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(Chest. 2002;121:1824-1832.)
© 2002 American College of Chest Physicians

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*

Elizabeth F. Juniper, MB, MSc; David B. Price, MB BChir; Patti A. Stampone, MS; Jacques P. H. M. Creemers, MD; Stijn J. M. Mol, MD and Philip Fireman, MD{dagger}

* From the Department of Clinical Epidemiology and Biostatistics (Ms. Juniper), McMaster University, Hamilton, ON, Canada; the Department of General Practice and Primary Care (Mr. Price), University of Aberdeen, UK; 3M Pharmaceuticals (Ms. Stampone), St Paul, MN; the Department of Pulmonology (Dr. Creemers), Catharina Ziekenhuis, Eindhoven, the Netherlands; St. Joseph Ziekenhuis (Dr. Mol), Veldhoven, the Netherlands; and Children’s Hospital of Pittsburgh (Dr. Fireman), Pittsburgh, PA. {dagger} A complete list of study participants is provided in the Appendix.

Correspondence to: Elizabeth F. Juniper, MCSP, MSc, 20 Marcuse Fields, Bosham, West Sussex, PO18 8NA, United Kingdom; e-mail: juniper{at}qoltech.co.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 
Study objective: Clinical trials of asthma treatments usually use measures of asthma control to assess efficacy. However, it is also important to determine whether patients themselves benefit from interventions. The aim of this study was to evaluate health-related quality of life in patients with asthma switched from conventional chlorofluorocarbon (CFC) beclomethasone dipropionate (BDP) to hydrofluroalkane-134a (HFA) BDP extrafine aerosol at half the daily dose.

Design: Open-label, 12-month, parallel-group, randomized trial.

Setting: Fifty-seven centers in four countries (United States, Belgium, the Netherlands, and United Kingdom).

Patients: Four hundred seventy-three patients with a >= 6-month history of asthma, stable symptoms, and maintained on CFC-BDP, 400 to 1,600 µg/d.

Interventions: HFA-BDP, 200 to 800 µg/d (n = 354), or CFC-BDP, 400 to 1,600 µg/d (n = 119).

Measurements and results: The Asthma Quality of Life Questionnaire (AQLQ) and pulmonary function tests were completed at months 0, 2, 4, 8, and 12. For 1 month before each visit, patients made daily recordings of symptoms, peak expiratory flow, and ß2-agonist use. Two hundred ninety-six patients completed the study (HFA-BDP, 83.6%; CFC-BDP, 83.2%). At month 12, improvements in overall AQLQ scores were greater in the HFA-BDP group than in the CFC-BDP group (p = 0.0024). The number of patients who need to be treated with HFA-BDP for one to have a clinically important improvement in overall asthma-specific quality of life compared with CFC-BDP was 7.3. There was no evidence of differences (p > 0.05) between treatment groups for airway caliber, symptoms, or ß2-agonist use.

Conclusion: Clinically important improvements in the AQLQ score were observed at month 12 for HFA-BDP vs CFC-BDP, while conventional clinical indexes of pulmonary function and asthma control were similar in the two groups.

Key Words: asthma • beclomethasone dipropionate • chlorofluorocarbon • clinical trial • hydrofluoroalkane-134a • inhaled corticosteroids • metered-dose inhaler • quality of life


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 
In many countries, the transition to non-ozone-depleting, chlorofluorocarbon (CFC)-free metered-dose inhalers (MDIs) is imminent, in response to the Montreal Protocol on substances that deplete the ozone layer.1 Although no deadline has yet been set for the United States, Canada aims to achieve total transition by 2005,2 and the European Commission3 predicts that there will be no need for CFC-based MDIs in the European Community by the year 2003. Therefore, patients will have to switch from their current traditional therapy of CFC beclomethasone dipropionate (BDP) to a CFC-free inhaler, such as a hydrofluoroalkane-134a (HFA) BDP extrafine aerosol.

