Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant

doi:10.1016/S0091-6749(99)70016-3

Journal of Allergy and Clinical Immunology

Volume 104, Issue 6, December 1999, Pages 1215-1222

https://doi.org/10.1016/S0091-6749(99)70016-3 Get rights and content

Abstract

Background: This study tested the hypothesis that there would be improved asthma control with increasing doses of beclomethasone dipropionate (BDP) formulated in hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP, this study also tested the hypothesis that HFA-BDP would provide more effective control of asthma than CFC-BDP. Methods: In this multicenter, randomized, parallel-group blinded study, asthmatic subjects who had deterioration in asthma control after discontinuation of inhaled corticosteroids were randomized to receive one of 6 possible treatments: 100 μg/d, 400 μg/d, or 800 μg/d of HFA-BDP or 100 μg/d, 400 μg/d, or 800 μg/d of CFC-BDP for 6 weeks. Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep disturbance scores, morning and evening peak expiratory flows, and daily use of inhaled β-agonist for symptom control on diary cards were assessed over 6 weeks of treatment. Results: Three hundred twenty-three patients were randomized to the 6 treatment groups, which had similar demographics and baseline lung function. There were significantly larger changes from baseline at week 6 in FEV₁ percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The FEV₁ percent predicted dose-response curve for HFA-BDP was shifted to the left compared with the dose-response curve for CFC-BDP. By using the Finney bioassay method, it was calculated that 2.6 times as much CFC-BDP would be required to achieve the same improvement in FEV₁ percent predicted as HFA-BDP (95% confidence interval, 1.1-11.6). All treatment groups except the 100 μg/d CFC-BDP group tolerated study drug well. Ten (17%) of 59 patients in this group reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports of increased asthma symptoms were classified as severe), or both, and 8 patients withdrew from the study (3 for adverse events related to asthma). Conclusions: Increasing doses of inhaled corticosteroids lead to improved lung function and asthma control. Moreover, the reformulation of BDP in HFA enables effective asthma control at much lower doses than CFC-BDP. (J Allergy Clin Immunol 1999;1215-22.)

Section snippets

Patient recruitment

Patients were recruited from clinics of study investigators. Inclusion criteria were age of greater than 18 years, asthma history of at least 12 months, 12% or greater FEV₁ reversibility to inhaled β-agonist, inhaled β-agonist use for asthma symptom control, screening FEV₁ of 50% to 75% predicted of predicted value,⁴ and use of 400 to 1000 μg/d flunisolide, triamcinolone acetonide, or CFC-BDP for 4 weeks before the prestudy visit. Exclusion criteria were smoking within the previous 12 months,

Patient disposition and characteristics

Between February and December 1996, 496 patients were screened for study entry, and 323 were randomized. The most common reason for screening ineligibility was an FEV₁ value outside the 50% to 75% predicted range. After randomization, 18 patients withdrew from the study (6 for personal reasons, 5 for adverse events, 3 for an inadequate response, and 4 for miscellaneous reasons). The 100 μg/d CFC-BDP group had 8 withdrawals; no other treatment group had more than 3.

No significant differences in

DISCUSSION

This study shows that increasing doses of inhaled corticosteroids in patients with severe asthma result in improved lung function and asthma control. Also, HFA-BDP provided larger increases in lung function than CFC-BDP, presumably because of improved pulmonary deposition.³

The effects of increasing doses of BDP in this study, expressed in terms of absolute FEV₁, are clinically meaningful.⁸ Patients treated with 800 μg/d HFA-BDP had on average a 170-mL larger increase in FEV₁ from baseline at

Acknowledgements

We thank the following investigators who entered patients into this trial: D. Briggs, Jr, Birmingham, Ala; A. Wanderer, Englewood, Colo; P. Chervinsky, North Dartmouth, Mass; R. Dockhorn, Lenexa, Kan; C. Banov, Charleston, SC; J. Ramsdell, San Diego, Calif; R. Cohen, Lawrenceville, Ga; D. Ledford, Tampa, Fla; E. Lisberg, Oak Park, Ill; R. Nathan, Pueblo, Colo; A. Nayak, Normal, Ill; D. Pearlman, Aurora, Colo; N. Segall, Atlanta, Ga; L. Southern, Princeton, NJ; F. Virant, Seattle, Wash; M.

