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From the Department of Clinical Epidemiology and Biostatistics (Prof. Juniper), McMaster University Medical Centre, Ontario, Canada; and the Department of Pulmonary and Critical Care Medicine (Dr. Buist), Oregon Health Sciences University Hospital, Portland, OR.
A complete list of participants is located in the Appendix.
Correspondence to: Elizabeth F. Juniper, MCSP, MSc, Clinical Epidemiology and Biostatistics, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8S 3Z5, Canada
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Background: HFA-BDP is a new CFC-free preparation of BDP, which was developed as a result of CFCs being phased out from metered dose inhalers.
Methods: Following 7 to 12 days of prednisone, 30 mg/d, 347 adults with moderate asthma were randomized to receive either 400 µg/d HFA-BDP, 800 µg/d CFC-BDP, or HFA placebo for 12 weeks (all other oral and inhaled steroids were withdrawn). Patients completed the Asthma Quality of Life Questionnaire (AQLQ), and clinical asthma status was measured at the end of a run-in period, at randomization (after oral steroid treatment), and at the end of the study treatment.
Results: Sixty-one patients withdrew, 43 due to worsening
asthma (33 placebo; 5 HFA-BDP; 5 CFC-BDP). There was a deterioration in
the AQLQ score (- 0.81) in the placebo group, and the difference
between this and the stability observed in both the HFA-BDP group
(+ 0.13) and the CFC-BDP group (- 0.03) was statistically
significant (p 
0.003). The difference between the two
active treatments was not significant (p = 0.290). The calculated
number of patients who needed to be treated in order to see a benefit
in one patient (with the placebo as the standard treatment) was 2.4 for
HFA-BDP and 3.0 for CFC-BDP. Only weak to moderate correlations
were observed between changes in AQLQ scores and between asthma
clinical status measures.
Conclusion: HFA-BDP (400 µg/d) was as effective as CFC-BDP (800 µg/d) in sustaining improvements in asthma quality of life following withdrawal of 7 to 12 days of prednisone treatment in moderate asthma.
Key Words: asthma • beclomethasone dipropionate • chlorofluorocarbon • hydrofluoroalkane • quality of life
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Inhaled corticosteroids are indicated for the long-term treatment of all but mild, intermittent asthma.4 One of the most commonly used of this class, worldwide, is beclomethasone dipropionate (BDP). Hydrofluoroalkane-134a (HFA) BDP is a new chlorofluorocarbon (CFC)-free preparation of BDP, which was developed following the mandatory requirement to replace CFC propellants with non-ozone-depleting alternatives.5
Preclinical studies have shown certain benefits of HFA-BDP compared with CFC-BDP, including a respirable fraction of 60%,6 an extra fine aerosol with a smaller particle size (mass median aerodynamic diameter approximately 1.2 µm),5 and improved lung deposition.7 8 9 The extent of drug delivery to the lung is known to be a significant factor in the therapeutic efficacy of inhaled corticosteroids.10 Therefore, this improved lung deposition suggests that asthma control equivalent to that produced by CFC-BDP may be provided with lower doses of HFA-BDP.
One of the primary aims of the study was to determine whether 400 µg/d HFA-BDP would be as effective as 800 µg/d CFC-BDP in maintaining asthma-specific HRQL. A fuller account of other aspects of the study, such as clinical efficacy and adverse events, is published elsewhere.11
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Patients completed a 10- to 12-day run-in period to establish the presence of symptoms, lung function parameters, and bronchodilator usage consistent with a classification of at least moderate severity asthma. Criteria for moderate asthma12 included the following: daily symptoms; exacerbations affecting activity and/or sleep; nighttime asthma symptoms experienced more than once per week; daily use of a ß-agonist; and PEF or FEV1 > 60% but < 80% of the predicted normal value (variability > 30%). During the run-in period, patients continued to take their ß-agonist and previously prescribed inhaled corticosteroid. Patients were required to show evidence of active asthma during the last 5 days of the run-in to be eligible to continue in the trial. This was defined as a mean morning (AM) PEF between 50% and 85% of the predicted normal value plus one or more of the following: sleep disturbance due to asthma on 1 or more nights; asthma symptoms on 3 or more days; and use of a ß-agonist inhaler on average at least twice daily to relieve symptoms. Patients who met these criteria took a 7- to 12-day course of oral steroid (prednisone, 30 mg/d) to demonstrate steroid responsiveness (defined as a mean improvement in AM PEF of at least 15% during the last 3 days of the oral steroid period). If the oral steroid response and the patient’s technique in the use of a metered-dose inhaler (MDI) were acceptable, they were randomized to the study interventions.
