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(Chest. 1999;115:343-351.)
© 1999 American College of Chest Physicians

Hydrofluoroalkane-134a Beclomethasone Dipropionate, 400 µg, Is as Effective as Chlorofluorocarbon Beclomethasone Dipropionate, 800 µg, 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 Group1

* 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.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 
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 ß-agonist and CFC-BDP [<= 400 µg/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 µg/d, CFC-BDP 800 µg/d, or HFA-placebo for 12 weeks.

Results: Morning peak expiratory flow (AM PEF) measurements showed that HFA-BDP 400 µg/d achieved equivalent control of asthma to CFC-BDP 800 µg/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.

Key Words: chlorofluorocarbon beclomethasone dipropionate • hydrofluoroalkane-134a beclomethasone dipropionate • moderate asthma


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix 1
 References
 
The efficacy of inhaled corticosteroids for the treatment of asthma is well recognized, with both national and international treatment guidelines recommending their use as first-line therapy for all 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 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 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 µm, whereas this HFA-BDP formulation has a mass median aerodynamic diameter of approximately 1.2 µm.8

Deposition studies have demonstrated that HFA-BDP 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 µg HFA-BDP extrafine aerosol would provide equivalent control of moderate or moderately severe asthma to that of 800 µg of CFC-BDP.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix 1
 References
 
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 µg/d (Table 1 ). Additional qualification criteria were concurrent use of ß-agonists for symptom relief and reversibility of FEV1 of >= 15% in response to pirbuterol (400 µg). Eligible patients entered a 10- to 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 ß-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 ß-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.


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  		Table 1. Randomized Patients: Characteristics and Pulmonary Function at Screening

 
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 µg/d [4 x 50 µg ex-valve twice daily]), CFC-BDP (Beclovent; GlaxoWellcome; Research Triangle Park, NC; 800 µg/d [8 x 50 µg 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 HFA-placebo) 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. 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 ß-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.

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 ß-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 = not present, 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 = no asthma symptoms during the night, 4 = 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.

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 ± 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 ± 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.


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



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  		Figure 1. Time to withdrawal from study due to asthma symptoms.

 
Compliance
Compliance (as determined by canister weights) was good (> 87%) and comparable in all treatment groups. No differences in compliance were observed 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 µg/d group compared with the CFC-BDP 800 µg/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.


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  		Table 2. Mean Change in AM PEF (L/min) From Oral Steroid Treatment*

 


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  		Figure 2. Adjusted mean AM PEF (L/min) by week.

 
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 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 ± 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 = 0.085; 90% CI, -0.019, 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).



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  		Figure 3. Adjusted mean FEV1 (L) by week.

 
HFA-BDP, 400 µg/d, and CFC-BDP, 800 µg/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 ß-agonist use were also equivalent in the two active treatment groups. Patients treated with HFA-BDP or CFC-BDP 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 CFC-BDP) (Fig 4 ). The mean change from this oral steroid treatment period in daily ß-agonist use was also significantly less at each time period with both HFA-BDP and CFC-BDP compared with HFA-placebo (p <= 0.003) (Fig 5 ). The use of ß-agonists decreased during the period of oral steroid treatment and subsequently changed little during the 12 weeks of inhaled steroid therapy. In contrast, ß-agonist use increased in placebo-treated patients during this time and was significantly different for active groups (p <= 0.003) (Fig 5 ).



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  		Figure 4. Adjusted mean percentage of nights without sleep disturbance.

 


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  		Figure 5. Adjusted mean change in daily ß-agonist use.

 
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 placebo-treated 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 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.


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  		Table 3. Adverse Events Most Commonly Considered Possibly or Probably Related to Study Medication

 
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 = 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
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix 1
 References
 
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 µg/d of HFA-BDP provides equivalent control to 1,500 µg/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 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 ,22 ,23 ,24 ,25 ,26 ,27 ,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 ,31 ,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 µg/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 µg/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 CFC-BDP, 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 HFA-BDP 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. 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 HFA-BDP 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 HFA-BDP 400 µg/d extrafine aerosol maintained equivalent control of pulmonary function to CFC-BDP 800 µg/d throughout the 12-week treatment period for all efficacy parameters evaluated. Both active treatments were significantly more effective than HFA-placebo, 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 µg HFA-BDP, despite the fact that some patients had been receiving 400 µg 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 drug- or 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 µg of HFA-BDP extrafine aerosol was found to be as effective as 800 µg 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 CFC-free 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.


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


   Acknowledgements
 
ACKNOWLEDGMENT: The authors would like to acknowledge the support of David Donnell MRPharmS (3M Pharmaceuticals, UK).


   Footnotes
 
This study was supported by a grant from 3M Pharmaceuticals.

A complete list of Study Group participants is located in the Appendix. Back

Correspondence to: Jennifer Vanden Burgt, 3M Pharmaceuticals, 3M Center, Building 270-3A-01, St. Paul, MN 55144-1000; e-mail: javandenburgt@mmm.com

Abbreviations: AM PEF = morning peak expiratory flow; ANOVA = analysis of variance; BDP = beclomethasone dipropionate; CFC = chlorofluorocarbon; CI = confidence interval; HFA = hydrofluoroalkane-134a; MDI = metered-dose inhaler; PM PEF = evening peak expiratory flow

Received for publication April 17, 1998. Accepted for publication August 12, 1998.


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

  1. Global Initiative for Asthma. Global strategy for asthma management and prevention. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health NHLBI/WHO workshop report; 1995; National Institutes of Health publication 95-3659
  2. National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. NIH publication No. 97-4051. Bethesda, MD: National Institutes of Health, 1997
  3. Jackson, C, Lipworth, B (1995) Optimizing inhaled drug delivery in patients with asthma. Br J Gen Pract 45,683-687[ISI][Medline]
  4. Newman, SP, Pavia, D, Clarke, SW (1981) Improving the bronchial deposition of pressurized aerosols. Chest 80,909-914[Medline]
  5. Thompson, P (1998) Drug delivery to the small airways. Am J Respir Crit Care Med 157(suppl),S199-S202
  6. Woolcock, A (1998) Effects of drugs on small airways. Am J Respir Crit Care Med 157(suppl),S203-S207[Medline]
  7. Laube, BL (1996) In vivo measurements of aerosol dose and distribution: clinical relevance. J Aerosol Med 9(suppl 1),S77-S92
  8. Leach, CL (1995) Approaches and challenges to use freon propellant replacements. Aerosol Sci Technol 22,328-334
  9. Leach, CL, Davidson, P, Heilman, J, et al (1997) Improved lung deposition and decreased oropharyngeal deposition with a new CFC-free beclomethasone metered dose inhaler. Am J Respir Crit Care Med 155,A667
  10. June, DS, Schultz, RK, Miller, NC (1994) A conceptual model for the delivery of pressurized metered-dose hydrofluoroalkane-based inhalation aerosols. Pharm Technol 18,40-52
  11. June, DS, Schultz, DW (1995) Improved performance characteristics of CFC-free aerosol MDIs. J Aerosol Med 8,91
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