The carbon footprint of as-needed budesonide-formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma (GINA). METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with: as-needed budesonide-formoterol DPI, as-needed salbutamol pMDI, or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e), per person year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide-formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide-formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.

START CARE: a protocol for a randomised controlled trial of step-wise budesonide-formoterol reliever-based treatment in children.

Background: Asthma is the most common chronic childhood respiratory condition globally. Inhaled corticosteroid (ICS)-formoterol reliever-based regimens reduce the risk of asthma exacerbations compared with conventional short-acting ß2-agonist (SABA) reliever-based regimens in adults and adolescents. The current limited evidence for anti-inflammatory reliever therapy in children means it is unknown whether these findings are also applicable to children. High-quality randomised controlled trials (RCTs) are needed. Objective: The study aim is to determine the efficacy and safety of budesonide-formoterol reliever alone or maintenance and reliever therapy (MART) compared with standard therapy: budesonide or budesonide-formoterol maintenance, both with terbutaline reliever, in children aged 5 to 11 years with mild, moderate and severe asthma. Methods: A 52-week, multicentre, open-label, parallel group, phase III, two-sided superiority RCT will recruit 400 children aged 5 to 11 years with asthma. Participants will be randomised 1:1 to either budesonide-formoterol 100/6 µg Turbuhaler reliever alone or MART; or budesonide or budesonide-formoterol Turbuhaler maintenance, with terbutaline Turbuhaler reliever. The primary outcome is moderate and severe asthma exacerbations as rate per participant per year. Secondary outcomes are asthma control, lung function, exhaled nitric oxide and treatment step change. Assessment of Turbuhaler technique and cost-effectiveness analysis are also planned. Conclusion: This will be the first RCT to compare the efficacy and safety of a step-wise budesonide-formoterol reliever alone or MART regimen with conventional inhaled ICS or ICS-long-acting ß-agonist maintenance plus SABA reliever in children. The results will provide a much-needed evidence base for the treatment of asthma in children.

The Anti-Inflammatory Reliever (AIR) Algorithm Study: a protocol for a single-group study of an AIR stepwise approach to the treatment of adult asthma.

Background: The stepwise approach to long-term asthma management, which traditionally incorporates short-acting ß2-agonist reliever therapy, has been a core feature of asthma guidelines for over 30 years. There have been no studies, however, directly investigating the use of an entire guideline-recommended track. Recently, inhaled corticosteroid-formoterol has been recommended as the preferred reliever therapy in adult asthma, in accordance with a stepwise "Anti-Inflammatory Reliever" (AIR) treatment track. Objective: The aim of this study was to evaluate the AIR stepwise approach recommended by the New Zealand adolescent and adult asthma guidelines, in combination with a novel algorithm for transitioning between treatment steps. Methods: This 52-week, open-label, single-group study will recruit 100 adults aged 18 to 75 years with mild, moderate and moderate-severe asthma (ACTRN12620001010987). Participants will be allocated to budesonide-formoterol 200/6 µg, one actuation as needed (Step 1), one actuation twice daily and as needed (Step 2), or two actuations twice daily and one as needed (Step 3). Treatment steps will be adjusted throughout the study, in response to reliever use and asthma attacks, according to a stepwise AIR algorithm. Following a 26-week period of investigator-led transitions, participants will adjust their own treatment step. The primary outcome is participant satisfaction as measured by the Global Satisfaction score of the Treatment Satisfaction Questionnaire for Medication. Secondary outcomes will assess efficacy and safety, and describe patterns of medication use and participant flow through the treatment steps. Conclusion: This is the first trial to assess the AIR treatment track and algorithm. The results will provide knowledge to guide the clinical use of this approach.

Asthma control with ICS-formoterol reliever versus maintenance ICS and SABA reliever therapy: a post hoc analysis of two randomised controlled trials.