The study was performed in accordance with the Declaration of Helsinki. Approval from an institutional review board for each study site was obtained and all patients gave written informed consent prior to the start of the study.
Study Design
This was a multicenter (27 sites in the US), parallel-group
study. Eligible patients received inhaled study treatment (via a
press-and-breathe MDI) for 12 weeks and those using other inhaled
steroids were instructed to stop using them for the duration of the
study. Patients were randomized to either 400 µg/d HFA-BDP (four
actuations of 50 µg twice daily), 800 µg/d CFC-BDP (eight
actuations of 50 µg twice daily), or an HFA placebo. Patients in the
placebo group were allocated to take four or eight inhalations twice
daily. Two different canister types were needed for the propellants
because CFC could not be used in the MDI canister specifically designed
for HFA. Patients were aware of the number of actuations they made but
were blinded as to whether they were taking active treatment or not.
Similarly, the investigators were not aware of whether patients were
taking active treatment or a placebo.
Patients were instructed to take the study treatment at approximately the same time in the AM and evening each day. Adverse events were assessed and recorded throughout the study period.
During the study, patients were instructed to contact the clinic if, on
2 consecutive days, their highest AM PEF score fell below an
individualized value (20% below their mean AM PEF pre-prednisone
run-in value) that had been recorded in their diary. A patient was
withdrawn if any one of the following criteria applied on these 2 days:
nighttime sleep disturbance score 
1 on 1 or both nights; any asthma
symptoms scores 3 on both days; any asthma symptoms score of 5 on 1
day; or ß-agonist use more than four times daily on both days.
Appropriate treatment was given at withdrawal if the investigator
decided that this was necessary. Patients who were withdrawn underwent
a postbaseline follow-up evaluation, which included efficacy and safety
assessments.
Outcome Measures
Asthma Quality of Life Questionnaire: Patients
completed the Asthma Quality of Life Questionnaire
(AQLQ)13
at the end of the run-in period, at the end of
the oral steroid treatment period (randomization), and at week 12 of
the study treatment period. The AQLQ was also completed by patients on
study withdrawal as part of the postbaseline evaluation. The AQLQ
measures areas of function (including both physical and emotional
aspects) that are important to adult asthma patients. The AQLQ consists
of 32 questions (items), each of which carries a 7-point series of
response options (a score of 1 indicates "totally/all the time"; a
score of 7 indicates "not at all/none of the time"). Items in the
AQLQ are grouped into the following four domains: activity limitations,
symptoms, emotional function, and exposure to environmental stimuli.
The AQLQ is a valid and reliable instrument for the determination of
the HRQL of asthma patients and has been shown to be highly responsive
to small changes in patient asthma status.14
A change in
AQLQ score of 0.5 was considered to be clinically
relevant.15
Other Efficacy Assessments: Patients were instructed to record PEF, asthma symptoms, and bronchodilator use in an asthma diary on a daily basis. PEF measurements were taken using a mini-Wright peak flowmeter before use of a ß-agonist or study medication, in the AM on awakening, and in the evening before retiring. Daytime asthma symptoms (wheezing, shortness of breath, chest tightness, and cough) were recorded using a 6-point assessment scale, and sleep disturbance scores were recorded using a 5-point assessment scale. Spirometry was performed in accordance with American Thoracic Society criteria16 to determine FEV1 and forced expiratory flow > 25 to 75% of the full FVC at the screening visit, the end of the run-in period, the end of the oral steroid treatment period, and the end of weeks 3, 6, 9, and 12. The percentage of predicted normal values for FEV1 were calculated according to the regression equation of Crapo and coworkers17 ; for PEF, the percentage of predicted normal values were calculated using the equation of Nunn and Gregg.18
Statistical Analysis
Asthma quality of life was expressed as the mean score per item
for each of the four AQLQ domains, and the overall score was derived
from the mean score of all items. All patients for whom there was a
postbaseline AQLQ assessment were included in the AQLQ analysis. For
each of the four domains and the overall score, mean changes were
analyzed using an analysis of variance model for treatment, center, and
treatment-by-center interaction. SDs given in the text are calculated
from the raw data and not from the adjusted mean data. Correlations
between change in HRQL and clinical indexes were examined using a
Pearson correlation coefficient.19
Data regarding the
number of patients who needed to be treated in order to see a benefit
in one patient were calculated using the method of Guyatt et
al.20
Compliance
In order to assess compliance, the weights of all study inhaler
canisters before dispensing were compared to those of the returned
canisters. The predicted and actual inhaler weights were then used to
estimate the number of administered doses and, by inference, the
compliance.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Full safety data including adverse events are reported elsewhere.11 Adverse events that were considered possibly or probably related to treatment and which led to withdrawal of therapy were reported for only one patient in the HFA-BDP group and three in the CFC-BDP group.
