Comparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients

doi:10.1016/j.jaci.2008.03.019

Journal of Allergy and Clinical Immunology

Volume 121, Issue 6, June 2008, Pages 1407-1414.e6

https://doi.org/10.1016/j.jaci.2008.03.019 Get rights and content

Background

The adjustable-dose budesonide/formoterol dry powder inhaler (DPI) has demonstrated similar or greater asthma control with less inhaled corticosteroid compared with the fixed-dose budesonide/formoterol DPI.

Objective

We sought to evaluate the efficacy, tolerability, and resource use of maintenance therapy with the adjustable-dose budesonide/formoterol pressurized metered-dose inhaler versus the fixed-dose budesonide/formoterol pressurized metered-dose inhaler and the fixed-dose fluticasone propionate/salmeterol DPI.

Methods

This was a randomized, open-label, multicenter study of patients (N = 1225) 12 years and older with moderate-to-severe persistent asthma. After 10 to 14 days of current therapy, patients were randomized 2:1 to fixed-dose budesonide/formoterol (160/4.5 μg × 2 inhalations [320/9 μg] twice daily) or fixed-dose fluticasone propionate/salmeterol (250/50 μg × 1 inhalation twice daily) for 1 month (treatment period 1), after which, the fixed-dose fluticasone propionate/salmeterol group continued therapy and the fixed-dose budesonide/formoterol group was randomized 1:1 to fixed-dose budesonide/formoterol or adjustable-dose budesonide/formoterol (adjustable from 2 inhalations [320/9 μg] twice daily to 2 inhalations [320/9 μg] once daily or 4 inhalations [640/18 μg] twice daily) for 6 months (treatment period 2).

Results

There were no significant between-group differences in asthma exacerbations (primary variable), asthma symptoms, or lung function during the 7-month treatment period. Less study drug (inhalations per day, P < .001) was used with adjustable-dose versus fixed-dose budesonide/formoterol. All treatments were well tolerated.

Conclusions

Adjustable-dose and fixed-dose budesonide/formoterol showed no differences in asthma control or tolerability versus fixed-dose fluticasone propionate/salmeterol.

Section snippets

Patients

Patients aged 12 years and older with a documented diagnosis of asthma, as defined by the American Thoracic Society,¹¹ for 6 months or more before screening and who were in stable condition were qualified to participate. Study procedures at screening are detailed in the Methods section of the Online Repository at www.jacionline.org. Patients were required to have a prebronchodilator FEV₁ of 50% or greater of predicted normal value and to have been maintained on a daily medium-dose ICS or

Patients

Patient disposition is shown in Fig 1. Baseline characteristics were generally similar across the 3 treatment groups (Table I). More than 99% of patients were using ICSs at study entry, the most common of which were fluticasone (either as a monoproduct or as a fluticasone propionate/salmeterol DPI) or budesonide. Compliance data are presented in the Results section in the Online Repository at www.jacionline.org.

Efficacy

There were no significant differences between the treatment groups in time to first

Discussion

This is the first study to compare clinical outcomes with the US-approved fixed-dose regimen of budesonide/formoterol pMDI with that of the fixed-dose fluticasone propionate/salmeterol DPI. In this study, measures of pulmonary function and asthma control, including the primary efficacy variable asthma exacerbations, were not significantly different in patients receiving the adjustable-dose budesonide/formoterol pMDI, the fixed-dose budesonide/formoterol pMDI, and the fixed-dose fluticasone

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Cited by (33)