Clinical trials4 5 6 have demonstrated that the level of asthma control achieved with CFC-BDP may be achieved with approximately half the total daily dose of HFA-BDP. This is probably due to improved lung deposition with the extrafine aerosol of HFA-BDP compared with the suspension aerosol of CFC-BDP.7 However, conventional clinical measures of asthma, such as pulmonary function, do not provide a complete picture of comparative efficacy. There is now extensive evidence that health-related quality of life (HRQL) correlates poorly with conventional measures of clinical status and, therefore, quality of life must be measured independently and not imputed from the clinical measures.8 9 10

The present analysis was designed to evaluate asthma-specific quality of life in adults who were switched from their previous asthma treatment of CFC-BDP to HFA-BDP, at half the daily dose. The analysis was part of a 12-month clinical safety and efficacy study, the results of which have been reported elsewhere.11 An open-label design was chosen to emulate what might happen in the clinical setting when patients change to a CFC-free preparation of BDP.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix 1
 References
 
Patients
The study enrolled patients (>= 12 years of age) with a >= 6-month history of asthma and stable symptoms for the past month. To be included, patients had to have an FEV1 >= 60% of predicted normal after withholding inhaled ß2-agonist for 6 h; have used inhaled steroids for >= 3 months before the prestudy visit; be maintained on CFC-BDP, 400 to 1,600 µg/d ex-valve (a stable dose via a press-and-breathe MDI), for 2 weeks before the prestudy visit; have an increase in FEV1 or morning peak expiratory flow (PEF) of >= 15% following inhalation of a ß2-agonist or a course of inhaled or oral steroids; or a positive methacholine or histamine challenge (20% reduction in FEV1 <= 8 mg/mL or equivalent) during the past 2 years or at the prestudy visit, and currently be using a short-acting ß2-agonist on an as-needed basis for symptom relief.

Patients with visible oral or pharyngeal candidiasis, symptoms of dysphonia, or an acute upper or lower respiratory tract infection were excluded. Patients using an inhaled steroid, other than BDP, within the past month or using > 400 µg/d of a nasal steroid were also excluded. Patients gave written informed consent prior to entry in accordance with the revised Declaration of Helsinki (Hong Kong, 1989).

Study Design
This open-label, randomized, parallel-group study was performed in the United States (24 sites), Belgium (7 sites), The Netherlands (8 sites), and the United Kingdom (18 sites). Treatment was administered, postrandomization, over a 12-month period. An active control was used since it would be unethical to permit steroid-dependent patients with asthma to receive placebo for such a long period.

Eligible patients entered a 2-week run-in period during which they used the same dose and strength of CFC-BDP they received prior to study entry. At the end of run-in period, patients were randomized (in a 3:1 ratio of HFA-BDP to CFC-BDP) to either CFC-BDP at the same dose and strength used during the run-in period or to HFA-BDP at approximately half the daily dose using a 50-µg or 100-µg per actuation-strength inhaler (dose range, 200 to 800 µg/d ex-valve) for 12 months. During the first 2 months postrandomization, the dose of study medication could not be altered. After this time, titration of the dose was permitted if necessary; the total daily dose of inhaled steroids could be increased or decreased by the investigator according to the patient’s clinical status. Titration down was not encouraged, as the primary focus of the study was safety. Exacerbations of asthma could be treated using the most appropriate course of treatment, as determined by the investigator. Incidences of asthma exacerbation (severe asthma symptoms needing urgent medical care, > 3 days of treatment with systemic steroids or hospitalization) were recorded; if symptoms did not improve after 2 weeks of systemic steroid treatment, the patient was withdrawn from the study. Any patient who experienced more than two asthma exacerbations in the first 2 months postrandomization or four or more exacerbations during the study was withdrawn.

There were eight clinic visits (on study day 1 [randomization], and at the end of months 1, 2, 4, 7, 8, 11, and 12). Patients had to withhold short-acting ß2-agonists for >= 6 h prior to clinic visits.