References (30)

DA Redelmeier et al.
Spirometry and dyspnea in patients with COPD
Chest
(1996)
JC Kidney et al.
Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model
J Allergy Clin Immunol
(1997)
S Pedersen et al.
Budesonide treatment of moderate and severe asthma in children: a dose-response study
J Allergy Clin Immunol
(1995)
Q Hamid et al.
Inflammation of small airways in asthma
J Allergy Clin Immunol
(1997)
LA Laitinen et al.
A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β₂-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial
J Allergy Clin Immunol
(1992)
MJ Welch et al.
Dose-ranging study of the clinical efficacy of twice-daily triamcinolone acetonide inhalation aerosol in moderately severe asthma
Chest
(1997)
RA Nathan et al.
A comparison of double-strength beclomethasone dipropionate (84 mg) MDI with beclomethasone dipropionate (42 mg) MDI in the treatment of asthma
Chest
(1997)
J Gaddie et al.
Aerosol beclomethasone dipropionate: a dose-response study in chronic bronchial asthma
Lancet
(1973)
JH Toogood et al.
Comparison of the antiasthmatic, oropharyngeal, and systemic glucocorticoid effects of budesonide administered through a pressurized aerosol plus spacer or the Turbuhaler dry powder inhaler
J Allergy Clin Immunol
(1997)
JH Toogood et al.
A graded dose assessment of the efficacy of beclomethasone dipropionate aerosol for severe chronic asthma
J Allergy Clin Immunol
(1977)

L Agertoft et al.

A randomized, double-blind dose reduction study to compare the minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler

J Allergy Clin Immunol

(1997)

P Chervinsky et al.

Fluticasone propionate aerosol for the treatment of adults with mild to moderate asthma

J Allergy Clin Immunol

(1994)

PJ Barnes et al.

Efficacy and safety of inhaled corticosteroids

Am J Respir Crit Care Med

(1998)

AK Kamada et al.

Issues in the use of inhaled corticosteroids

Am J Respir Crit Care Med

(1996)

CL Leach et al.

Improved airway targeting with the CFC-free HFA-beclomethasone metered dose inhaler compared to CFC-beclomethasone

Eur J Respir Dis

(1998)

Cited by (246)

