Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts

Shigeo Muro, Hisatoshi Sugiura, Patrick Darken, Paul Dorinsky, Shigeo Muro, Hisatoshi Sugiura, Patrick Darken, Paul Dorinsky

Abstract

Background: In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied.

Methods: KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12-24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported.

Results: Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population.

Conclusions: In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://ichgcp.net/clinical-trials-registry/NCT02497001.

Keywords: Asthma-like features; Budesonide; COPD; Exacerbation; Formoterol fumarate; Glycopyrrolate; KRONOS; Pulmonary function; Triple therapy.

Conflict of interest statement

SM has received lecture fees from AstraZeneca, GSK, Nippon Boehringer Ingelheim, and Novartis Pharma. HS has received lecture fees from AstraZeneca, GSK, Nippon Boehringer Ingelheim, and Novartis Pharma. PDo is an employee of AstraZeneca and holds stock and/or stock options in the company. PDa is an employee of AstraZeneca and holds stock and/or stock options in the company.

Figures

Fig. 1
Fig. 1
Change in morning pre-dose trough FEV1 over 12–24 weeks (patients with non-reversible airways and EOS < 300 cells/mm3). Bars are LSM (95% SE). Data analyzed in the mITT population using an efficacy estimand. Treatment comparisons are RR (95% CI). BFF, budesonide/formoterol fumarate dihydrate; BGF, budesonide/glycopyrronium/formoterol fumarate dihydrate; BUD/FORM, budesonide/formoterol fumarate dihydrate; FEV1, forced expiratory volume in 1 s; GFF, glycopyrronium/formoterol fumarate dihydrate; LSM, least squares mean; mITT, modified intent-to-treat; SE, standard error
Fig. 2
Fig. 2
Adjusted rate of moderate or severe COPD exacerbations (patients with non-reversible airways and EOS 3). Bars are adjusted rate (± SE). Treatment comparisons are RR (95% CI). Data analyzed in the mITT population using an efficacy estimand. BFF, budesonide/formoterol fumarate dihydrate; BGF, budesonide/glycopyrronium/formoterol fumarate dihydrate; BUD/FORM, budesonide/formoterol fumarate dihydrate; CI, confidence interval; COPD, chronic obstructive pulmonary disease; EOS, blood eosinophil count; GFF, glycopyrronium/formoterol fumarate dihydrate; mITT, modified intent-to-treat; RR, rate ratio; SE, standard error

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