Elsevier

The Lancet

Volume 394, Issue 10202, 14–20 September 2019, Pages 919-928
The Lancet

Articles
Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial

https://doi.org/10.1016/S0140-6736(19)31948-8Get rights and content

Summary

Background

In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting β-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting β-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide–formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline.

Methods

We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18–75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 μg–formoterol 6 μg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 μg Turbuhaler (one inhalation twice daily) plus terbutaline 250 μg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437.

Findings

Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide–formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide–formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48–1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide–formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed.

Interpretation

In adults with mild to moderate asthma, budesonide–formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid–formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma.

Funding

Health Research Council of New Zealand.

Introduction

Most people with asthma have intermittent or mild disease. Despite generally having few symptoms, these patients still have exacerbations.1, 2 Many of these exacerbations could be prevented by low-dose inhaled corticosteroids,2, 3 but health-care professionals often do not prescribe these drugs to patients with intermittent or mild disease and such patients may be poorly adherent, as the intermittent nature of symptoms makes commitment to a regular maintenance regimen problematic.4, 5, 6

An alternative approach is to use a combination of an inhaled corticosteroid with formoterol (a fast-onset long-acting β-agonist [LABA]) as reliever monotherapy, which reduces the risk of severe exacerbations by more than half compared with a short-acting β-agonist (SABA) reliever alone.7, 8 However there is uncertainty about the relative efficacy and safety of this regimen compared with maintenance inhaled corticosteroid plus as-needed SABA. Two large, randomised, placebo-controlled trials7, 9 reported non-inferiority in the risk of severe exacerbations between these two regimens, whereas an open-label study more closely aligned to clinical practice reported a halving of the risk of severe exacerbations with budesonide–formoterol reliever therapy compared with maintenance budesonide plus as-needed salbutamol.8 In all three studies, maintenance budesonide plus as-needed SABA achieved greater improvement in symptom control, although this improvement was less than the minimum clinically important difference.

Research in context

Evidence before this study

Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma; however, in clinical practice adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. An alternative approach that potentially overcomes the problem of poor adherence is the use of an inhaled corticosteroid–formoterol combination as sole reliever therapy, thereby titrating use according to symptoms. We searched MEDLINE and Embase for studies published between Jan 1, 2000, and July 1, 2019, using the terms “inhaled corticosteroid-formoterol”, “budesonide-formoterol”, “as-required”, “asthma”, “adults”, and “randomised controlled trial”. Four studies of adults with mild or moderate asthma were identified which investigated the efficacy of budesonide–formoterol reliever monotherapy, all of which were published after this study was designed. In two studies, comparisons were made versus short-acting β-agonist (SABA) reliever monotherapy or with maintenance budesonide plus SABA reliever therapy; in one, versus maintenance budesonide plus SABA reliever therapy; and in one versus regular budesonide-formoterol plus SABA reliever therapy. Budesonide–formoterol reliever therapy was superior to SABA reliever therapy in patients with mild asthma, reducing the risk of severe exacerbations by at least 50% after a follow-up of 12 months. Of the three studies investigating budesonide–formoterol reliever therapy and maintenance budesonide plus SABA reliever therapy in patients with mild asthma, two were regulatory and one was a real-world study; there was non-inferiority in severe exacerbation risk in the two regulatory studies, whereas the real world study reported a significantly lower severe exacerbation risk with budesonide–formoterol reliever therapy compared with maintenance budesonide therapy plus SABA reliever. Budesonide-formoterol reliever monotherapy was inferior to regular budesonide-formoterol plus as-needed SABA for the outcome of treatment failure but not different for severe exacerbations in patients with moderate asthma. As a result, there is uncertainty about the relative efficacy and safety of inhaled corticosteroid–formoterol reliever monotherapy compared with maintenance inhaled corticosteroid plus SABA reliever therapy.

Added value of this study

This was the first independently funded open-label study comparing inhaled corticosteroid–formoterol reliever therapy with maintenance inhaled corticosteroid plus SABA reliever therapy in adults with mild to moderate asthma in a real-world setting. Budesonide–formoterol reliever therapy resulted in fewer severe exacerbations, and patients on this therapy had a longer time to first severe exacerbation, compared with patients on maintenance budesonide plus as-needed terbutaline. FENO was lower with budesonide maintenance. There was no significant between-group difference in asthma symptom control as measured by Asthma Control Questionnaire 5. The findings of sub-group analyses were consistent with the treatment effect being similar in all patient subgroups, suggesting that the findings are generalisable across the spectrum of mild and moderate asthma.

Implications of all the available evidence

Budesonide–formoterol reliever therapy is superior to maintenance budesonide plus SABA reliever therapy in adults with mild to moderate asthma in the real-world setting, reducing the risk of severe exacerbations without a clinically important worsening in asthma symptom control. Together the available evidence suggests that, for prevention of severe exacerbations, budesonide–formoterol reliever therapy is preferred to SABA reliever therapy for step 1 treatment, confirming the recommendation in the Global Initiative for Asthma (GINA) 2019 guidelines that adults and adolescents with asthma should not be treated with SABA alone. The evidence also supports the inclusion of budesonide–formoterol reliever therapy as an alternative to maintenance low-dose corticosteroids plus SABA reliever in GINA step 2. With the addition of this study, the evidence now also suggests that, of these two regimens, budesonide–formoterol reliever therapy might be the preferred option for prevention of severe exacerbations in mild to moderate asthma.

We designed the PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long-acting beta agonist (PRACTICAL) study with the aim of comparing the efficacy of as needed budesonide–formoterol reliever therapy with maintenance budesonide plus as-needed terbutaline in an open-label clinical trial in adults with mild to moderate asthma. This is the first independently funded randomised controlled trial comparing inhaled corticosteroid–formoterol as sole reliever therapy with maintenance inhaled corticosteroid plus SABA reliever therapy in patients with asthma for whom low dose maintenance inhaled corticosteroid therapy was recommended at step 2 of the 2014 Global Initiative for Asthma (GINA) strategy.10

Section snippets

Study design and participants

PRACTICAL was an investigator-led, pragmatic, 52 week, open-label, parallel-group, multicentre, superiority, randomised controlled trial undertaken at 15 primary care or hospital-based clinical trials units and primary care practices across New Zealand. Ethical approval was provided by the Northern B Health and Disability Ethics Committee. The study was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki, and the trial protocol has been published.11

Eligible

Results

Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment (figure 1); the intention-to-treat dataset included 885 eligible participants (baseline characteristics are in table 1, and the appendix pp 31–34). No follow-up data were available for 14 participants (appendix p 35). At study entry participants had a mean ACQ-score of 1·15; 12% reported a severe exacerbation in the previous 12 months. At baseline 264 (30%) of 885 participants were taking SABA reliever therapy

Discussion

This randomised controlled trial provided modest evidence that combination budesonide–formoterol used as-needed for symptom relief reduced the rate of severe exacerbations compared with maintenance low-dose budesonide plus terbutaline as needed in adults with mild to moderate asthma, for whom low-dose inhaled corticosteroids or as-needed inhaled corticosteroids–formoterol are, as of 2019, recommended.16 The 31% reduction in severe exacerbation risk was achieved despite participants using about

Data sharing

De-identified individual participant data collected during the PRACTICAL trial will be shared at 2 years after article publication with no end date. These data will be available to researchers who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal. Proposals should be directed to Prof Richard Beasley via email ([email protected]) and will be reviewed by the PRACTICAL study management committee. Requests to access data to

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    *

    Joint first authors

    PRACTICAL study investigators are listed in the appendix p 6

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