Outcome Measures
The Asthma Quality of Life Questionnaire (AQLQ) measures the functional impairments that are most troublesome to adults with asthma, and consists of 32 questions with a 7-point scale of responses for each (eg, 1 = all of the time, to 7 = none of the time).12 13 The overall score may be reported and/or the questions grouped into four domains: symptoms, emotional function, environmental stimuli, and activity limitation. Patients completed the AQLQ on day 1 and at the end of months 2, 4, 8, and 12, and if applicable on withdrawal.

Patients recorded PEF, asthma symptoms, sleep disturbance, and ß2-agonist use in a diary each day during study months 1 to 2, 7 to 8, and 11 to 12. Pulmonary function was measured using a spirometer, in accordance with American Thoracic Society guidelines14 on day 1 and at the end of months 2, 4, 8, and 12.

Statistical Analysis
For the AQLQ, the mean score per question was calculated for each of the four domains, and the overall score derived from the mean of all questions. SDs were calculated from the raw data, rather than from the adjusted mean data. Mean changes from baseline were analyzed (for all patients who provided both a baseline and posttreatment AQLQ score) overall and for the four domains. An analysis of variance model was used with the last observation carried forward for any missing data points (intention to treat). A 95% confidence interval was used for the mean difference between HFA-BDP and CFC-BDP. Two-sided p values <= 0.05 were considered statistically significant. An unstructured covariance model was used to assess the effect of treatment, time, and treatment-by-time interactions for change from baseline, in overall quality of life and each domain across months 2, 4, 8, and 12. Correlations between change in HRQL and various clinical outcome measures were assessed using a Pearson correlation coefficient.15

The number needed to treat (NNT) was calculated from the proportion of patients showing clinically important improvements and deteriorations (ie, scores >= ± 0.5) in each treatment group.16 The NNT is the number of patients who need to be treated with HFA-BDP in order for one patient to experience a clinically important improvement in quality of life in comparison with CFC-BDP. The change from baseline in overall AQLQ at month 12 was used for the NNT calculation, and was based on a minimal important change of >= 0.5.17

Compliance
Compliance was measured over the course of the study by weighing inhalers. If the inhaler weight was within ± 40% of the predicted value, then patients were designated as compliant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix 1
 References
 
Patient Characteristics
A total of 473 patients were eligible for randomization: 354 patients received HFA-BDP and 119 patients received CFC-BDP. The characteristics of the two treatment groups were similar at baseline (Table 1 ), except there was a significantly greater proportion of men in the HFA-BDP group compared with the CFC-BDP group (p = 0.005).


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  		Table 1.. Patient Characteristics, ß2-Agonist Use, Lung Function, and Quality-of-Life Score at Baseline

 
A total of 296 patients (83.6%) in the HFA-BDP group and 99 patients (83.2%) in the CFC-BDP group completed the whole 12-month study. Throughout the study, 58 patients (16.4%) in the HFA-BDP group and 20 patients (16.8%) in the CFC-BDP group withdrew. The most frequent reasons for withdrawal were noncompliance (2.8%) and reasons personal to the patient (3.1%) in the HFA-BDP group, and patients unavailable for follow-up (5.0%) and noncompliance (4.2%) in the CFC-BDP group. There was a low incidence of patients withdrawing from the study due to asthma exacerbations (1.4% in the HFA-BDP group and none in the CFC-BDP group). There were no major differences observed in the baseline characteristics of the patients who completed the study and those who withdrew (Table 2 ).


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  		Table 2.. Baseline Characteristics of Patients Who Completed the Study and Those Who Withdrew From the Study

 
At baseline, patients in the two treatment groups had a similar history of asthma drug therapy (Table 1) . During the 12 months of the study, a similar percentage of patients in each group received oral steroids (HFA-BDP, 21.2%; CFC-BDP, 22.7%) or a long-acting ß2-agonist (HFA-BDP, 2.3%; CFC-BDP, 2.5%) concomitantly during the study. Five patients (1.4%) in the HFA-BDP group and three patients (2.5%) in the CFC-BDP group received non-study inhaled steroids (BDP).