May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide?
2022, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Another study [50] showed more symptom-free days and lower annual exacerbation incidence with SALM/FP compared with BUD/FORM. Finally, no differences between treatments were found in one study [51,52]. As a further development of the BUD/FORM adjustable maintenance therapy the BUD/FORM maintenance and reliever therapy (MART) was introduced.
The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile.
In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon.
Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as “maintenance plus reliever therapy” (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles.
We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as “anti-inflammatory reliever”.
Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β<inf>2</inf>-adrenoceptor agonists
2019, Bioorganic and Medicinal Chemistry
Citation Excerpt :
There are two major components in the pathophysiology of both diseases, airway inflammation and smooth muscle dysfunction.7 The respiratory diseases are widely treated with β2-adrenoceptor agonists or muscarinic antagonists in combination with corticosteroids when the severity of symptoms is from moderate to severe.8,9 The β2-adrenoceptor, a member of the superfamily of the seven transmembrane G protein-coupled receptors (GPCRs), is widely expressed in the respiratory tract.10
A series of novel β₂-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β₂-adrenoceptor agonistic effects and high β₂/β₁-selectivity with EC₅₀ values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.
Traditional Therapies for Severe Asthma
2016, Immunology and Allergy Clinics of North America
Citation Excerpt :
In comparison with fixed maintenance dosing, they noted that adjustable maintenance dosing of combination ICS/LABA therapy resulted in various clinical outcomes, including a lower rate of exacerbations, lower costs, decreased use of ICS/LABA therapy, improved health-related quality of life, and decreased nocturnal awakenings.23–29 In contrast, a randomized, multicenter study by Busse and colleagues30 did not show any difference in control or lung function comparing adjustable versus fixed-dose budesonide/formoterol and fixed-dose fluticasone propionate/salmeterol. Although not adopted in the United States, use of ICS/LABA for maintenance and relief has been adopted in other countries and is part of the GINA guidelines.11
A Comparison of long-term anti-inflammatory effect of two ICS/LABA combination inhalers; fix-dosed maintenance therapy with budesonide/formoterol and salmeterol/fluticasone
2014, Allergology International
The clinical usefulness of fixed-dose maintenance therapy with salmeterol/fluticasone (SFC) and budesonide/formoterol combination inhaler (BUD/FM) has been established, though evidence of the long-term anti-inflammatory effects of these 2 inhalers are limited.
Patients with moderate persistent adult asthma who had received SFC 50/250 μg bid with well-control status were recruited. After switching to 8-week therapy with fixed-dose BUD/FM 4 puffs (640/18 μg) (phase-1), patients chose either SFC or BUD/FM. FeNO and ACT score were evaluated every 8 weeks until the end of the 52-week treatment period for both treatment groups (phase-2).
In total, 103 patients were examined: BUD/FM was chosen by 34 patients (BUD/FM group), while SFC was chosen by 23 (SFC group). Thirty-six received SFC consistently from the beginning of the study (control). Patients in the BUD/FM and SFC groups showed significant improvements in ACT scores and FeNO levels in phase-1; these beneficial effects persisted for 52 weeks in the BUD/FM group. On the other hand, in the SFC group, although the FeNO level decreased from 54.3 ± 26.4 ppb to 41.9 ± 18.3 ppb in phase-1, it increased to 54.5 ± 26.2 ppb, a level similar to the baseline prior to the beginning of BUD/FM therapy, at 8 weeks in phase-2, and remained at 50-odd ppb thereafter.
These results suggest that maintenance therapy with fixed-dose BUD/FM is a useful treatment option exerting an airway anti-inflammatory effect for a period as long as 1 year, even for asthmatics who could not accomplish total control with SFC.
An investigation into the structure-activity relationships associated with the systematic modification of the β<inf>2</inf>-adrenoceptor agonist indacaterol
2012, Bioorganic and Medicinal Chemistry Letters
The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the β₂-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical β₂-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating ‘super agonist’.
Asthma outcomes: Exacerbations
2012, Journal of Allergy and Clinical Immunology
The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation” or about how to characterize an episode’s severity.
National Institutes of Health institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies.
We used comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health–organized workshop in March 2010 and finalized in September 2011.
No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalizations, and (3) use of short-acting β-agonists as quick-relief (sometimes referred to as “rescue” or “reliever”) medications.
The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Furthermore, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component.

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: Support for this study was provided by AstraZeneca LP.

: Disclosure of potential conflict of interest: W. W. Busse has received research support from Novartis, Dynavax, Wyeth, Centocor, GlaxoSmithKline, Medicinova, Sanofi-Aventis, Dey, Pfizer, Astellas Pharma, Inflazyme, and Biowa/MedImmune and is on the speakers' bureau for Novartis, Merck, AstraZeneca, and GlaxoSmithKline. S. R. Shah has consulting arrangements with AstraZeneca, GlaxoSmithKline, MedPointe, Schering-Plough, and Alcon; has received research support from AstraZeneca, GlaxoSmithKline, MedPointe, Schering-Plough, Alcon, Merck, and Sanofi-Aventis; and is on the speakers' bureau for AstraZeneca, GlaxoSmithKline, MedPointe, Schering-Plough, Alcon, Merck, and Sanofi-Aventis. L. Somerville has received research support from AstraZeneca, GlaxoSmithKline, Aventis, Novartis, Genentech, Accentia, Alcon, Greer, Medicinova, Merck, Naryx, Novum, Schering-Plough, Allergy Therapeutics, and Skye. B. Parasuraman is employed by AstraZeneca. P. Martin and M. Goldman are employed by and own stock in AstraZeneca.

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Asthma and lower airway diseaseComparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients

Background

Objective

Methods

Results

Conclusions

Section snippets

Patients

Patients

Efficacy

Discussion

J Allergy Clin Immunol

Respir Med

Respir Med

Pulm Pharmacol Ther

Clin Ther

Expert panel report 3: guidelines for the diagnosis and management of asthma—Full report

Nonadherence in asthmatic patients: is there a solution to the problem?

Ann Allergy Asthma Immunol

Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol fluticasone in moderate to severe asthma

Curr Med Res Opin

Economic assessment of adjustable maintenance treatment with budesonide/formoterol in a single inhaler versus fixed treatment in asthma

Pharmacoeconomics

Asthma and lower airway disease
Comparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients