Triple therapy in a single inhaler effective for COPD irrespective of exacerbation history
Triple therapy with budesonide, glycopyrrolate, and formoterol in one metered dose inhaler (BGF MDI) appears effective and is well-tolerated in patients with symptomatic moderate-to-severe chronic obstructive pulmonary disease (COPD) irrespective of exacerbation history, the multicentre, phase III KRONOS* trial has shown.
Over 24 weeks, treatment with BGF MDI significantly improved lung function – one of the primary endpoints – among COPD patients compared with two of three dual therapies, as measured by FEV1 area under the curve from 0–4 hours (AUC 0–4). [Lancet Respir Med 2018;doi:10.1016/S2213-2600(18)30327-8]
The KRONOS study randomized 1,902 COPD patients to receive triple therapy with BGF in a 320/18/9.6 μg MDI (n=640), glycopyrrolate plus formoterol fumarate (GFF) in 18/9.6 μg MDI (n=627), budesonide/formoterol fumarate (BFF) in 320/9.6 μg MDI (n=316), or open-label budesonide/formoterol fumarate (BUD FORM) in 400/12 μg dry-powder inhaler (DPI, n=319) as two inhalations twice daily for 24 weeks. Patients were 40 –80 years of age, and current or former smokers (smoking history ≥10 pack-years). All patients received salbutamol sulphate as rescue medication as needed throughout the study. No exacerbation criteria were required of patients prior to study enrolment.
There was a 104-mL least squares mean (LSM) difference in FEV1 AUC 0–4 for BGF MDI vs those on BFF MDI and a 91-mL difference vs BUD FORM DPI (p<0.0001 for both) over 24 weeks, reported study investigator Prof Gary Ferguson from the Pulmonary Research Institute of Southeast Michigan in Farmington Hills, Michigan, US. For the co-primary endpoint of change in morning pre-dose trough FEV1, BGF MDI demonstrated a 22-ML improvement vs GFF MDI (p=0.0139).
In terms of moderate or severe exacerbations, the model estimated rates (performed as part of a secondary analysis) showed that patients on BGF MDI had 0.46 exacerbations per year, lower than for GFF and BFF MDIs (0.95 and the 0.56 per year, respectively), or BUD FORM MDI (0.55 per year).
At week 24, patients on BGF MDI had a 116 mL improvement in FEV1 AUC0-4 vs those on BFF MDI (p<0.0001). There was also a nonsignificant 13 mL numerical advantage for BGF MDI in trough FEV1 over the GFF MDI. Common treatment-emergent adverse events were nasopharyngitis (8 percent in the BGF MDI group, 7 percent in the GFF MDI group, 8 percent in the BFF MDI group, and 9 percent in the BUD FORM DPI group) and upper respiratory tract infection (10 percent, 6 percent, 6 percent, and 7 percent, respectively). Pneumonia incidence was low at less than 2 percent and was similar across treatments. Two treatment-related deaths occurred in the GFF MDI group.
Ferguson said the results of KRONOS could change how physicians treat patients 1 or 2 years down the road, with the triple therapy working even for GOLD B patients with a lower risk of exacerbations. He said he hopes to see biomarkers into play to identify patients who would benefit the most from BGF MDI.
In an accompanying commentary, Dr Mona Bafadhel from the University of Oxford in London, UK said although it would seem that patients in KRONOS had symptomatic COPD without an exacerbation risk, it is conceivable that the majority of patients were responders to inhaled corticosteroids (ICS) and continuation of ICS helped to reduce their exacerbation risk. Nevertheless, she called for a longer study to confirm KRONOS’ results. [Lancet Respir Med 2018;doi:10.1016/S2213-2600(18)30370-9]