At month 12 (or on discontinuation), there were similar proportions of patients in both treatment groups for whom the dose of study treatment had been increased or decreased or stayed the same, compared with the initial dose (Table 3 ). In the HFA-BDP group, 62 patients (17.5%) had their dose changed; of these, 20 patients returned to the dose they initially received. In the CFC-BDP group, 19 patients (16.0%) had their dose changed; of these, 7 patients returned to the dose they initially received. The percentage of patients reporting one or more asthma exacerbations was slightly higher in the CFC-BDP group (22.7%) than in the HFA-BDP group (16.9%).


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  		Table 3.. Proportion of Patients for Whom the Total Daily Dose of Study Medication at Month 12 (or Upon Discontinuation) Had Decreased, Remained the Same, or Increased Compared With the Initial Dose*

 
Asthma-Specific Quality of Life
There were 335 patients in the HFA-BDP group and 113 patients in the CFC-BDP group who had a posttreatment AQLQ score available, regardless of whether they completed the study. Eighteen patients in the HFA-BDP group and 5 patients in the CFC-BDP group did not have a postbaseline AQLQ score, but did provide a baseline score. In addition, one patient in each group provided neither a baseline nor a postbaseline AQLQ score.

Baseline mean AQLQ scores, overall and for each domain, were marginally higher in the HFA-BDP group than in the CFC-BDP group (Table 4 ); however, this difference was not statistically significant. There were 101 of 347 patients (29%) in the HFA-BDP group and 26 of 117 patients (22%) in the CFC-BDP group who had a baseline overall AQLQ score of > 6, indicating minimal impairment of asthma-specific quality of life at the start of the study. Improvements from baseline in overall AQLQ scores were seen for both treatment groups at each time point (Fig 1 , top), but these improvements were consistently higher for HFA-BDP than for CFC-BDP (Table 4) . Similar improvements occurred in all domains of the AQLQ, except emotional function in the CFC-BDP group at 12 months only (Fig 1 , middle and bottom). At month 12, there was a statistically significant difference between treatment groups in change from baseline in overall AQLQ in favor of HFA-BDP (p = 0.019), which was also seen in the symptom (p = 0.041) and emotional function (p = 0.025) domains. For the activity limitation domain, the difference between groups at month 12 approached statistical significance (p = 0.073).


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  		Table 4.. Mean AQLQ Scores for Each Domain and Overall at Each Study Time Point for Both Treatment Groups*

 


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  		Figure 1.. Mean (SE) change from baseline in overall AQLQ score (top), AQLQ score for the symptom and emotional function domains (middle), and AQLQ score for the environmental stimuli and activity limitation domains (bottom). *Statistically significant difference between treatments, p < 0.05; **difference between treatment groups, p = 0.07.

 
Analysis of the repeated-measures design for change from baseline in overall quality of life across months 2, 4, 8, and 12 showed significant effects for treatment (p = 0.0024) and time (p = 0.001), but no significant treatment-by-time interaction (p = 0.138). A similar pattern was seen in each of the quality of life domains.

Although the mean improvement in overall AQLQ score over 12 months was greater in the HFA-BDP group (0.34) than in the CFC-BDP group (0.10), the difference between these values was only 0.24 (95% confidence interval, 0.039 to 0.428), which is less than the minimal important difference of 0.5.17 However, looking at the proportion of patients for whom quality of life had improved, been maintained, or deteriorated (Table 4) , there was a greater proportion of patients in the HFA-BDP group (44.4%) who had an overall improvement than in the CFC-BDP group (35.7%). There was also a smaller percentage of patients in the HFA-BDP group (9.1%) for whom overall quality of life had deteriorated than in the CFC-BDP group (19.6%). From these proportions, the NNT was determined to be 7.3 (Table 5 ). NNTs for each of the domains are shown in Table 5 .


