Budesonide-glycopyrronium-formoterol fumarate dihydrate improved lung function and reduced severe exacerbations versus budesonide-formoterol in inadequately controlled asthma.

This study was a phase 3 randomised, double-blind, double-dummy, parallel-group trial conducted across 378 sites in 20 countries (KALOS) and 324 sites in 15 countries (LOGOS). The trial enrolled 8820 participants aged 12 to 80 years who had inadequately controlled asthma despite daily use of medium-dose or high-dose inhaled corticosteroid-long-acting beta-agonist (ICS-LABA) therapy. Participants were randomised to receive either budesonide-glycopyrronium-formoterol fumarate dihydrate (BGF) or budesonide-formoterol fumarate dihydrate using Aerosphere co-suspension delivery technology (BFF). The follow-up period spanned 24 to 52 weeks.

The intervention involved BGF administered at doses of 320 µg, 28·8 µg, and 10 µg (BGF 28·8) or 320 µg, 14·4 µg, and 10 µg (BGF 14·4). The comparator was BFF administered at 320 µg and 10 µg, or 320 µg, 9 µg, and 10 µg. The primary outcomes assessed were the change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 h to 3 h (AUC) and morning pre-dose trough FEV1 from day 1 to week 24, as well as annualised severe exacerbations in the pooled analysis.

Analysis of the change from baseline in trough FEV1 and FEV1 AUC revealed that BGF 28·8 favoured outcomes over BFF. The least squares mean difference for trough FEV1 was 76 mL (95% CI 57-94), and for FEV1 AUC, it was 90 mL (72-108). These differences were statistically significant with a p-value less than 0·0001. Regarding severe exacerbation rates, BGF 28·8 reduced rates versus BFF, with an incidence rate ratio of 0·86 (95% CI 0·76-0·97; p=0·012). In the pooled analysis, BGF 28·8 further reduced severe exacerbation rates versus BFF, showing an incidence rate ratio of 0·82 (95% CI 0·71-0·94; p=0·0043). A separate analysis of the exacerbation rate ratio for BGF 28·8 versus BFF yielded an effect size of 0·90 (95% CI 0·78-1·03; p=0·12), which was not statistically significant.

Safety and tolerability findings indicated that 627 participants (53·2%) experienced adverse events with BGF 28·8, 436 (60·0%) with BGF 14·4, 666 (55·2%) with BFF, and 698 (58·4%) with BFF. No deaths were reported as treatment-related. Serious adverse events and discontinuations were not reported in the provided data. The overall tolerability profile appeared consistent across the treatment arms.

These results compare to prior landmark studies by demonstrating efficacy in a population with inadequately controlled asthma on existing ICS-LABA therapy. The study design, including the large sample size and multi-country setting, strengthens the generalisability of the findings. However, the specific comparison of BGF 28·8 versus BFF in this context provides new evidence for treatment escalation strategies.

Key methodological limitations include the observational nature of some real-world data often associated with such trials, though this specific study was randomised. Potential biases related to site recruitment and patient selection across 702 sites in 35 countries may exist. The funding source was AstraZeneca, which may introduce potential conflicts of interest. The study did not report causality notes or specific certainty assessments, suggesting caution in interpreting the absolute magnitude of benefits without further independent validation.

Clinically, these results suggest that BGF could benefit individuals with inadequately controlled asthma without requiring a recent episode of acute deterioration on ICS-LABA before escalation. This finding is significant for practice decisions, offering a potential pathway for earlier intensification of therapy. However, the lack of reported serious adverse events and discontinuations limits the ability to fully assess long-term safety profiles in this specific comparison.

Several questions remain unanswered. The long-term safety beyond 52 weeks requires further investigation. The specific mechanisms driving the difference in exacerbation rates between BGF and BFF need elucidation. Additionally, the cost-effectiveness of switching to BGF versus continuing with BFF in various healthcare systems has not been addressed in this study. Further research is needed to determine if these benefits persist in patients with different phenotypes of asthma or those with comorbidities.