BACKGROUND: In randomised controlled trials, as-needed inhaled corticosteroid (ICS)-formoterol reliever therapy reduces severe exacerbation risk compared with maintenance ICS plus short-acting beta2-agonist (SABA) reliever in adolescent and adult asthma, but results in slightly worse control of asthma symptoms, as measured by mean Asthma Control Questionnaire-5 (ACQ-5) score. OBJECTIVE: To assess the levels and changes in asthma control for as-needed budesonide-formoterol versus maintenance budesonide plus SABA in post hoc analyses from the Novel START and PRACTICAL clinical trials. METHODS: The number and proportion of participants at study end in each ACQ-5 category ('well-controlled', 'partly controlled' or 'inadequately controlled' symptoms), and in each responder category based on the minimal clinically important difference for ACQ-5 of 0.5 (improved, no change and worse) with as-needed budesonide-formoterol and maintenance budesonide plus SABA treatment were calculated. RESULTS: With last observation carried forwards, 189/214 (88.3%) and 354/434 (81.6%) of patients in the budesonide-formoterol group had 'well-controlled' or 'partly controlled' symptoms at the end of the study, vs 183/214 (85.5%) and 358/431 (83.1%) in the budesonide maintenance group, for Novel START and PRACTICAL, respectively. The proportion of patients whose symptom control was either improved or unchanged from baseline was 190/214 (88.8%) and 368/434 (84.8%) for budesonide-formoterol, vs 185/214 (86.4%) and 376/431 (87.2%) for maintenance budesonide, in Novel START and PRACTICAL respectively. CONCLUSIONS: There were no clinically important differences in the proportions of patients with 'well-controlled' or 'partly controlled' asthma symptoms, or proportions who improved or maintained their level of control, with as-needed budesonide-formoterol versus maintenance budesonide plus SABA.

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

OBJECTIVES: As-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 on patient attitudes toward these regimens. This study explored the comparative implementation experiences and future treatment preferences of mild asthma patients who had experienced these two treatment regimens. SETTING: A subgroup of adults randomised to maintenance ICS or as-needed ICS-formoterol in a multinational, 52-week open-label randomised controlled trial (NovelSTART) in mild asthma patients were interviewed to explore their motivations for treatment use during the study and their preferences for future treatment. PARTICIPANTS: Semistructured interviews were conducted with 74 participants (Maintenance group: n=39, As-needed group n=35, mean age 38 (range 19-69)) and thematically analysed from transcribed audiorecordings. RESULTS: Emergent themes from analysis comprised: 'How much my asthma affects me' (how their asthma's impact affected their self-management motivation); 'What I know about asthma' (limited knowledge impeded appropriate self-management decision making); 'How much effort this treatment regimen involves for me' (treatment complexity and/or difficulty establishing a medication routine impeded implementation, particularly in the Maintenance group); and 'My beliefs about the benefits and risks of this treatment' (patients who considered their treatment as ineffective, eg, limited difference in symptoms relative to salbutamol (both groups) or slower onset of relief (As-needed group) had poor motivation to use the treatment). Due to the simplicity of the as-needed combination strategy, this was the preferred future regimen, even by patients who had not yet tried it. CONCLUSIONS: Key patient perspectives on the implementation of preventer treatments for mild asthma included factors relating to perceived asthma burden, disease knowledge, treatment complexity and treatment usefulness or safety. The as-needed budesonide-formoterol regimen was preferred to maintenance ICS treatment in mild asthma though patient education is urgently needed to address implementation motivation. TRIAL REGISTRATION NUMBER: ACTRN12615000999538.

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.

BACKGROUND: Asthma is the most common chronic disease in children, many of whom are managed solely with a short-acting ß2-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. OBJECTIVE: The 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. METHODS: A 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. CONCLUSION: This 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.

ICS-formoterol reliever versus ICS and short-acting ß2-agonist reliever in asthma: a systematic review and meta-analysis.

BACKGROUND: The Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting ß2-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. METHODS: We 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). RESULTS: Four 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). CONCLUSION: As-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.

How big is your bubble? Characteristics of self-isolating household units ('bubbles') during the COVID-19 Alert Level 4 period in New Zealand: a cross-sectional survey.

