As-needed Budesonide-formoterol Research Articles

Cost-effectiveness of budesonide-formoterol vs inhaled epinephrine in US adults with mild asthma

BackgroundThe management of mild asthma has lacked an over-the-counter (OTC) option aside from inhaled epinephrine, which is available in the United States. However, inhaled epinephrine use without an inhaled corticosteroid may increase the risk of asthma death. ObjectiveTo compare the cost-effectiveness of OTC as-needed budesonide-formoterol as a plausible alternative to inhaled epinephrine. MethodsWe developed a probabilistic Markov model to compare OTC as-needed budesonide-formoterol inhaler use vs inhaled epinephrine use in adults with mild asthma from a US societal perspective over a lifetime horizon, with a 3% annual discount rate (2022 US dollars). Inputs were derived from the SYmbicort Given as-needed in Mild Asthma (SYGMA) trials, published literature, and commercial costs. Outcomes were quality-adjusted life-years (QALY), costs, incremental net monetary benefit (INMB), severe asthma exacerbations, well-controlled asthma days, and asthma-related deaths. Microsimulation was used to evaluate underinsured Americans living with mild asthma (n = 5,250,000). ResultsInhaled epinephrine was dominated (with lower QALYs gains at a higher cost) by both as-needed budesonide-formoterol (INMB, $15,541 at a willingness-to-pay of $100,000 per QALY) and the no-OTC inhaler option (INMB, $1023). Adults using as-needed budesonide-formoterol had 145 more well-controlled asthma days, 2.79 fewer severe exacerbations, and an absolute risk reduction of 0.23% for asthma-related death compared with inhaled epinephrine over a patient lifetime. As-needed budesonide-formoterol remained dominant in all sensitivity and scenario analyses, with a 100% probability of being cost-effective compared with inhaled epinephrine in probabilistic sensitivity analysis. ConclusionIf made available, OTC as-needed budesonide-formoterol for treating mild asthma in underinsured adults without HCP management improves asthma outcomes, prevents fatalities, and is cost-saving.

Cost-effectiveness of as-needed budesonide-formoterol versus over-the-counter as-needed inhaled epinephrine in adults with mild asthma in the US

Inhaled epinephrine is the only current over-the-counter (OTC) option for the management of mild asthma in the United States (US). Given concerns of beta2-agonist overuse, and evidence-based guidelines recommending as-needed inhaled corticosteroid-formoterol as first-line reliever therapy, we examined the cost-effectiveness of OTC as-needed budesonide-formoterol compared to as-needed inhaled epinephrine and a no OTC inhaler option.

Efficacy and Safety of As-Needed Budesonide-Formoterol in Adolescents With Mild Asthma

Efficacy and Safety of As-Needed Budesonide-Formoterol in Adolescents With Mild Asthma

A Pilot Randomized Trial of As-Needed Budesonide-Formoterol for Stepping Down Controller Treatment in Moderate Asthma with Complete Remission.

BackgroundThe use of low-dose inhaled corticosteroid-formoterol as reliever monotherapy has recently been recommended in the asthma treatment guidelines. However, the efficacy of this treatment strategy has not yet been determined during the stepping-down period in moderate asthma. This study aimed to evaluate the feasibility of reducing treatment to as-needed budesonide-formoterol (BFM) in moderate asthma with complete remission.MethodsWe randomly assigned 31 patients (8 males and 23 females with a mean age of 57.2 years) with complete remission of asthma by inhaled BFM (160/4.5 μg) twice daily to receive BFM (160/4.5 μg) as needed (16 patients), or budesonide (BUD) (200 μg) twice daily (15 patients). The study was an open-label study done for 48 weeks, with the primary outcome as the cumulative percentages of patients with treatment failure (asthma exacerbation or loss of asthma control or lack of satisfaction after using medications) in the two groups.ResultsSix patients (42%) using as-needed BFM had treatment failure, as compared with three patients (21.4%) using BUD maintenance (hazards ratio for as-needed BFM, 1.77; 95% confidential interval, 0.44–7.12; p=0.41). The changes in forced expiratory volume in 1 second were −211.3 mL with as-needed BFM versus −97.8 mL with BUD maintenance (difference, 113.5 mL; p=0.75) and the change in fractional exhaled nitric oxide was significantly higher in both groups, at 8.68 parts per billion (ppb) in the as-needed BFM group and 2.5 ppb. in the BUD maintenance group (difference, 6.18 ppb; p=0.049).ConclusionCompared with BUD maintenance, there were no significant differences in treatment failure rate in patients who received as-needed BFM during the stepping down period in moderate asthma. However, they showed reduced lung function and relapsed airway inflammation. The results are limited by imprecision, and further large RCTs are needed.

Perspectives of mild asthma patients on maintenance versus as-needed preventer treatment regimens: a qualitative study

ObjectivesAs-needed low-dose combination budesonide-formoterol is recommended by asthma guidelines in many countries as an alternative to maintenance inhaled corticosteroids (ICS) for treatment of mild asthma, but there are few data...

Cost-utility of as-needed ICS-formoterol versus to maintenance ICS in mild to moderate persistent asthma

BackgroundRecent asthma guidelines, such as the Global Initiative for Asthma (GINA), recommend in adult patients as-needed inhaled corticosteroids (ICS)-formoterol as an alternative to maintenance ICS in mild to moderate persistent asthma. The introduction of these recommendations concerns whether using as-needed budesonide-formoterol would be more cost-effective than to maintenance ICS. This study aimed to evaluate the cost-effectiveness of as-needed combination low-dose budesonide-formoterol compared to short-acting β2-agonist (SABA) reliever therapy in patients with mild asthma.MethodsA probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with mild asthma in Colombia. Total costs and QALYs of low-dose budesonide-formoterol compared to short-acting β2-agonist (SABA) were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000.ResultsThe model suggests a potential gain of 0.37 QALYs and per patient per year on as-needed ICS-formoterol and a reduction in the discounted cost per person-year, of as-needed ICS-formoterol to maintenance ICS, of US$40. This position of dominance of as-needed ICS-formoterol negates the need to calculate an incremental cost-effectiveness ratio. In the deterministic and probabilistic sensitivity analysis, our base‐case results were robust to variations in all assumptions and parameters.ConclusionLow-dose budesonide-formoterol as a reliever was cost-effective when added to usual care in patients with mild asthma. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.

The cost-effectiveness of as-needed budesonide-formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in Canada

BackgroundThe Global Initiative for Asthma recommends the use of as-needed low-dose inhaled corticosteroid (ICS)-formoterol as a preferred controller therapy for patients with mild asthma. These recommendations were based, in part, on evidence from the SYGMA 1 and 2 studies of as-needed budesonide-formoterol. This analysis aimed to compare the cost-effectiveness of as-needed budesonide-formoterol to low-dose maintenance ICS plus as-needed short-acting β2-agonist (SABA) in patients with mild asthma.MethodsA Markov cohort model was designed that included three possible health states (non-exacerbation, severe exacerbation, and death) to compare as-needed budesonide-formoterol 200–6 μg to twice-daily budesonide 200 μg maintenance therapy (low-dose ICS) plus as-needed terbutaline 0.5 mg (SABA). The deterministic base-case analysis used severe exacerbation, adverse event (AE), and healthcare resource use data from SYGMA 2, and was conducted from a Canadian public payer perspective with a 50-year time horizon, and a discount rate of 1.5% per annum. Moderate exacerbation was modelled on data from SYGMA 1 in sensitivity analyses. Utility values were derived from SYGMA 2 quality of life data. All-cause- and asthma-related mortality rates and costs (reported in 2019 Canadian dollars) were based on published data, using Canada-specific values where available. One-way deterministic sensitivity, probabilistic sensitivity, and eight scenario analyses were conducted to examine the robustness of the results.ResultsAs-needed budesonide-formoterol was the dominant treatment option in the base-case analysis, providing incremental cost savings of $9882 per patient and quality-adjusted life year (QALY) gains of 0.002 versus low-dose maintenance ICS plus as-needed SABA over a 50-year time horizon. Using a willingness-to-pay threshold of $50,000/QALY ($100,000/QALY), as-needed budesonide-formoterol had a 94% (95%) probability of being cost-effective compared with maintenance ICS plus as-needed SABA. Cost-saving was mostly driven by lower overall medication and AE-related costs. As-needed budesonide-formoterol remained the dominant treatment in sensitivity and scenario analyses.ConclusionsAs-needed budesonide-formoterol is a cost-saving option for the treatment of mild asthma from the perspective of the Canadian public payer compared with low-dose maintenance ICS plus as-needed SABA.

A patient decision aid for mild asthma: Navigating a new asthma treatment paradigm

IntroductionIn mild asthma, as-needed budesonide-formoterol offers similar protection from severe exacerbations as daily inhaled corticosteroids (ICS), with lower ICS exposure but slightly increased symptoms. We sought to develop an electronic decision aid to guide discussions about the pros and cons of these first-line options, while identifying and integrating user preferences. MethodsFollowing International Patient Decision Aid Standards, we created a mild asthma decision aid prototype comparing convenience, clinical outcomes, cumulative ICS dose exposure, costs, and side-effects of each option. After face validation, the prototype was iteratively adapted through rapid-cycle development. Each cycle consisted of a patient focus group and a primary care physician interview. We made user preference-based improvements after each round, until reaching a pre-set stopping criterion (no new critical issues identified). We then performed a summative qualitative content analysis. ResultsOver 5 cycles, we recruited 21 asthma patients (12/21 women, 10/21 ≥ 60 years old) and 5 physicians. Serial changes included simplification and reduction of text and reading level, inclusion of an ICS “myths” section and elaboration of patient-friendly infographics for numerical comparisons. User preferences fell within Content, Format, and tool use Process themes. In response to decision-making preferences, we created a complementary one-page conversation aid for patient-provider use at the point-of-care. ConclusionsWe present preference-based electronic patient decision and conversation aids for treatment of mild asthma. Our user preference analyses offer useful insights for development of such tools in other chronic diseases. These tools now require integration into point-of-care workflows for measurement of real-world uptake and impact.

The Children's Anti-inflammatory Reliever (CARE) study: a protocol for a randomised controlled trial of budesonide-formoterol as sole reliever therapy in children with mild asthma.

BackgroundAsthma is the most common chronic disease in children, many of whom are managed solely with a short-acting β2-agonist (SABA). In adults, the evidence that budesonide-formoterol as sole reliever therapy markedly reduces the risk of severe exacerbations compared with SABA alone has contributed to the Global Initiative for Asthma recommending against SABA monotherapy in this population. The current lack of evidence in children means it is unknown whether these findings are also relevant to this demographic. High-quality randomised controlled trials (RCTs) are needed.ObjectiveThe aim of this study is to determine the efficacy and safety of as-needed budesonide-formoterol therapy compared with as-needed salbutamol in children aged 5 to 15 years with mild asthma, who only use a SABA.MethodsA 52-week, open-label, parallel group, phase III RCT will recruit 380 children aged 5 to 15 years with mild asthma. Participants will be randomised 1:1 to either budesonide-formoterol (Symbicort Rapihaler®) 50/3 µg, two actuations as needed, or salbutamol (Ventolin®) 100 µg, two actuations as needed. The primary outcome is asthma attacks as rate per participant per year. Secondary outcomes assess asthma control, lung function, exhaled nitric oxide and treatment step change. A cost-effectiveness analysis is also planned.ConclusionThis is the first RCT to assess the safety and efficacy of as-needed budesonide-formoterol in children with mild asthma. The results will provide a much-needed evidence base for the treatment of mild asthma in children.

Positioning As-needed Budesonide-Formoterol for Mild Asthma: Effect of Prestudy Treatment in Pooled Analysis of SYGMA 1 and 2.

Rationale: The SYGMA (Symbicort Given as Needed in Mild Asthma) studies evaluated the efficacy and safety of as-needed budesonide (BUD)–formoterol (FORM) in patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators (subgroup 1) or controlled on inhaled corticosteroids (ICS) or leukotriene receptor antagonists (subgroup 2).Objectives: To assess the influence of prestudy treatment in a post hoc analysis of the SYGMA studies.Methods: In the SYGMA 1 (NCT022149199) and SYGMA 2 (NCT02224157) 52-week, double-blind, randomized, parallel-group studies, 6,735 patients with mild asthma were randomized to as-needed BUD–FORM, low-dose BUD + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only). Exacerbation rates and changes in symptom control and lung function were compared among treatments for both subgroups.Results: In a pooled analysis of SYGMA 1 and 2, the annual severe exacerbation rate in subgroup 1 was significantly lower with as-needed BUD–FORM (0.08 [95% confidence interval (CI), 0.06–0.10]) than with BUD maintenance (0.10 [95% CI, 0.09–0.13]) (rate ratio [RR], 0.74 [95% CI, 0.56–0.98]; P = 0.03), and similar results were shown in subgroup 2 with BUD–FORM (0.12 [95% CI, 0.10–0.14]) and BUD maintenance (0.10 [95% CI, 0.09–0.13]) (RR, 1.10 [95% CI, 0.86–1.41]; P = 0.44). In SYGMA 1, the annual severe exacerbation rate in both subgroups was significantly lower with as-needed BUD–FORM than with as-needed terbutaline (subgroup 1: RR, 0.34 [95% CI, 0.20–0.58]; P < 0.001; subgroup 2: RR, 0.37 [95% CI, 0.25–0.54]; P < 0.001). The number needed to treat to prevent one severe exacerbation with as-needed BUD–FORM and BUD maintenance versus as-needed terbutaline were 20 and 34 in subgroup 1 and 13 and 12 in subgroup 2, respectively.Conclusions: These findings suggest that, for patients with mild asthma currently receiving short-acting β2-agonists alone, as-needed low-dose ICS–FORM should be preferred over maintenance ICS as initial controller treatment. For patients whose asthma is controlled on maintenance low-dose ICS, as-needed BUD–FORM is an alternative to maintenance ICS without the need for daily treatment, and both of these options are safer than switching to short-acting β2-agonist–only treatment.

