the 12-week treatment period. The most common reason for withdrawal from therapy was worsening of asthma symptoms (43 patients [12.4%]). As
shown in Figure 1, this was experienced by significantly more placebo-treated patients than in either
of the active treatment groups (33 patients [28.2%]
receiving placebo compared with 5 [4.4%] receiving
HFA-BDP and 5 [4.3%] receiving CFC-BDP;
p # 0.001).
Compliance
Compliance (as determined by canister weights)
was good (. 87%) and comparable in all treatment
groups. No differences in compliance were observed
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345
Figure 1. Time to withdrawal from study due to asthma symptoms.
for patients receiving placebo from a white study
inhaler compared with a cream-colored inhaler, indicating that the different number of inhalations
required (four and eight, respectively) did not affect
compliance.
Asthma Control
The mean changes in am PEF following cessation
of oral steroid therapy are summarized in Table 2.
There was a statistically equivalent mean change
following the cessation of oral steroid treatment in
am PEF for the HFA-BDP 400 mg/d group compared with the CFC-BDP 800 mg/d group over the
12 weeks of the study (Table 2; Fig 2). The mean
change in am PEF following oral steroid therapy was
significantly smaller for both active treatments than
HFA-placebo at all time intervals (p # 0.003). am
PEF declined in the placebo treatment group
throughout the 12-week treatment period. The
greatest reduction occurred within 1 week of withdrawal of oral steroid therapy, with the effect of the
oral steroid treatment appearing to be negligible by
week 4.
All other efficacy variables supported the findings
of this primary efficacy analysis. As with am PEF, the
mean change in pm PEF after the period of oral
Table 2—Mean Change in
AM
steroid treatment was equivalent for HFA-BDP and
CFC-BDP treatment at each time interval. Similarly,
both HFA-BDP and CFC-BDP maintained the improvement in FEV1 seen following oral steroid therapy throughout the 12-week treatment period (Fig
3). Using 6 0.2 L as an equivalence limit, the
HFA-BDP and CFC-BDP groups were found to be
equivalent in terms of mean change from oral steroid
treatment in FEV1 at weeks 3, 9, and 12. However,
at week 6, the HFA-BDP mean was higher than that
for CFC-BDP (p 5 0.085; 90% CI, 20.019, 0.220).
Mean changes following oral steroid therapy in both
pm PEF and FEV1 were significantly smaller for
both active treatments than for HFA-placebo at all
time intervals (p # 0.003).
HFA-BDP, 400 mg/d, and CFC-BDP, 800 mg/d,
provided equivalent asthma symptom control as
measured by symptom scores for wheezing, cough,
shortness of breath, and chest tightness. The numbers of symptom-free days and nights and b-agonist
use were also equivalent in the two active treatment
groups. Patients treated with HFA-BDP or CFCBDP experienced significantly more symptom-free
days or nights than those who received HFA-placebo
(p # 0.003 for HFA-BDP and p # 0.05 for CFCBDP) (Fig 4). The mean change from this oral
PEF (L/min) From Oral Steroid Treatment*
Characteristic
HFA-BDP, 400 mg/d
CFC-BDP, 800 mg/d
HFA-Placebo
Overall p Value
Run-in
Oral steroid treatment
Change at wk 1–3
Change at wk 4–6
Change at wk 7–9
Change at wk 10–12
369.6 (8.09)
453.5 (9.11)
28.4 (4.09)
28.4 (4.77)
25.5 (5.24)
25.3 (5.44)
372.7 (7.72)
451.9 (8.69)
217.3 (3.92)
217.0 (4.57)
215.0 (5.03)
214.0 (5.22)
373.5 (8.07)
453.3 (9.08)
242.7 (4.08)
256.6 (4.76)
259.8 (5.24)
263.4 (5.44)
0.936
0.991
, 0.001
, 0.001
, 0.001
, 0.001
*Values are mean (SD). p values are based on an ANOVA with treatment, center, and treatment-by-center interaction terms in the model.
Comparisons of active treatment with placebo.