OBJECTIVE: To characterise the self-isolating household units (bubbles) during the COVID-19 Alert Level 4 lockdown in New Zealand. DESIGN, SETTING AND PARTICIPANTS: In this cross-sectional study, an online survey was distributed to a convenience sample via Facebook advertising and the Medical Research Institute of New Zealand's social media platforms and mailing list. Respondents were able to share a link to the survey via their own social media platforms and by email. Results were collected over 6 days during Alert Level 4 from respondents living in New Zealand, aged 16 years and over. MAIN OUTCOMES MEASURES: The primary outcome was the mean size of a self-isolating household unit or bubble. Secondary outcomes included the mean number of households in each bubble, the proportion of bubbles containing essential workers and/or vulnerable people, and the mean number of times the home was left each week. RESULTS: 14 876 surveys were included in the analysis. The mean (SD) bubble size was 3.58 (4.63) people, with mean (SD) number of households 1.26 (0.77). The proportion of bubbles containing one or more essential workers, or one or more vulnerable persons was 45.3% and 42.1%, respectively. The mean number of times individual bubble members left their home in the previous week was 12.9 (12.4). Bubbles that contained at least one vulnerable individual had fewer outings over the previous week compared with bubbles that did not contain a vulnerable person. The bubble sizes were similar by respondent ethnicity. CONCLUSION: In this New Zealand convenience sample, bubble sizes were small, mostly limited to one household, and a high proportion contained essential workers and/or vulnerable people. Understanding these characteristics from a country which achieved a low COVID-19 infection rate may help inform public health interventions during this and future pandemics.

Combination budesonide/formoterol inhaler as sole reliever therapy in Maori and Pacific people with mild and moderate asthma.

AIM: In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Maori and Pacific peoples, populations with worse asthma outcomes. METHOD: The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. RESULTS: Seventy-two participants (8%) identified as Maori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70). CONCLUSION: The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Maori and Pacific adults compared with New Zealand European/Other.

What matters most to patients when choosing treatment for mild-moderate asthma? Results from a discrete choice experiment.

BACKGROUND: An as-needed combination preventer and reliever regimen was recently introduced as an alternative to conventional daily preventer treatment for mild asthma. In a subgroup analysis of the PRACTICAL study, a pragmatic randomised controlled trial of budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild asthma, we recently reported that about two-thirds preferred as-needed combination preventer and reliever therapy. The aim of this study was to determine the relative importance of attributes associated with these two asthma therapies in this subgroup of participants who indicated their preferred treatment in the PRACTICAL study. METHODS: At their final study visit, a subgroup of participants indicated their preferred treatment and completed a discrete choice experiment using the Potentially All Pairwise RanKings of all possible Alternatives method and 1000minds software. Treatment attributes and their levels were selected from measurable study outcomes, and included: treatment regimen, shortness of breath, steroid dose and likelihood of asthma flare-up. RESULTS: The final analysis dataset included 288 participants, 64% of whom preferred as-needed combination preventer and reliever. Of the attributes, no shortness of breath and lowest risk of asthma flare-up were ranked highest and second highest, respectively. However, the relative importance of the other two attributes varied by preferred therapy: treatment regimen was ranked higher by participants who preferred as-needed treatment than by participants who preferred maintenance treatment. CONCLUSIONS: Knowledge of patient preferences for treatment attributes together with regimen characteristics can be used in shared decision-making regarding choice of treatment for patients with mild-moderate asthma. TRIAL REGISTRATION NUMBER: ACTRN12616000377437.

Self-titration of inhaled corticosteroid and ß2-agonist in response to symptoms in mild asthma: a pre-specified analysis from the PRACTICAL randomised controlled trial.