Efficacy and Safety of As-Needed Budesonide-Formoterol in Adolescents with Mild Asthma

Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide. This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents. SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years orolder with mild asthma. Patients were randomized to twice-daily placebo+ as-needed BUD-FORM 200/6 μg, twice-daily BUD 200 μg+ as-needed terbutaline (BUD maintenance), or twice-daily placebo+ as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years). Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P= .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P= .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P= .500). No new or unexpected safety concerns were identified. In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.

Safety of As-Needed Budesonide-Formoterol in Mild Asthma: Data from the Two Phase III SYGMA Studies.

IntroductionBudesonide-formoterol taken as needed is an emerging treatment for mild asthma.ObjectiveWe used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide.MethodsSYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 μg, twice-daily budesonide 200 μg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone.ResultsThe pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%).ConclusionsBudesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified.ClinicalTrial.gov IdentifiersNCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-020-01041-z.

ICS-formoterol reliever versus ICS and short-acting β2-agonist reliever in asthma: a systematic review and meta-analysis.

BackgroundThe Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting β2-agonist (SABA) reliever at step 2 of its stepwise treatment algorithm. Our aim was to assess the efficacy and safety of these two treatment regimens, with a focus on prevention of severe exacerbation.MethodsWe performed a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing as-needed ICS-formoterol with maintenance ICS plus SABA. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov were searched from database inception to 12 December 2019. The primary outcome was time to first severe exacerbation. RCTs were excluded if they used as-needed budesonide-formoterol as part of a maintenance and reliever regimen, or did not report on severe exacerbations. The review is registered with PROSPERO (identifier number CRD42020154680).ResultsFour RCTs (n=8065 participants) were included in the analysis. As-needed ICS-formoterol was associated with a prolonged time to first severe exacerbation (hazard ratio 0.85, 95% CI 0.73–1.00; p=0.048) and reduced daily ICS dose (mean difference −177.3 μg, 95% CI −182.2–−172.4 μg). Asthma symptom control was worse in the as-needed group (Asthma Control Questionnaire-5 mean difference 0.12, 95% CI 0.09–0.14), although this did not meet the minimal clinically important difference of 0.50 units. There was no significant difference in serious adverse events (OR 1.07, 95% CI 0.84–1.36).ConclusionAs-needed ICS-formoterol offers a therapeutic alternative to maintenance low-dose ICS plus SABA in asthma and may be the preferred option when prevention of severe exacerbation is the primary aim of treatment.

Patient experiences of as-needed budesonide-formoterol by Turbuhaler® for treatment of mild asthma; a qualitative study

BackgroundCombination low-dose budesonide-formoterol, taken as-needed for symptom relief reduces exacerbation risk and is recommended for treatment of mild asthma. The NovelQ qualitative study explored patients’ attitudes toward using this novel therapy. MethodsAdults with mild asthma using reliever-only treatment were randomised to as-needed budesonide-formoterol Turbuhaler® in a multinational, 52-week open-label randomised controlled trial (NovelSTART-ACTRN12615000999538). A subgroup were interviewed to explore their attitudes to use of as-needed budesonide-formoterol after receiving it for ≥10 months. Semi-structured interviews were conducted until saturation, audio-recorded, and thematically analysed. ResultsAnalysis of 35 participants (66% female; mean age 43.5 [range 18–74]; mean Asthma Control Questionnaire score 1.09 ± SD0.55) interviews identified 5 themes, each including both barriers and facilitators to therapy use. Themes were: ‘Treatment effectiveness’ i.e. how well symptoms were relieved and/or prevented; ‘Lifestyle fit of the regimen’ e.g. the extent to which the treatment regimen integrated into the patient's daily life; ‘Attitudes toward medication use and safety’ e.g. openness for new reliever treatments, beliefs about treatment necessity or side effects; ‘Device attributes’ e.g. perceived ease of use; and ‘Doctor-patient relationship’ e.g. impact of health professional support on new treatment acceptance. ConclusionsA wide range of factors seem to drive the opinions of mild asthma patients on as-needed budesonide-formoterol therapy. Many patients perceived both positive and negative treatment attributes, and their individual evaluation of these attributes determined their likelihood of using it after the study. Supportive patient-physician interactions appear key to addressing patient barriers. Recommendations for patient-centred discussions, developed from this research, are provided.