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  		Table 5.. Patients for Whom Quality of Life Had Improved, Been Maintained, or Deteriorated*

 
Pulmonary Function
Complete clinical efficacy and safety results are reported elsewhere.11 In summary, there were no statistically significant differences between the HFA-BDP and CFC-BDP treatment groups (p > 0.05) for morning PEF, FEV1, FVC, and forced expiratory flow over 25 to 75% of the FVC. The two groups were generally similar in terms of mean change from baseline at month 12 in daytime and nighttime asthma symptoms and ß2-agonist use. When changes in AQLQ score between baseline and month 12 were correlated with changes in clinical indexes over this period, associations were only weak to moderate (Table 6 ).


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  		Table 6.. Correlation Between Change in Clinical Indexes and Change in AQLQ Score*

 
Compliance
Compliance (according to the definition used) was similar in the two treatment groups. Overall median percentage compliance was determined as 91.3% during the run-in period, 88.1% from study day 1 to the end of month 2, 84.4% from the start of month 7 to the end of month 8, and 86.4% from the start of month 11 to the end of month 12.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix 1
 References
 
Patients with asthma who are currently using a CFC-containing corticosteroid inhaler will soon have to change to a CFC-free inhaler, due to the Montreal Protocol1 directive intended to completely phase out CFCs from pharmaceutical preparations. It is, therefore, important to assess the efficacy of alternative treatment options, for example, CFC-free inhalers, particularly in those patients already stabilized on inhaled corticosteroids, such as CFC-BDP.

This 12-month study shows that patients switched from their regular dose of CFC-BDP to approximately half the dose of the CFC-free inhaler, HFA-BDP extrafine aerosol (average particle size, 1.1 µm),7 may experience a significant improvement in their asthma-specific quality of life, even when no differences in conventional clinical measures of lung function are observed.

The reason for the discrepancy between quality of life and clinical outcomes in the present study is not clear. It may be that the HFA-BDP spray is deposited in more peripheral airways and that this is associated with changes in the smaller airways, which manifest themselves as changes in the patient’s quality of life but are not captured by FEV1 or PEF assessments. Alternatively, the clinical indexes were not sufficiently sensitive to detect changes. The lack of correlation between quality of life and clinical outcome measures was not unexpected, as it is a well-documented finding,8 9 10 that highlights the need to assess asthma-specific quality of life in clinical trials.

The improvement in quality of life seen in the present study developed progressively over 12 months, with the data suggesting that the improvement may not have reached a plateau even after 1 year. A shorter study9 of 12 weeks in duration showed a trend toward improved quality of life in the HFA-BDP group compared with the CFC-BDP group, but the difference between treatments did not reach statistical significance. It is possible that the benefit seen with the new treatment is only achieved after long-term therapy. Further studies are, therefore, required to explore the time course in greater depth.

An important consideration in HRQL assessment is being able to place a clinical interpretation on the results. With a sufficiently large sample size, even a trivial difference between treatment groups may reach statistical significance. In the present study, the difference between the mean improvements in overall quality of life score in the HFA-BDP and CFC-BDP groups was statistically significant, but was only 0.24. This is considerably less than the minimal clinically important individual difference identified for the AQLQ (0.5).17 However, to reject these results as being clinically unimportant would be erroneous, since 0.24 only represents the difference between mean values and does not take into account the heterogeneity of patients’ responses to the interventions.16 Clearly, there were patients who had a clinically important improvement in their quality of life when they were switched to HFA-BDP. Using the proportion of patients who both improved and deteriorated by > 0.5 in each group, the NNT was calculated. This is the number of patients who need to be treated with HFA-BDP, so that one patient has a clinically important improvement in their asthma-specific quality of life, over and above that which he of she would have had using CFC-BDP.16 The NNT of between 7 and 8 compares favorably with similar single-digit NNTs, which have been observed for differences between salmeterol and salbutamol16 and budesonide (800 µg) plus formoterol compared with other interventions.10