INTRODUCTION: In mild asthma, as-needed budesonide-formoterol is superior or noninferior to maintenance budesonide plus as-needed short-acting ß2-agonist in reducing severe exacerbations. In this pre-specified analysis, we investigated patterns of inhaled corticosteroid (ICS) and ß2-agonist use in PRACTICAL, a randomised controlled trial. METHODS: Participants were randomised 1:1 to as-needed budesonide-formoterol (200/6 µg Turbuhaler, one actuation) or maintenance budesonide (200 µg Turbuhaler, one actuation twice a day) with as-needed terbutaline (250 µg, two actuations) for 52 weeks. 110 participants had electronic monitors attached to their study inhalers which captured the time and date of every actuation. Key outcome measures were patterns of ICS and ß2-agonist use. One actuation of budesonide-formoterol was considered to be an equivalent bronchodilator dose as two actuations of terbutaline. RESULTS: Participants randomised to as-needed budesonide-formoterol had more days with no ICS use compared with maintenance budesonide (median total days of no use 156 versus 22 days, respectively), lower median daily budesonide dose (164 versus 328 µg, respectively) and a greater median number of days of ≥4 budesonide actuations (4 versus 1 days, respectively). Participants randomised to as-needed budesonide-formoterol took higher equivalent doses of ß2-agonist both overall (median number of actuations 0.8 versus 0.3 per day, respectively) and in response to worsening asthma (total number of "overuse days" of >8 or >16 actuations of budesonide-formoterol or terbutaline 33 versus 10 days, respectively). CONCLUSIONS: The timing of ICS dose when self-titrated to ß2-agonist use is more important than total ICS dose in reducing severe exacerbation risk in mild asthma, when associated with greater overall use of as-needed ß2-agonist.

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.

BACKGROUND: 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. METHODS: In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only ß 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: AstraZeneca, Health Research Council of New Zealand.

Patient preferences for symptom-driven or regular preventer treatment in mild to moderate asthma: findings from the PRACTICAL study, a randomised clinical trial.

Symptom-driven low-dose inhaled corticosteroid-formoterol is safe and effective in mild asthma and has been recommended as one of the preferred treatment regimens at steps 1 and 2 in the 2019 update of the Global Initiative for Asthma. However, there are no data on patient preferences for this regimen.A subgroup of participants in the PRACTICAL study (ACTRN12616000377437), a randomised controlled trial comparing symptom-driven budesonide-formoterol with maintenance budesonide plus as-needed terbutaline completed a survey on treatment preferences, satisfaction, beliefs and experience at their final study visit.306 (75%) out of 407 eligible participants completed the survey. Regimen preference was strongly associated with randomised treatment, as were preferences for and beliefs about preventer inhaler use. Combination preventer and reliever as-needed therapy was preferred by 135 (90%, 95% CI 85.2-94.8%) out of 150 who were randomised to as-needed budesonide-formoterol, and by 63 (40%, 95% CI 32.7-48.1%) out of 156 who were randomised to maintenance budesonide. By contrast, twice-daily preventer inhaler with a reliever inhaler as required was preferred by 15 (10%) out of 150 of those randomised to as-needed budesonide-formoterol and 93 (60%) out of 156 of those randomised to maintenance budesonide. Satisfaction with all study inhalers was high. Of patients randomised to as-needed budesonide-formoterol 92% (n=138) were confident using it as a reliever at the end of the study.Although most participants preferred the regimen to which they had been randomised, this association was much stronger for those randomised to budesonide-formoterol as needed, indicating that most patients preferred as-needed corticosteroid-formoterol therapy if they had experienced it.

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.

BACKGROUND: In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting ß-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting ß-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.

Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma.