Combined analysis of five non-interventional studies of the effectiveness, tolerability, and safety of the extrafine fixed dose beclomethasone/formoterol combination in the treatment of asthma in Austria
2023, Respiratory Medicine
The real-world effectiveness and tolerability of an extrafine fixed dose beclomethasone/formoterol (BDP/FF) treatment of patients with partially or non-controlled asthma was evaluated in five non-interventional studies (NISs) from Austria.
Asthma patients enrolled in these five NISs were treated with beclomethasone/formoterol (Foster® or Foster® Nexthaler®) as maintenance and reliever over 12 weeks. Asthma control, lung function and symptom scores were assessed at baseline, after 4–8 weeks and at the end of the investigations in week 12. In addition, tolerability and handling of the devices were evaluated by questionnaires.
The combined analysis included 891 patients (53% female, aged 49.3 years) demonstrating significant improvements in asthma control, lung function parameters (PEF, FEV₁ and FVC) and symptom scores (reduction of breathlessness, wheezing, chest tightness and cough). These changes were already detectable after 4–8 weeks. The treatment was effective irrespective of smoking status, exercise, or previous medication. Tolerability of the therapy with extrafine BDP/FF was rated as “very good” or “good” in 98% of the patients. 95% of the patients intended to continue the treatment, and nearly all (99%) rated the handling of the device as “very good” or “good”. No serious adverse reactions were reported.
This combined analysis of five non-interventional studies confirms the effectiveness and tolerability of the extrafine fixed-dose BDP/FF combination (Foster® and Foster® Nexthaler®) in a heterogenous patient population suffering from partially or non-controlled asthma. Therapy was associated with a high patient satisfaction and the absence of serious adverse reactions.
Corticosteroid resistance in asthma: Cellular and molecular mechanisms
2022, Molecular Aspects of Medicine
Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.
Inhaled Corticosteroids and Endocrine Effects in Childhood
2020, Endocrinology and Metabolism Clinics of North America
A Systematic Review of Patient- and Family-Level Inhaled Corticosteroid Adherence Interventions in Black/African Americans
2019, Journal of Allergy and Clinical Immunology: In Practice
Inhaled corticosteroid (ICS) adherence rates are suboptimal among adult black/African Americans. Comprehensive studies characterizing the effectiveness and the methodological approaches to the development of interventions to improve ICS adherence in adult black/African Americans have not been performed.
Conduct a systematic review of patient/family-level interventions to improve ICS adherence in adult black/African Americans.
We searched MEDLINE, EMBASE, Web of Science, and CINAHL from inception to August 2017 for English-language US studies enrolling at least 30% black/African Americans comparing patient/family-level ICS adherence interventions with any comparator. Two investigators independently selected, extracted data from, and rated risk of bias. We collected information on intervention characteristics and outcomes, and assessed whether studies were informed by behavior theory, stakeholder engagement, or both.
Among 1661 abstracts identified, we reviewed 230 full-text articles and identified 4 randomized controlled trials (RCTs) and 1 quasi-experimental (pre-post design) study meeting criteria. Study participants (N range, 17-333) varied in mean age (22-47 years), proportion black/African Americans studied (71%-93%), and sex (69%-82% females). RCTs evaluated problem-solving classes, self-efficacy training, technology-based motivational interviewing program, and the use of patient advocates. The RCT testing self-efficacy training was the only intervention informed by both behavior theory and stakeholder engagement. All 4 RCTs compared interventions with active control and rated as medium risk of bias. No RCTs found a statistically significant improvement in adherence.
Few studies assessing asthma adherence interventions focused on adult black/African-American populations. No RCTs demonstrated improved ICS adherence in participants. Future studies that are informed by behavior change theory and stakeholder engagement are needed.
Extrafine compared to non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma
2017, Respiratory Medicine
Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to more smoking-induced small airways disease. Thus targeting small airways may be important in treating asthmatic (ex-)smokers. We hypothesized that extrafine particle ICS improve small airways function more than non-extrafine particle ICS in asthmatic (ex-)smokers.
We performed an open-label, randomized, three-way cross-over study comparing extrafine beclomethasone (HFA-QVAR) to non-extrafine beclomethasone (HFA-Clenil) and fluticasone (HFA-Flixotide) in 22 smokers and 21 ex-smokers with asthma (≥5 packyears).
Improvement from baseline in PD₂₀ adenosine after using QVAR, Clenil or Flixotide was 1.04 ± 1.71, 1.09 ± 2.12 and 0.94 ± 1.97 doubling doses, mean ± standard deviation (SD), respectively. The change from baseline in R₅-R₂₀ at PD₂₀ adenosine after using QVAR, Clenil or Flixotide was −0.02 ± 0.27, 0.02 ± 0.21, and −0.02 ± 0.31 kPa sL⁻¹, mean ± SD, respectively. The change in PD₂₀ adenosine and R₅-R₂₀ at PD₂₀ adenosine were neither statistically significant different between QVAR and Clenil (p = 0.86 and p = 0.82) nor between QVAR and Flixotide (p = 0.50 and p = 0.96).
Similar effectiveness in improving small airways function was found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers.
Management of Severe Asthma before Referral to the Severe Asthma Specialist
2017, Journal of Allergy and Clinical Immunology: In Practice
Severe asthma is associated with significant morbidity and can be challenging to assess and control, due to heterogeneity of disease, complexity of diagnosis, and impact of comorbidities. A structured approach to the assessment and management of severe asthma may be helpful to the practicing clinician. First, it is important to confirm a diagnosis of asthma. In patients who are either not responding to treatment, or who require high doses of medication to control symptoms, it is highly possible that disease mimickers or comorbidities are present and can inhibit therapeutic responsiveness. The assessment and management of common comorbidities of asthma may dramatically impact disease control and thus medication requirement. Determining medication adherence and optimizing drug dose and delivery may separate out truly severe asthmatics from those not using medications regularly or properly. Next, although true personalized medicine for severe asthma is not yet realized, for those individuals with severe asthma, phenotypic characteristics of each patient may guide which therapeutic options may be most effective for that patient. Finally, evaluation and management of severe asthma at a referral center can add additional phenotyping, therapeutic, and diagnostic strategies.

View all citing articles on Scopus

^☆: Supported by a research grant from 3M Pharmaceuticals. K. S., J. V. B., S. H., and G. L. C. are full-time employees of 3M Pharmaceuticals.

^☆☆: Reprint requests: Gene L. Colice, MD, Director Pulmonary and Respiratory Services, Washington Hospital Center, 110 Irving St, NW, Washington, DC 20010.

^★: 0091-6749/99 $8.00 + 0 1/1/102870

View full text

Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant☆,☆☆,★

Abstract

Section snippets

Patient recruitment

Patient disposition and characteristics

DISCUSSION

Acknowledgements

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

Chest

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Efficacy and safety of inhaled corticosteroids

Am J Respir Crit Care Med

Issues in the use of inhaled corticosteroids

Am J Respir Crit Care Med

Improved airway targeting with the CFC-free HFA-beclomethasone metered dose inhaler compared to CFC-beclomethasone

Eur J Respir Dis