Quality of Life Assessment
Thirteen patients did not complete the AQLQ postbaseline (two in
the HFA-BDP group, four in the CFC-BDP group, and seven in the placebo
group) and so were not part of the postbaseline AQLQ analysis. Of these
thirteen, only one patient in the CFC-BDP group completed the 12-week
study.
The AQLQ scores at randomization and week 12 are shown in Table 2 . Overall and for each domain, quality of life deteriorated over the
12-week study period in the placebo group (Figure 1
) (overall mean change of - 0.81; SE, 0.11; SD, 1.21). In contrast,
there was minimal change in AQLQ scores in the HFA-BDP group (mean,
+ 0.13; SE, 0.11; SD, 0.85) and the CFC-BDP group (mean, - 0.03; SE,
0.11; SD, 0.99). The changes in each of the active treatment groups
were significantly different from those observed in the placebo group
(p 0.003). Although there was a trend in favor of HFA-BDP compared
with CFC-BDP, the difference was small and not statistically
significant (p = 0.29).
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Other Efficacy Measures
The results for conventional measures of efficacy are presented
elsewhere.11
In summary, AM PEF measurements showed that
HFA-BDP (400 µg/d) achieved equivalent asthma control as CFC-BDP (800
µg/d) did at all time intervals over the 12-week period. Asthma
control was maintained in each of the active treatment groups showing
both treatments to be effective. This finding was supported by other
efficacy variables measured, such as FEV1 and
asthma symptom scores.
Quality of Life and Clinical Efficacy Measurements
Comparison between change in AQLQ and change in clinical indexes
showed that there was moderate correlation between change in overall
AQLQ and either patient-recorded symptoms or daily ß-agonist use
(Table 4
). However, there was weak correlation (r = 0.305) between changes in
FEV1 and overall change in AQLQ. A general trend
observed was that as the change in AQLQ score increased, the change in
ß-agonist use and asthma symptom scores decreased.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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The results of the present study demonstrate that HFA-BDP (400 µg/d) provides asthma control equivalent to that of CFC-BDP (800 µg/d) as determined by quality of life parameters. There was a consistent tendency for HFA-BDP (400 µg/d) to give slightly better AQLQ scores than those given by CFC-BDP (800 µg/d), but this difference was small and did not reach statistical significance. Nevertheless, this trend suggests that it is highly unlikely that the therapeutic benefit of HFA-BDP (400 µg) is less than that of CFC-BDP (800 µg). Data regarding the number of patients who needed to be treated also showed the two active treatments to be comparable; using placebo as the standard treatment, 12 patients would need to be treated with HFA-BDP, or 15 with CFC-BDP, in order for five patients to benefit from treatment.
