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Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study.

ABSTRACT: The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.The acute protective effect of inhaled budesonide was tested in a model of temporarily increased airway inflammation with repeated indirect airway challenges, mimicking an acute asthma exacerbation. A randomised, double-blind, cross-over study design was used. Asthmatic patients (n = 17, mean FEV1 95% of predicted) who previously demonstrated a > or = 30% fall in forced expiratory volume in 1 second (FEV1) after inhaling adenosine 5'-monophosphate (AMP), were challenged on four consecutive test days, with the same dose of AMP (at 09:00, 12:00 and 16:00 hours). Within 1 minute of the maximal AMP-induced bronchoconstriction at 09:00 hours, the patients inhaled one dose of either budesonide/formoterol (160/4.5 microg), formoterol (4.5 microg), salbutamol (2 x 100 microg) or placebo. The protective effects of the randomised treatments were assessed by serial lung function measurements over the test day.In the AMP provocations at 3 and 7 hours after inhalation, the budesonide/formoterol combination provided a greater protective effect against AMP-induced bronchoconstriction compared with formoterol alone, salbutamol and placebo. In addition all three active treatments significantly increased FEV1 within 3 minutes of administration, at a time when inhaled AMP had induced the 30% fall in FEV1.A single dose of budesonide/formoterol provided a greater protective effect against inhaled AMP-induced bronchoconstriction than formoterol alone, both at 3 and at 7 hours after inhalation. The acute protection against subsequent bronchoconstrictor stimuli such as inhaled AMP and the rapid reversal of airway obstruction supports the use of budesonide/formoterol for both relief and prevention in the treatment of asthma.

SUBMITTER: Aalbers R

PROVIDER: S-EPMC2890647 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study.

Aalbers René R Boorsma Martin M van der Woude Hanneke J HJ Jonkers René E RE

Respiratory research 20100528

<h4>Background</h4>The budesonide/formoterol combination is successfully used for fast relief of asthma symptoms in addition to its use as maintenance therapy. The temporarily increased corticosteroid dose during increasing inhaler use for symptom relief is likely to suppress any temporary increase in airway inflammation and may mitigate or prevent asthma exacerbations. The relative contribution of the budesonide and formoterol components to the improved asthma control is unclear.<h4>Methods</h4 ...[more]

PMID: 20509942

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Project description:BackgroundBudesonide and formoterol (BF) Spiromax® is a dry powder inhaler designed to deliver BF with maximum ease of use for patients with asthma or chronic obstructive pulmonary disease.MethodsA phase 3b, 12-week, multicenter, double-blind, double-dummy, randomized, controlled trial in patients (≥12 years) with persistent asthma.Primary objectiveto demonstrate non-inferiority of twice-daily BF Spiromax 160/4.5 mcg to BF Turbuhaler® 200/6 mcg in change from baseline in weekly average of daily trough morning peak expiratory flow (PEF). Secondary endpoints included: Patient Satisfaction and Preference Questionnaire scores, change from baseline in evening PEF, trough forced expiratory volume in one second, percentage of symptom-free and rescue-free 24-hour periods, and safety.ResultsThe analysis was based on the per-protocol population (BF Spiromax, n = 290; BF Turbuhaler, n = 284). The least squares mean change from baseline to week 12 in morning PEF was: BF Spiromax, 18.8 L/min and BF Turbuhaler, 21.8 L/min. Non-inferiority of BF Spiromax vs BF Turbuhaler was demonstrated (the lower limit of the 95% two-sided confidence interval was -9.02 L/min, which is greater than -15 L/min [the criteria specified for non-inferiority]). The mean difference in the total performance domains scores for BF Spiromax vs BF Turbuhaler were 0.248 at baseline and 0.353 at week 12 (both, p <0.001), indicating statistical superiority for BF Spiromax. No statistical or numerical differences were recorded in the total convenience domain score between the two devices. Scores for 'device preference' and 'willingness to continue' supported BF Spiromax at baseline and at week 12 (p = 0.0005 vs BF Turbuhaler). No significant between-group differences were observed in the other secondary efficacy endpoints. Both treatments were well tolerated, with no significant differences in adverse events or asthma exacerbations.ConclusionsThis study demonstrates the non-inferiority of BF Spiromax vs BF Turbuhaler in patients (≥12 years) with asthma. More patients preferred the Spiromax device over Turbuhaler for its performance, and were willing to continue therapy with BF Spiromax beyond the 12-week study period.Trial registrationNCT01803555; February 28, 2013.

Project description:BACKGROUND:Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy). OBJECTIVES:The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler. SEARCH STRATEGY:We last searched the Cochrane Airways Group trials register in September 2008. SELECTION CRITERIA:Randomised controlled trials in adults and children with chronic asthma. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes. MAIN RESULTS:Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited.Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0.56; 95% CI 0.28 to 1.09), but fewer patients on single inhaler therapy needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64). These results translate into an eleven month number needed to treat of 14 (95% CI 12 to 18), to prevent one patient being treated with oral corticosteroids for an exacerbation. The run-in for these studies involved withdrawal of long-acting beta(2)-agonists, and patients were recruited who were symptomatic during run-in.One study included children (N = 224), in which single inhaler therapy was compared to higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with single inhaler therapy, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also 1 cm greater in the single inhaler therapy group, [95% CI 0.3 to 1.7 cm].There was no significant difference found in fatal or non-fatal serious adverse events for any of the comparisons. AUTHORS' CONCLUSIONS:Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance inhaled corticosteroids. Guidelines and common best practice suggest the addition of regular long-acting beta(2)-agonist to inhaled corticosteroids for uncontrolled asthma, and single inhaler therapy has not been demonstrated to significantly reduce exacerbations in comparison with current best practice, although results of five large trials are awaiting full publication. Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom.

Project description:BACKGROUND:Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting ?2-agonists. METHODS:In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ?1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients. RESULTS:Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05-6.95], p?<?0.001). Longitudinal phase data indicated that the odds of maintaining inhaler mastery at 12 weeks were not statistically significantly different (OR 1.26 [95% CI 0.80-1.98], p =?0.316). Asthma control improved in both groups with no significant difference between groups (OR 0.11 [95% CI -0.09-0.30]). An exploratory analysis indicated that the odds of maintaining independent expert-verified device mastery were significantly higher for patients using Spiromax versus Turbuhaler (OR 2.11 [95% CI 1.25-3.54]). CONCLUSIONS:In the cross-sectional phase, a significantly greater proportion of patients using Spiromax versus Turbuhaler achieved device mastery; in the longitudinal phase, the proportion of patients maintaining device mastery with Spiromax versus Turbuhaler was similar. An exploratory independent expert-verified analysis found Spiromax was associated with higher levels of device mastery after 12 weeks. Asthma control was improved by treatment with both BF Spiromax and BF Turbuhaler. TRIAL REGISTRATION:EudraCT 2013-004630-14 (registration date 23 January 2014); NCT02570425 .

Project description:BackgroundFor patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3.MethodsPatients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study.ResultsA total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF.ConclusionsAs observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD.Trial registration ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Dataset Information

Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study.

Publications

Protective effect of budesonide/formoterol compared with formoterol, salbutamol and placebo on repeated provocations with inhaled AMP in patients with asthma: a randomised, double-blind, cross-over study.

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