Eosinophil-guided inhaled corticosteroid de-escalation and its impact on acute exacerbations in stable chronic obstructive pulmonary disease (COPD) patients receiving triple inhaled therapy: A single-center randomized controlled trial

Background: Acute exacerbations of COPD increase hospitalization and death risk. Randomized evidence on blood eosinophil-guided inhaled corticosteroid (ICS) dose reduction in stable triple-therapy patients is lacking. Objectives: To evaluate whether blood eosinophil stratification modifies the effect of budesonide dose reduction (from 160 µg to 80 µg per actuation) on acute exacerbations in stable COPD patients receiving budesonide/ glycopyrrolate/formoterol (BGF) triple therapy. Methods: This double-blind randomized controlled trial enrolled 600 stable COPD patients on maintenance BGF for ≥12 weeks with ≥1 prior exacerbation. Patients were stratified by blood eosinophils (<300 vs ≥300 cells/µL) and randomized 1:1 to ICS reduction (budesonide 80 µg) or maintenance (budesonide 160 µg) for 52 weeks. The primary outcome was the annualized rate of moderate-to-severe exacerbations, analyzed using negative binomial regression with interaction testing. The trial was registered with the China Clinical Trial Registration Center (MR-51-22-003984). Results: In the ITT population, the annualized exacerbation rate was higher with ICS reduction, but the difference was not significant (IRR=1.17, P=0.064). A significant treatment-by-eosinophil interaction was present (P=0.006). At eosinophils ≥300 cells/µL, dose reduction increased exacerbations (IRR=1.57, P=0.002) and shortened time to first exacerbation (HR=1.69, P=0.002). At eosinophils <300 cells/µL, no difference was observed (IRR=1.03). Pneumonia (5.74% vs 10.40%, P=0.049) and local adverse events were less frequent with dose reduction. Conclusion: Blood eosinophils significantly modify the effect of ICS dose reduction (P_interaction=0.006). Dose reduction is not recommended when eosinophils ≥300 cells/µL. When eosinophils <300 cells/µL, cautious dose reduction may be considered to reduce adverse events without increasing exacerbations.