A limiting consideration of this study was that some patients had minimal impairment of asthma quality of life at enrollment. In both groups, approximately 20 to 30% of patients had baseline scores of > 6.0 on the 7-point AQLQ scale and, therefore, had little room for further improvement. In addition, mean baseline scores were slightly higher in the HFA-BDP group than in the CFC-BDP group. This suggests that the room for improvement may have been more limited in the HFA-BDP group than in the CFC-BDP group and, therefore, it is possible that the difference observed between groups may be an underestimate of the true difference between treatments.

Aspects of the study design were chosen to closely emulate what might happen in the normal clinical setting, when patients are switched from their current therapy of CFC-BDP to a CFC-free preparation, including the open-label design, the broad range of initial inhaled steroid doses, allowing dosage changes on clinical grounds, and permitting the normal treatment of exacerbations and asthma symptoms. By using an open-label design, however, there was potential for bias either against CFC-BDP (some patients may like the idea of receiving a "new" treatment) or against HFA-BDP (some patients may be inclined toward their previous therapy with which they were familiar). However, any such effect would be likely to reduce over a 12-month study period.

Minimum steroid use was not established for patients at the start of the study, so some could potentially have been treated with a higher dose than the minimum needed to maintain adequate control. Because patients were randomized to study treatment, however, this should not have biased the study outcome.

Clinicians were allowed to titrate the dose of study drug after the first 8 weeks to optimize patients’ asthma control. Clinicians knew which study therapy their patients were receiving, and this may have influenced their treatment decisions. However, it is unlikely that this lack of blindness affected the results of the study, as < 20% of patients in either group had their dose adjusted. Although the doses of concomitant asthma therapies were not monitored throughout the study, the proportion of patients who reported using these medications was recorded. A small and similar proportion of patients in the two treatment groups received other asthma medications. Therefore, concomitant asthma therapies are unlikely to have influenced the study results.

In conclusion, this study has shown that patients who are switched to HFA-BDP extrafine aerosol (200 to 800 µg/d ex-valve) from their previous therapy of CFC-BDP (400 to 1,600 µg/d ex-valve) may experience clinically important improvements in their asthma-specific quality of life, even though their pulmonary function measurements remain unchanged. This long-term study also confirmed findings from shorter-term studies that asthma control can be maintained with HFA-BDP at half the daily dose compared with CFC-BDP.


   Appendix 1
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
References
 
The following investigators participated in the study: United Kingdom, Dr. W. Bhatiani, Dr. M.D. Blagdon, Dr. W.I.C. Clark, Dr. A.J.J. Darrah, Dr. M. Doyle, Dr. I. James, Dr. M.E. Johnson, Dr. A. Jones (Swansea), Dr. A. Jones (Pontarddulais), Dr. T.K. Khong, Dr. C.J. Kyle, Dr. T. Lynas, Dr. W. Lynch, Dr. A. Matthews, Dr. C. Morgan, Dr. A. Penrose, Dr. A. Smithers, Dr. M. Spencer, Dr. H. Thomas, and Dr. J.A. Wood; the Netherlands, Dr. A.P.M. Greefhorst, Dr. A. Peters, Dr. F.W.J.M. Smeenk, Dr. R.A.L.M. Stallaert, Dr. C.N.F. Van De Moosdijk, and Dr. W.C.J. Van Veldhuizen; Belgium, Dr. J. Bockaert, Dr. D. Coolen, Professor M. Demedts, R.J.L. Halloy, Dr. J.P. Quarre, Dr. F. Smeets, and Professor W. Vincken; United States, Dr. W. Berger, Dr. D. Briggs, Dr. R. Cohen, Dr. S. Fiel, Dr. J. Fink, Dr. A. Floreani, Dr. C. Grum, Dr. P. Korenblat, Dr. R.J. Lapidus, Dr. D. Ledford, Dr. A. Luskin, Dr. A. Nayak, Dr. B. Prenner, Dr. A. Rooklin, Dr. L. Rossoff, Dr. N. Segall, Dr. G. Settipane, Dr. L. Southern, Dr. W. Stricker, Dr. A. Wanderer, Dr. M. White, Dr. H. Windom, and Dr. J.D. Wolfe.


