Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Exacerbation Outcomes in Patients with COPD without a Recent Exacerbation History: A Subgroup Analysis of KRONOS

Figures & data

Table 1 Patient Demographics and Characteristics by Reported History of Exacerbations

	BGF MDI 320/18/9.6 µg		GFF MDI 18/9.6 µg		BFF MDI 320/9.6 µg		BUD/FORM DPI 400/12 µg
Patient exacerbation history	No prior (n=469)	Prior (n=170)	No prior (n=473)	Prior (n=152)	No prior (n=235)	Prior (n=79)	No prior (n=234)	Prior (n=84)
Mean age, years (range)	65.4 (42−80)	63.5 (40–80)	65.3 (42–80)	64.6 (46–80)	65.8 (48–80)	63.5 (46–78)	66.1 (45–80)	65.4 (46–79)
Male, %	73	70	70	64	75	59	75	71
Race, %
Asian	42	52	44	49	45	47	44	46
Black	4	3	7	4	4	8	5	2
White	54	45	49	47	51	46	51	51
Current smokers, %	41	36	42	38	37	35	40	35
ICS use at screening, %	71	76	70	76	69	78	67	81
Blood eosinophil count
<150 cells per mm^3, %	48	53	47	44	44	61	50	46
≥150 cells per mm^3, %	52	47	53	56	56	39	50	54
Post-bronchodilator FEV1, mean % predicted	51	49	51	49	51	48	51	50

Notes: The following races, n (%), were recorded in the no-exacerbation subgroup only: Native Hawaiian or Other Pacific Islander, 1 (0.2) in the GFF MDI 18/9.6 µg treatment group; American Indian or Alaska Native, 1 (0.2) in the BGF MDI 320/18/9.6 µg treatment group.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; FEV₁, forced expiratory volume in 1 s; GFF, glycopyrrolate/formoterol fumarate; ICS, inhaled corticosteroids; MDI, metered dose inhaler.

Table 2 Exacerbation Outcomes by Reported History of Exacerbations in the Previous 12 Months (Efficacy Estimand, mITT Population)

	BGF MDI 320/18/9.6 μg	GFF MDI 18/9.6 μg	BFF MDI 320/9.6 μg	BUD/FORM DPI 400/12 μg
Overall population
Patients, N	N=639	N=625	N=314	N=318
Rate of moderate/severe COPD exacerbations
Number of events, n	132	228	74	77
Adjusted annualized rate (SE)	0.46 (0.05)	0.95 (0.09)	0.56 (0.08)	0.55 (0.08)
Rate ratio, BGF MDI vs comparator (95% CI)	–	0.48 (0.37, 0.64)	0.82 (0.58, 1.17)	0.83 (0.59, 1.18)
p-value	–	<0.0001	0.2792	0.3120
Time to first moderate/severe COPD exacerbation
Number of patients with exacerbations, n (%)	108 (16.9)	157 (25.1)	65 (20.7)	61 (19.2)
Hazard ratio, BGF MDI vs comparator (95% CI)	–	0.59 (0.46, 0.76)	0.75 (0.55, 1.02)	0.85 (0.62, 1.17)
Cox regression p-value	–	<0.0001	0.0635	0.3225
Log rank p-value	–	0.0001	0.0281	0.0832
Rate of severe COPD exacerbations
Number of events, n	17	40	9	12
Adjusted annualized rate (SE)	0.047 (0.01)	0.131 (0.03)	0.055 (0.02)	0.068 (0.02)
Rate ratio, BGF MDI vs comparator (95% CI)	–	0.36 (0.18, 0.70)	0.85 (0.34, 2.13)	0.69 (0.29, 1.61)
p-value	–	0.0026	0.7363	0.3861
No prior exacerbations
Patients, N	N=469	N=473	N=235	N=234
Rate of moderate/severe COPD exacerbations
Number of events, n	85	147	42	47
Adjusted annualized rate (SE)	0.41 (0.06)	0.80 (0.09)	0.42 (0.08)	0.47 (0.09)
Rate ratio, BGF MDI vs comparator (95% CI)	–	0.52 (0.37, 0.72)	0.98 (0.63, 1.54)	0.88 (0.57, 1.36)
p-value	–	0.0001	0.9384	0.5710
Time to first moderate/severe COPD exacerbation
Number of patients with exacerbations, n (%)	72 (15.4)	105 (22.2)	38 (16.2)	37 (15.8)
Hazard ratio, BGF MDI vs comparator (95% CI)	–	0.64 (0.47, 0.86)	0.92 (0.62, 1.36)	0.93 (0.62, 1.38)
Cox regression p-value	–	0.0032	0.6643	0.7105
Log rank p-value	–	0.0041	0.3829	0.4415
Rate of severe COPD exacerbations
Number of events, n	12	26	6	6
Adjusted annualized rate (SE)	0.046 (0.02)	0.108 (0.03)	0.043 (0.02)	0.046 (0.02)
Rate ratio, BGF MDI vs comparator (95% CI)	–	0.42 (0.19, 0.93)	1.05 (0.36, 3.11)	0.99 (0.33, 2.92)
p-value	–	0.0316	0.9279	0.9817
Prior exacerbations
Patients, N	N=170	N=152	N=79	N=84
Rate of moderate/severe COPD exacerbations
Number of events, n	47	81	32	30
Adjusted annualized rate (SE)	0.63 (0.12)	1.50 (0.24)	1.05 (0.25)	0.84 (0.20)
Rate ratio, BGF MDI vs comparator (95% CI)	–	0.42 (0.26, 0.67)	0.60 (0.34, 1.08)	0.75 (0.42, 1.35)
p-value	–	0.0003	0.0892	0.3423
Time to first moderate/severe COPD exacerbation
Number of patients with exacerbations, n (%)	36 (21.2)	52 (34.2)	27 (34.2)	24 (28.6)
Hazard ratio, BGF MDI vs comparator (95% CI)	–	0.51 (0.33, 0.79)	0.52 (0.32, 0.86)	0.71 (0.42, 1.20)
Cox regression p-value	–	0.0022	0.0110	0.2019
Log rank p-value	–	0.0031	0.0052	0.0434
Rate of severe COPD exacerbations
Number of events, n	5	14	3	6
Adjusted annualized rate (SE)	*	*	*	*