Given the potential for interindividual variation in response to inhaled corticosteroids,22 23 24 an essential requirement of equivalence studies is the need to establish that patients are steroid responsive. Patients enrolled in this study were symptomatic and were receiving an inhaled steroid dose of 0 to 400 µg/d. Because this is less than the recommended dose for patients with moderate asthma, the patients were, by inference, undertreated at the time of recruitment. Oral steroid therapy (30 mg/d prednisone) was used and only those patients demonstrating an improvement in AM PEF of at least 15% were included in the study. This screening ensured that patients randomized were steroid responders and provided an "in-study" baseline of "optimal" asthma control, against which changes due to study medication could be compared. Recently, there has been considerable interest in the reasons for steroid resistance in asthma.24 25 26 In the present study, lack of steroid responsiveness in AM PEF among screened patients (observed in > 25%) was one of the main reasons for ineligibility for randomization.
One of the aims of the study was to evaluate the individual effects of both HFA-BDP and CFC-BDP compared with the placebo. Extensive withdrawal criteria were established to permit the inclusion of a placebo group.
A criticism of this study was the method of blinding, but it was impossible for HFA and CFC propellants to be delivered from identical canisters. A complex double-dummy system could have been designed to achieve double-blinding, but this would have exposed all patients to both propellants, thus making it difficult to assess potential inhalation effects, and the regimen would have been too complex for patients to follow. The study design used ensured that neither patients nor investigators knew whether patients were taking active treatment or placebo. In addition, there was no evidence of any difference in the responses of patients taking placebo from the two types of canisters. This suggests that the method of blinding was sufficient and was unlikely to have had an effect on the estimation of the true treatment effect.
ß-agonist use tended to be slightly lower at baseline in the placebo group than in the other treatment groups. However, in light of the similarity of the other clinical indexes and AQLQ scores at baseline, it is unlikely that this influenced the observed treatment effect between groups for quality of life.
Results of the HRQL outcome assessment reported here are similar to those obtained from measurement of conventional indexes (AM PEF, FEV1), which also showed equivalent asthma control between HFA-BDP (400 µg/d) and CFC-BDP (800 µg/d).11 A recent dose-response study of HFA-BDP and CFC-BDP27 showed that a lower effective dose of HFA-BDP was sufficient for providing asthma control (as measured by FEV1) equivalent to that obtained when using higher doses of CFC-BDP. This is likely to be due to the improved lung deposition seen with HFA-BDP. In a study evaluating the transition from CFC-BDP to HFA-BDP, patients found switching from CFC-BDP to HFA-BDP easy and acceptable, and a benefit to patients of a reduced number of puffs required per dose (four compared with eight) was reported.28
The weak to moderate correlations between change in HRQL and change in clinical outcomes observed here are consistent with those seen in previous studies.14 29 30 This emphasizes the importance of HRQL assessment in research studies in ensuring that the patient’s perceptions of effectiveness are taken into consideration. For example, an individual who shows a small improvement in clinical outcome measurements may show a large improvement in HRQL. Determination of HRQL is also important in the evaluation of cost-effectiveness of therapy, as highlighted by the National Asthma Education and Prevention Working Group.31
One of the major goals of treatment is to improve the functioning and well-being of the patient; thus HRQL assessment is an important measure of the effectiveness of a treatment regimen. In conclusion, HFA-BDP (400 µg/d) is as effective as CFC-BDP (800 µg/d) in sustaining improvements in asthma quality of life following withdrawal of 7 to 12 days of prednisone treatment in moderate asthma.
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Appendix 1 |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Acknowledgements |
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Footnotes |
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The study was sponsored by 3M Pharmaceuticals.
Received for publication January 22, 1999. Accepted for publication June 8, 1999.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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This article has been cited by other articles:
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  E. F. Juniper, D. B. Price, P. A. Stampone, J. P. H. M. Creemers, S. J. M. Mol, and P. Fireman Clinically Important Improvements in Asthma-Specific Quality of Life, But No Difference in Conventional Clinical Indexes in Patients Changed From Conventional Beclomethasone Dipropionate to Approximately Half the Dose of Extrafine Beclomethasone Dipropionate* Chest, June 1, 2002; 121(6): 1824 - 1832. [Abstract] [Full Text] [PDF]
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 J Wright, D Brocklebank, and F Ram Inhaler devices for the treatment of asthma and chronic obstructive airways disease (COPD) Qual. Saf. Health Care, January 12, 2002; 11(4): 376 - 382. [Abstract] [Full Text] [PDF]
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