Abstract
Background: Recommendations for the use of inhaled corticosteroid-formoterol reliever-based regimens are limited by the absence of randomised controlled trials (RCTs) in patients with asthma using maintenance inhaled corticosteroids, and scarce evidence for the effect on type 2 airway inflammation. We aimed to examine the clinical efficacy and safety of maintenance inhaled corticosteroids plus budesonide-formoterol reliever or terbutaline reliever in patients with mild-to-moderate asthma.
Methods: This open-label, parallel-group, randomised, controlled, phase 4 trial was conducted at Wellington Hospital and two community-based primary care facilities in New Zealand. Eligible participants were aged 16-75 years, had a self-reported doctor's diagnosis of asthma, were using reliever only therapy or maintenance inhaled corticosteroids with short-acting β2-agonist reliever therapy, and were registered with a general practitioner. Participants had to have reported mean reliever use on two or more occasions per week in the 12 weeks before enrolment and had evidence of airway inflammation (FeNO ≥25 parts per billion [ppb]) at screening. Participants were randomly assigned (1:1) to budesonide-formoterol (budesonide 200 μg and formoterol 6 μg) reliever or terbutaline 250 μg reliever therapy using a computer-generated sequence in block sizes of four and six, stratified by region, baseline inhaled corticosteroids maintenance dose, and history of severe asthma exacerbation in the previous 12 months. All participants received maintenance budesonide 200 μg. During a 26-week treatment period, participants attended visits at weeks 0 (screening and randomisation), 13, and 26. The primary outcome was FeNO at week 26, measured in the intention-to-treat (ITT) population. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12622001304729 (completed).
Findings: Between March 28, 2023, and Aug 27, 2024, 290 participants were assessed for eligibility, 109 were ineligible, and 181 were randomly assigned to budesonide-formoterol (n=93) or terbutaline reliever therapy (n=88; ITT population). Participants had a mean age of 33·91 years (SD 15·54). 119 (66%) of 181 participants were female and 62 (34%) were male. Geometric mean FeNO was 62·18 ppb (SD 1·86) at baseline and 39·65 ppb (2·12) at week 26, for the budesonide-formoterol group and 68·03 ppb (1·97) at baseline and 52·98 ppb (2·27) at week 26 for the terbutaline group. Budesonide-formoterol reliever therapy resulted in a mean reduction in geometric mean FeNO of 18·50% (95% CI 2·72-31·73; p=0·024) at week 26 compared with terbutaline reliever therapy. 77 (83%) of 93 participants in the budesonide-formoterol group versus 69 (78%) of 88 in the terbutaline group had at least one adverse event (relative risk 1·06 [95% CI 0·91-1·22]; p=0·46). There were no deaths in the study.
Interpretation: Budesonide-formoterol reliever therapy resulted in a reduction in FeNO compared with terbutaline reliever in adults with asthma using maintenance inhaled corticosteroids. Budesonide-formoterol reliever is a safe and effective alternative to short-acting β2-agonist reliever therapy for adults using maintenance inhaled corticosteroids.