Notes: Treatments are compared adjusting for baseline post-bronchodilator percent predicted FEV₁ and baseline eosinophil count as continuous covariates and country and inhaled corticosteroid use at screening (yes/no) as categorical covariates using negative binomial regression. *As the number of events is low, this precludes analysis for this group.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CI, confidence interval; COPD, chronic obstructive pulmonary disease; GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler; mITT, modified intent-to-treat; SE, standard error.

Figure 1 Treatment comparisons for rate of moderate/severe exacerbations by reported exacerbation history (mITT population; efficacy estimand).

Notes: Data presented as rate ratio (95% CI); *p≤0.0001; ^#p=0.0003. Eosinophil data are baseline counts in cells per mm³ across treatment groups.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CI, confidence interval; GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler; mITT, modified intent-to-treat.

Figure 2 Rate of moderate/severe exacerbations for patients reporting (A) a prior exacerbation and (B) no prior exacerbations as a function of baseline eosinophil and treatment group (mITT population, efficacy estimand). Generalized additive model plot. Banded areas represent 95% CIs.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CI, confidence interval; COPD, chronic obstructive pulmonary disease; GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler; mITT, modified intent-to-treat.

Table 3 Comparison of TEAEs for No Prior Exacerbations and Prior Exacerbations Subgroups (Safety Population)

	BGF MDI 320/18/9.6 μg		GFF MDI 18/9.6 μg		BFF MDI 320/9.6 μg		BUD/FORM DPI 400/12 μg
Patient exacerbation History	No prior (n=469)	Prior (n=170)	No prior (n=473)	Prior (n=152)	No prior (n=235)	Prior (n=79)	No prior (n=234)	Prior (n=84)
Patients with at least one TEAE, n (%)	283 (60.3)	105 (61.8)	288 (60.9)	96 (63.2)	125 (53.2)	50 (63.3)	129 (55.1)	54 (64.3)
Patients with drug-related TEAEs,^† n (%)	81 (17.3)	31 (18.2)	66 (14.0)	25 (16.4)	30 (12.8)	18 (22.8)	30 (12.8)	10 (11.9)
Patients with serious TEAEs, n (%)	39 (8.3)	16 (9.4)	49 (10.4)	19 (12.5)	16 (6.8)	5 (6.3)	18 (7.7)	11 (13.1)
Patients with drug-related serious TEAEs,^† n (%)	5 (1.1)	2 (1.2)	8 (1.7)	4 (2.6)	1 (0.4)	2 (2.5)	5 (2.1)	1 (1.2)
Patients with TEAEs leading to early discontinuation, n (%)	26 (5.5)	4 (2.4)	26 (5.5)	4 (2.6)	7 (3.0)	4 (5.1)	8 (3.4)	3 (3.6)
Deaths (all causes), n (%)	6 (1.3)	0	1 (0.2)	2 (1.3)	2 (0.9)	0	1 (0.4)	0
Patients with confirmed major adverse CV event,* n (%)	2 (0.4)	0	2 (0.4)	1 (0.7)	1 (0.4)	1 (1.3)	2 (0.9)	0
Patients with confirmed pneumonia,** n (%)	7 (1.5)	5 (2.9)	6 (1.3)	4 (2.6)	5 (2.1)	1 (1.3)	2 (0.9)	2 (2.4)

Notes: *Confirmed by clinical endpoint committee. **Confirmed by chest imaging, antibiotic treatment and at least two symptoms.¹⁰ †Possibly, probably, or definitely related, in the opinion of the investigator.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CV, cardiovascular; GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler; TEAE, treatment-emergent adverse event.

Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, Phase 3 randomised controlled trial. Lancet Respir Med. 2018;6(10):747–758. doi:10.1016/S2213-2600(18)30327-8

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