   Acknowledgements
 
The authors thank Jessie Song (3M Pharmaceuticals) for her help with the statistical analyses.


   Footnotes
 
Abbreviations: AQLQ = Asthma Quality of Life Questionnaire; BDP = beclomethasone dipropionate; CFC = chlorofluorocarbon; HFA = hydrofluoroalkane-134a; HRQL = health-related quality of life; MDI = metered-dose inhaler; NNT = number needed to treat; PEF peak expiratory flow

This study was sponsored by 3M Pharmaceuticals.

Professor Elizabeth Juniper received a consultancy fee for her participation in the study (analysis plan, interpretation of the results, and writing of the article), and has sat on committees funded by educational grants from 3M Pharmaceuticals.

Mr. David Price, either through his role at the University of Aberdeen or personally, has received grants, honoraria, or educational support from 3M Pharmaceuticals. Mr. Price has received honoraria from 3M Pharmaceuticals for speaking at meetings sponsored by the company and for sitting on company advisory boards, and his university department has also received sponsorship for one other research study by 3M Pharmaceuticals. Mr. Price was involved in the study concept, data analysis planning, and analysis of the study data.

Ms. Patti Stampone is an employee of 3M Pharmaceuticals and was responsible for statistical analysis of the study data.

Dr. Jacques Creemers has no financial involvement with 3M Pharmaceuticals other than receiving remuneration for enrolling patients into the study. Dr. Creemers participated in the recruitment and treatment of patients in the study.

Dr. Stijn Mol has no financial involvement with 3M Pharmaceuticals other than receiving remuneration for enrolling patients into the study. Dr. Mol participated in the recruitment and treatment of patients in the study.

Dr. Philip Fireman received a grant from 3M Pharmaceuticals and participated in the study design, study supervision, and recruitment of the study patients.

Received for publication April 30, 2001. Accepted for publication January 16, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 

  1. . The Montreal Protocol (1994) The Montreal Protocol on substances that deplete the ozone layer: final act (Nairobi: UNEP 1987). Federal Register 59,56276-56298
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  3. . European Commission (1998) European Community: strategy for the phaseout of CFCs in metered dose inhalers. A communication from the European Commission to the Council and the European Parliament. Official Journal of the European Communities 41(C355),2-30
  4. Busse, WW, Brazinsky, S, Jacobson, K, et al (1999) Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 104,1215-1222[CrossRef][ISI][Medline]
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  6. Gross, G, Thompson, PJ, Chervinsky, P, et al (1999) Hydrofluoroalkane-134a beclomethasone dipropionate, 400 µg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 µg, for the treatment of moderate asthma. Chest 115,343-351[Abstract/Free Full Text]
  7. Leach, CL (1998) Improved delivery of inhaled steroids to the large and small airways. Respir Med 92(suppl A),3-8
  8. Juniper, EF, Johnston, PR, Borkhoff, CM, et al (1995) Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care Med 151,66-70[Abstract]
  9. Juniper, EF, Buist, AS (1999) Health-related quality of life in moderate asthma: 400 µg hydrofluoroalkane beclomethasone dipropionate vs 800 µg chlorofluorocarbon beclomethasone dipropionate; The Study Group. Chest 116,1297-1303[Abstract/Free Full Text]
  10. Juniper, EF, Svensson, K, O’Byrne, PM, et al (1999) Asthma quality of life during 1 year of treatment with budesonide with or without formoterol. Eur Respir J 14,1038-1043[Abstract]
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