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Clinical Investigations
Figure 2. Adjusted mean am PEF (L/min) by week.
steroid treatment period in daily b-agonist use was
also significantly less at each time period with both
HFA-BDP and CFC-BDP compared with HFAplacebo (p # 0.003) (Fig 5). The use of b-agonists
decreased during the period of oral steroid treatment
and subsequently changed little during the 12 weeks
of inhaled steroid therapy. In contrast, b-agonist use
increased in placebo-treated patients during this
time and was significantly different for active groups
(p # 0.003) (Fig 5).
Safety
The safety profile of HFA-BDP was found to
compare favorably with that of CFC-BDP, with no
unexpected adverse events associated with the new
formulation. As might be expected, more placebotreated patients withdrew from the study due to
adverse events (18 [15.4%]) than those who received
HFA-BDP or CFC-BDP (7 [6.2%] and 2 [1.7%],
respectively). The greater number of withdrawals
with HFA-placebo is presumably due to the fact that
more patients reported worsening of asthma symptoms in the placebo treatment group (28.2% vs 4.4%
for HFA-BDP and 4.3% with CFC-BDP; p # 0.001
for comparison of time to withdrawal for asthma
symptoms) (Fig 1). Adverse events leading to withdrawal of therapy were considered to be possibly or
probably related to therapy in only one patient
(0.9%) in the HFA-BDP treatment group and three
of those treated with CFC-BDP (2.6%).
Adverse events considered to be possibly or probably related to study medication were reported by 52
patients overall (15.0%), and occurred in fewer
patients treated with HFA-BDP (11 [9.7%]) than
those treated with CFC-BDP or HFA-placebo (23
[19.7%] and 18 [15.4%], respectively). Specific attention was paid to adverse events most commonly
considered to be related to study medication, in
particular those that could be related to the inhaled
route of administration. Such adverse events tended
Figure 3. Adjusted mean FEV1 (L) by week.
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Figure 4. Adjusted mean percentage of nights without sleep disturbance.
to occur most frequently in patients treated with
CFC-BDP (Table 3). Analysis of throat and mouth
swabs failed to detect levels of Candida exceeding
the normal oral flora in any patient reporting clinical
symptoms during the course of the study.
At week 12, $ 96% of patients (those for whom
there was a run-in, end of oral steroid, and end of
study value) had normal plasma cortisol levels in the
HFA-BDP, CFC-BDP, and HFA-placebo groups
(n 5 96/99, 98/101, and 76/79, respectively). At week
12, the mean percentage change in plasma cortisol
from run-in was 9.7%, 0.1%, and 1.9% for the
HFA-BDP, CFC-BDP, and HFA-placebo groups,
respectively. No clinically meaningful changes in
clinical chemistry or vital signs were reported in any
treatment group at the end of the 12-week treatment
period.
Discussion
The imminent phasing out of CFC propellants in
pharmaceutical aerosols has made it important to
assess the comparable efficacy and safety of alternative CFC-free formulations to the original products.
HFA-134a has been identified as a substitute for
CFCs in pressurized MDIs.8 Preclinical studies have
shown it to be well tolerated and to present no safety
concerns.17 HFA formulations of salbutamol and
fluticasone propionate have been shown previously
to be as effective and well tolerated as CFC products
at equivalent doses.18,19 The results of the present
study show that HFA-BDP extrafine aerosol is able
to maintain equivalent control of moderate asthma to
CFC-BDP at half the total daily dose following a
short course of prednisone therapy. Presumably, this
is due to improved lung deposition of inhaled steroid
seen with the HFA formulation.9 This finding is
consistent with the results of another study that show
that 800 mg/d of HFA-BDP provides equivalent
control to 1,500 mg/d of CFC-BDP in patients with
moderate-to-severe asthma.20
The difficulty in establishing therapeutic equivalence, particularly for inhaled asthma medications,
has been the subject of much discussion in recent
Figure 5. Adjusted mean change in daily b-agonist use.