BACKGROUND: In double-blind, placebo-controlled trials, budesonide-formoterol used on an as-needed basis resulted in a lower risk of severe exacerbation of asthma than as-needed use of a short-acting ß2-agonist (SABA); the risk was similar to that of budesonide maintenance therapy plus as-needed SABA. The availability of data from clinical trials designed to better reflect clinical practice would be beneficial. METHODS: We conducted a 52-week, randomized, open-label, parallel-group, controlled trial involving adults with mild asthma. Patients were randomly assigned to one of three treatment groups: albuterol (100 µg, two inhalations from a pressurized metered-dose inhaler as needed for asthma symptoms) (albuterol group); budesonide (200 µg, one inhalation through a Turbuhaler twice daily) plus as-needed albuterol (budesonide maintenance group); or budesonide-formoterol (200 µg of budesonide and 6 µg of formoterol, one inhalation through a Turbuhaler as needed) (budesonide-formoterol group). Electronic monitoring of inhalers was used to measure medication use. The primary outcome was the annualized rate of asthma exacerbations. RESULTS: The analysis included 668 of 675 patients who underwent randomization. The annualized exacerbation rate in the budesonide-formoterol group was lower than that in the albuterol group (absolute rate, 0.195 vs. 0.400; relative rate, 0.49; 95% confidence interval [CI], 0.33 to 0.72; P<0.001) and did not differ significantly from the rate in the budesonide maintenance group (absolute rate, 0.195 in the budesonide-formoterol group vs. 0.175 in the budesonide maintenance group; relative rate, 1.12; 95% CI, 0.70 to 1.79; P = 0.65). The number of severe exacerbations was lower in the budesonide-formoterol group than in both the albuterol group (9 vs. 23; relative risk, 0.40; 95% CI, 0.18 to 0.86) and the budesonide maintenance group (9 vs. 21; relative risk, 0.44; 95% CI, 0.20 to 0.96). The mean (±SD) dose of inhaled budesonide was 107±109 µg per day in the budesonide-formoterol group and 222±113 µg per day in the budesonide maintenance group. The incidence and type of adverse events reported were consistent with those in previous trials and with reports in clinical use. CONCLUSIONS: In an open-label trial involving adults with mild asthma, budesonide-formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations. (Funded by AstraZeneca and the Health Research Council of New Zealand; Novel START Australian New Zealand Clinical Trials Registry number, ACTRN12615000999538.).

Description of the protocol for the PRACTICAL study: a randomised controlled trial of the efficacy and safety of ICS/LABA reliever therapy in asthma.

INTRODUCTION: In adult asthma, combination inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) used solely as reliever therapy may represent an effective and safe alternative to ICS maintenance and short-acting beta agonist (SABA) reliever therapy. OBJECTIVE: To compare the efficacy and safety of ICS/fast-onset LABA reliever therapy with ICS maintenance and SABA reliever therapy in adults with asthma. METHODS AND ANALYSIS: A 52-week, open-label, parallel group, multicentre, phase III randomised controlled trial with 1:1 randomisation to either budesonide/formoterol Turbuhaler 200/6 µg, one actuation as required for symptom relief, or budesonide Turbuhaler 200 µg, one actuation twice daily and terbutaline Turbuhaler 250 µg, two actuations as required for symptom relief. 890 adults aged 18-75 years with asthma for whom maintenance ICS and SABA reliever therapy is indicated by current guidelines will be recruited in New Zealand. The primary outcome variable is the rate of severe exacerbations per patient per year. This study will investigate a novel treatment regimen that might lead to a paradigm shift in asthma management for adults for whom guidelines currently recommend maintenance ICS and SABA reliever therapy. ETHICS AND DISSEMINATION: Ethical approval has been granted (15/NTB/178). Study findings will be published according to Iinternational Committee of Medical Journal Editors' recommendations. TRIAL REGISTRATION NUMBER: ACTRN12616000377437; Pre-results.

RCT of the effect of berryfruit polyphenolic cultivar extract in mild steroid-naive asthma: a cross-over, placebo-controlled study.