2019 Year in Review: Aerosol Therapy.

Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with Mycobacterium avium complex pulmonary disease. During 2019, lung injury associated to e-cigarette or vaping was reported, including 60 casualties.

Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial

Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only β agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 μg in a pressurised metered dose inhaler), maintenance budesonide (200 μg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 μg), or as-needed budesonide-formoterol (one inhalation of 200 μg budesonide and 6μg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with <0·15 × 109/L, six [6%] of 93 with 0·15 to <0·3 × 109/L, and 15 [19%] of 77 with ≥0·3 × 109/L; p=0·014). There were no significant interactions between blood eosinophil count or FeNO level and the effect of as-needed budesonide-formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil count subgroups and the effect of maintenance budesonide plus as-needed salbutamol compared with as-needed salbutamol, both for exacerbations (p=0·0006) and severe exacerbations (p=0·0007). Maintenance budesonide plus as-needed salbutamol was more effective than as-needed salbutamol in patients with blood eosinophil counts of 0·3 × 109/L or more, both for exacerbations (rate ratio 0·13 [95% CI 0·05-0·33]) and severe exacerbations (risk odds ratio 0·11 [0·03-0·45]). This difference was not seen for blood eosinophil counts of less than 0·15 × 109/L (1·15 [0·51-1·28] for exacerbations and 5·72 [0·97-33·60] for severe exacerbations). There was no consistent interaction between treatment response and FeNO or the composite score. In patients with mild asthma, the effects of as-needed budesonide-formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. AstraZeneca, Health Research Council of New Zealand.

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

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. 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. 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. 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. Health Research Council of New Zealand.

Lessons learned from clinical trials of asthma.

Exacerbations of persistent or intermittent asthma should be anticipated by physicians and health-care professionals. Patients who are likely to experience an exacerbation often have a history of an exacerbation in the previous year, and the absolute eosinophil count in peripheral blood is ≥ 400/μL. Similarly, expectorated or induced sputum eosinophilia of ≥2% is associated with exacerbations. These phenotypic findings have led to effective biologic therapies, which target eosinophils or immunoglobulin E or the T-helper type 2 phenotype, especially in children, adolescents, and adults with frequent exacerbations. In children, a reduced forced expiratory volume in the first second of expiration (FEV1) to forced vital capacity ratio can be associated with future exacerbations, although the FEV1 may be in the normal range, even with children who have persistent severe asthma. Asthma control questionnaires did not differentiate between children with or children without a future exacerbation. Alternatively, in adults, the lower baseline FEV1 (2.3 L [74% predicted] versus 2.5 L [78% predicted]) identified patients more likely to have a future exacerbation compared with patients who were not having an exacerbation. After correcting for FEV1, the asthma control questionnaire data were associated with exacerbations. In adolescents (ages ≥ 12 years) and adults with persistent mild asthma, most (73%) did not have sputum eosinophilia, and some of these patients responded well to the anticholinergic, tiotropium, which would argue differently from administration of an inhaled corticosteroid as first-line controller therapy. In a three-track study of patients with persistent mild asthma, as-needed budesonide-formoterol and scheduled budesonide were associated with approximately one-half of the annual exacerbation rate of as-needed albuterol. In patients with persistent moderate-to-severe asthma, tiotropium added to controller therapy caused an increase in FEV1 without improving the asthma control questionnaire findings. There were two studies that explored whether either quadrupling or quintupling the inhaled corticosteroid at the first sign of loss of control of asthma would provide meaningful reductions of severe exacerbations of asthma, but the findings did not support this strategy. Both biologic therapies and environmental control (dust mite impermeable encasings) have resulted in reductions of exacerbations in patients with persistent moderate and severe asthma.

Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study

The contributions of as-needed inhaled corticosteroids and long-acting beta2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting beta2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy. We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 microg and 4.5 microg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications-terbutaline (0.4 mg), formoterol (4.5 microg), or budesonide-formoterol (160 microg and 4.5 microg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more. Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0.0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0.0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0.67 [95% CI 0.56-0.80; p<0.0001]; budesonide-formoterol versus terbutaline 0.52 [0.44-0.62; p<0.0001]; formoterol versus terbutaline 0.78 [0.67-0.91; p=0.0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated. Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.