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Clinical Investigations
Table 3—Adverse Events Most Commonly Considered Possibly or Probably Related to Study Medication
Adverse Event
HFA-BDP, 400 mg/d
CFC-BDP, 800 mg/d
HFA-Placebo
Patients reporting at least one adverse event, No. (%)
Inhalation route effects, No. (%)
Dysphonia
Cough
Adverse inhalation feel/pharyngitis
Adverse inhalation taste
Laryngitis
Respiratory system effects, No. (%)
Increased asthma symptoms
11 (9.7)
23 (19.7)
18 (15.4)
3 (2.7)
1 (0.9)
5 (4.4)
1 (0.9)
2
6 (5.1)
3 (2.6)
9 (7.9)
1 (0.9)
1 (0.9)
2 (1.7)
1 (0.9)
4 (3.4)
2
2
1 (0.9)
1 (0.9)
9 (7.7)
years. Regulatory agencies in the United States and
Europe have issued guidelines covering various aspects of this subject, and numerous recommendations have been published.21–28 Currently, there are
four accepted approaches for equivalence testing of
inhaled products: in vitro particle sizing methods, in
vivo assessment of radiolabeled drug distribution,
pharmacokinetic studies, and comparative clinical
trials. Clinical studies are the most therapeutically
relevant measure of efficacy and, consequently, comparative trials remain the “gold standard” for demonstration of therapeutic equivalence provided certain criteria are met.28
A fundamental requirement for the assessment of
therapeutic equivalence is the need for a measurable
effect, yet being able to demonstrate effectiveness
when comparing inhaled corticosteroid treatments is
known to be highly dependent on the index that is
chosen to measure the therapeutic response.29 In
clinical assessments, improvements in pulmonary
function and, particularly, am PEF are generally
used. In the present study, PEF was included to
assess daily fluctuations and to provide a large
number of data points. Although most patients with
asthma respond favorably to treatment with inhaled
steroids, a small proportion of cases remain difficult
to control despite high-dose therapy, even when
combined with an oral steroid.30 Such interindividual
variation in response to inhaled corticosteroid therapy30 –32 may mask treatment effects in analyses of
population-derived data. An essential requirement of
equivalence studies assessing the use of inhaled
corticosteroids for the treatment of asthma should be
the need to establish an “in-study” baseline of steroid
responsiveness, using a clinically relevant parameter
against which the effects of the study medications
can be assessed.
The present study was designed to address such
concerns, incorporating several features of critical
interest. The 10- to 12-day run-in period confirmed
that patients met established criteria of at least
moderate asthma as well as being inadequately controlled by any current therapy (# 400 mg/d CFC-
BDP) and therefore requiring additional treatment.
In line with accepted clinical practice, these patients
then received a short course of oral steroid therapy.
Only those demonstrating an improvement in am
PEF of at least 15% were randomized to study
treatment. This design ensured that patients randomized were steroid responders, as well as providing an in-study baseline of improved asthma control
against which changes on study medication could be
compared. It is of interest that lack of steroid
responsiveness was one of the main reasons for
ineligibility for randomization among screened patients and, in keeping with this, there has been
considerable interest recently in the reasons for
steroid resistance in asthma.30,33,34
The doses of study medications used were selected according to current treatment guidelines.
The reference dose of CFC-BDP (800 mg/d) is
consistent with Global Initiative for Asthma recommendations for the treatment of moderate asthma.1 The dose of HFA-BDP used was based on the
assumption that the HFA-BDP extrafine aerosol
would provide equivalent asthma control to CFCBDP, but at a significantly lower dose, due to the
improved delivery of drug to the lungs with this
new formulation.9
A recent article by Barnes et al35 emphasizes the
importance of dose-response comparisons including
at least two doses that are considered to be comparable to allow a within-trial comparison of dose
response. A direct 1:1 dose comparison of HFABDP with CFC-BDP was not included in the
present study. However, a definitive dose-response
comparison of three equal doses of HFA-BDP and
CFC-BDP has been investigated in a separate
study.36 The results showed that higher doses of
CFC-BDP were needed to produce equivalent improvements in FEV1 as HFA-BDP.
The incorporation of a placebo group in the
present study allowed mean changes in asthma control from oral steroid therapy on active treatment to
be compared against placebo and also permitted an
assessment of the carryover effect of the oral steroid.
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Week-by-week analysis of changes in pulmonary
function in placebo-treated patients suggested that
the washout effect occurred mainly during the first
week after withdrawal of oral steroid therapy, with
the effect of the oral steroid appearing to be negligible by week 4.
