Efficacy and safety of a budesonide/formoterol reliever therapy regimen in mild-moderate asthma: A randomised controlled trial
Background Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma. In clinical practice however, adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. In this thesis I explore an alternative approach, that of an inhaled corticosteroid/formoterol combination used as sole reliever therapy, that potentially overcomes the problem of poor adherence. I report the results of my research, known as the PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long acting beta agonist (PRACTICAL) study. Research aims To investigate the efficacy and safety of as-needed budesonide/formoterol, an inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) combination, as compared with maintenance budesonide (ICS) plus as-needed terbutaline, a short-acting beta-agonist (SABA), in adult patients with mild-moderate asthma. Methods This research was performed as a 52-week, open-label, parallel-group, multicentre, phase III randomised controlled trial of adults aged 18-75 with mild to moderate asthma using SABA for symptom relief, with or without low to moderate doses of maintenance ICS in the previous 12 weeks. Participants were randomly assigned (1:1) to either: (i) budesonide/formoterol Turbuhaler, an ICS/fast-onset LABA, 200/6 micrograms (μg), one inhalation as needed for relief of symptoms, or (ii) budesonide Turbuhaler, an ICS, 200µg, one inhalation twice daily, plus terbutaline Turbuhaler, a SABA, 250µg, two inhalations as needed. Participants and investigators were not masked to group assignment. Participants were seen for six study visits: randomisation, and at weeks 4, 16, 28, 40 and 52. The primary outcome was rate of severe exacerbations per patient per year, with severe exacerbations defined as the use of systemic glucocorticoids for at least three days because of asthma, or a hospitalisation or emergency department visit because of asthma requiring systemic glucocorticoids. Findings Between May 4, 2016 and Dec 22, 2017, 890 participants were assigned to treatment. The analysis included 885 of 890 randomised participants; 437 assigned to budesonide/formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. 70% of participants were using ICS at entry. The annualised severe exacerbation rate was lower with as-needed budesonide/formoterol than with maintenance budesonide (absolute rate 0.119 vs 0.172; relative rate, 0.69 [95% confidence interval [CI], 0.48 to 1.00]; p=0.049). The Asthma Control Questionnaire-5 score with budesonide/formoterol was not significantly different from budesonide maintenance (mean difference, 0.06; 95% CI -0.005 to 0.12). Conclusion This research has demonstrated that in adults with mild to moderate asthma in the real-world setting, budesonide/formoterol reliever therapy was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline without a clinically important worsening in asthma control. The evidence presented in this thesis supports the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid/formoterol reliever therapy is an alternative regimen to maintenance low-dose inhaled corticosteroid and SABA reliever for the prevention of severe exacerbations for patients with mild to moderate asthma.