OBJECTIVE: There is preclinical evidence that consumption of berryfruit extract may reduce chronic airways inflammation and modify airway remodelling in allergen-induced models of lung inflammation. We investigated the effect of berryfruit extract on the fractional expired nitric oxide (FeNO), a biomarker of eosinophilic airways inflammation, in adults with steroid-naïve asthma. DESIGN: Randomised placebo-controlled cross-over double-blind trial. SETTING: Single-centre community-based trial. PARTICIPANTS: 28 steroid-naïve mild asthmatics with Feno >40 ppb, of whom 25 completed both study interventions. INTERVENTIONS: Participants were randomised to receive, according to the cross-over design, 100 mg berryfruit polyphenolic extract (BFPE) or placebo for 4 weeks, with a 4-week washout period between the interventions. PRIMARY OUTCOME MEASURE: The primary outcome variable was FeNO at 4 weeks, analysed by a mixed linear model, with a random effect for participant and baseline FeNo as a covariate. RESULTS: The mean (SD) natural logarithm transformed (ln) FeNO after 4 weeks of treatment for the BFPE and placebo groups was 4.28 (0.47) and 4.22 (0.47), respectively. The paired change from baseline mean (SD) BFPE minus placebo ln FeNO was -0.03 (0.39), N=25. The mixed linear model estimate, with baseline covariate adjustment, difference in ln FeNO, was -0.002 (95% CI -0.15 to 0.14), p=0.98. This is equivalent to a ratio of geometric mean FeNO of 1.0 (95% CI 0.86 to 1.15). CONCLUSIONS: In steroid-naïve participants with mild asthma and elevated FeNO, there was no effect of BFPE on FeNO, a biomarker of eosinophilic airways inflammation. Caution is required in the extrapolation of apparent benefit in murine models of lung eosinophilia to clinical efficacy in patients with asthma. TRIAL REGISTRATION NUMBER: ANZCTR: 12613000451707; Results.

Day-time variation of serum periostin in asthmatic adults treated with ICS/LABA and adults without asthma.

BACKGROUND: We aimed to determine the effect of sampling time during the day on serum periostin levels in adult participants with and without asthma. METHODS: Serum periostin was measured at 2-h intervals from 0800 to 1800 h in 16 adult participants with stable asthma prescribed inhaled corticosteroid and long-acting beta-agonist therapy, and in 16 otherwise healthy participants without asthma. Mixed linear models were used to compare time zero (08:00 h) with subsequent measurement time for serum periostin for both groups. RESULTS: In both asthma and non-asthma, the mean (SD) serum periostin levels continuously reduced during the day from 53.5 (13.6) ng/mL at 0800 h to 50.9 (13.4) ng/mL at 1800 h (difference log periostin -0.05, P ≤ 0.001) and 50.5 (13.0) ng/mL at 0800 h to 46.2 (11.5) ng/mL at 1800 h (difference log periostin -0.08, P ≤ 0.001) respectively. CONCLUSIONS: Periostin values are higher in the morning compared with the afternoon in asthmatic and non-asthmatic adults. The small magnitude of the variation in serum periostin levels suggests that the time of day in which the serum periostin measurements are made is unlikely to influence treatment decisions if a specific serum periostin level is used to predict treatment responsiveness. Trial registration Australia New Zealand Trials Registry (ACTRN12614000072617).

Validation of a metered dose inhaler electronic monitoring device: implications for asthma clinical trial use.

BACKGROUND: The SmartTouch Ventolin monitor (Adherium, Auckland, New Zealand) is an electronic monitor for use with a Ventolin metered dose inhaler, which records the date and time of inhaler actuations. This technology has the potential to allow in-depth analysis of patterns of inhaler use in clinical trial settings. The aim of this study was to determine the accuracy of the SmartTouch Ventolin monitor in recording Ventolin actuations. METHODS: 20 SmartTouch Ventolin monitors were attached to Ventolin metered dose inhalers. Bench testing was performed over a 10-week period, to reflect the potential time frame between visits in a clinical trial. Inhaler actuations were recorded in a paper diary, which was compared with data uploaded from the monitors. RESULTS: 2560 actuations were performed during the 10-week study period. Monitor sensitivity for diary-recorded actuations was 99.9% with a lower 97.5% confidence bound of 99.7%. The positive predictive value for diary-recorded actuations was 100% with a 97.5% lower confidence bound of 99.9%. CONCLUSIONS: The SmartTouch Ventolin monitor is highly accurate in recording and retaining electronic data. It can be recommended for use in clinical trial settings in which training and quality control systems are incorporated into study protocols to ensure accurate data acquisition.