A potential for bias existed for the novel HFABDP due to the smaller number of inhalations
required (four inhalations bid) compared with the
CFC-BDP (eight inhalations bid) but this appears to
be small since the HFA-placebo group had similar
compliance regardless of the device used (white or
cream-colored inhaler). A desire to only expose
patients to one propellant in order to adequately
assess the potential for inhalation effects meant that
a double-dummy design was not feasible. Potential
bias could also have occurred with the subject-driven
recordings of PEF and other secondary outcome
measures (such as symptom scores). However, the
consistency of the results across parameters (whether objective or subjective) indicates that this bias (if
any) may have been small.
The results of this study confirmed that HFABDP 400 mg/d extrafine aerosol maintained equivalent control of pulmonary function to CFC-BDP 800
mg/d throughout the 12-week treatment period for
all efficacy parameters evaluated. Both active treatments were significantly more effective than HFAplacebo, with placebo-treated patients more likely to
withdraw from the study due to inadequate response
to therapy than those treated with either HFA-BDP
or CFC-BDP (p # 0.001). With both active treatments, there was a slight decline in am PEF on
discontinuation of oral steroid treatment, although
both treatments were able to maintain the improvement to a statistically equivalent extent. This is
noteworthy as it clearly suggests that the patients in
both treatment groups were not “overtreated,” indicating that patients still had some room for improvement, thus further supporting the comparison. It is
interesting that 12 weeks after oral steroid treatment,
good control was maintained with 400 mg HFABDP, despite the fact that some patients had been
receiving 400 mg of BDP at study start and were
symptomatic.
The safety profile of HFA-BDP compared favorably with that of CFC-BDP and there were no drugor propellant-related safety concerns. Although no
statistical analysis of the subgroup was carried out,
evaluation of adverse events attributable to the study
medication, and specifically those related to the
inhaled route of drug delivery, revealed such effects
to occur more frequently in patients treated with
CFC-BDP than those who received either of the
HFA formulations. This finding is not unexpected
given the greater level of oropharyngeal deposition
of inhaled steroid known to occur with CFC-BDP
compared with the HFA formulation (70 to 90% vs
27 to 31%, respectively).9
In summary, 400 mg of HFA-BDP extrafine aerosol was found to be as effective as 800 mg of
CFC-BDP in maintaining improvement in airway
caliber following a course of oral prednisone therapy
in patients with asthma of at least moderate severity.
There were no clinically significant differences in
safety and tolerability. This finding supports the
hypothesis that the reformulation of BDP in CFCfree propellant HFA-134a with a finer particle size
results in improved lung deposition of the drug,
providing equivalent efficacy at a lower total daily
dose than CFC-BDP.
ACKNOWLEDGMENT: The authors would like to acknowledge the support of David Donnell MRPharmS (3M Pharmaceuticals, UK).
Appendix
The Study Group includes the following: Eugene Bleecker, MD;
Baltimore, MD; Dick Briggs, MD, Birmingham, AL; Edwin
Bronsky, MD, Salt Lake City, UT; Stuart Brooks, MD, Tampa,
FL; A. Sonia Buist, MD; Portland, OR; Paul Chervinsky, MD,
North Dartmouth, MA; Edward, Diamond, MD, Elk Grove
Village, IL; Robert Dockhorn, MD, Lenexa, KS; Thomas Edwards, MD, Albany, NY; Stanley Galant, MD, Orange, CA; Gary
Gross, MD, Dallas, TX; Jay Grossman, MD, Tucson, AZ; F.
Charles Hiller, MD, Little Rock, AR; Harold Kaiser, MD,
Minneapolis, MN; Mitchell Kaye, MD, Minneapolis, MN; Michael Lawrence, MD, Taunton, MA; Anthony Montanero, MD,
Portland, OR; Richard Morris, MD, Minneapolis, MN; Robert
Nathan, MD, Colorado Springs, CO; Nancy Ostrom, MD, San
Diego, CA; David Pearlman, MD, Aurora, CO; Bruce Prenner,
MD, San Diego, CA; Joe Ramsdell, MD, San Diego, CA; Loren
Southern, MD, Princeton, NJ; David Tinkelman, MD, Atlanta,
GA; Frank Virant, MD, Seattle, WA; Alan Wanderer, MD,
Denver, CO.
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