Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD: A Subgroup Analysis of the KRONOS Study

Figures & data

Table 1 Demographic and Baseline Disease Characteristics (Japanese Safety Population)

	BGF MDI 320/18/9.6 µg N=139	GFF MDI 18/9.6 µg N=138	BFF MDI 320/9.6 µg N=70	BUD/FORM DPI 400/12 µg N=69
Mean age, years (SD)	69.4 (7.1)	69.0 (6.1)	69.7 (6.1)	70.1 (6.8)
Male, n (%)	130 (93.5)	126 (91.3)	68 (97.1)	68 (98.6)
Mean body mass index, kg/m^2 (SD)	22.7 (3.5)	22.5 (3.3)	23.1 (3.6)	23.0 (2.9)
Current smoker, n (%)	40 (28.8)	41 (29.7)	19 (27.1)	21 (30.4)
Median number of pack-years smoked^a (range)	51.0 (10.0–186.1)	52.0 (10.0–135.0)	50.0 (11.5–192.0)	55.0 (12.5–180.0)
COPD severity, n (%)
Moderate	72 (51.8)	74 (53.6)	38 (54.3)	37 (53.6)
Severe	54 (38.8)	60 (43.5)	29 (41.4)	28 (40.6)
Very severe	13 (9.4)	4 (2.9)	3 (4.3)	4 (5.8)
Mean COPD duration, years (SD)	5.4 (3.9)	5.2 (4.4)	5.6 (5.0)	5.2 (3.7)
Moderate or severe COPD exacerbations in the past 12 months, n (%)
0	103 (74.1)	114 (82.6)	58 (82.9)	58 (84.1)
1	25 (18.0)	16 (11.6)	10 (14.3)	6 (8.7)
≥2	11 (7.9)	8 (5.8)	2 (2.9)	5 (7.2)
Moderate/severe exacerbation rate
Mean (SD)	0.4 (0.8)	0.2 (0.6)	0.2 (0.5)	0.2 (0.6)
Median (range)	0 (0–5)	0 (0–4)	0 (0–3)	0 (0–2)
Eosinophils
Median cells/mm^3 (range)	150.0 (30–670)	162.5 (25–2465)	140.0 (30–920)	165.0 (40–1040)
≥150 cells/mm^3, n (%)	70 (50.4)	75 (54.3)	34 (48.6)	39 (56.5)
≥300 cells/mm^3, n (%)	18 (13.0)	22 (15.9)	8 (11.4)	7 (10.1)
Mean post-albuterol FEV1, % predicted (SD)	51.1 (14.4)	52.2 (13.1)	52.2 (14.8)	52.7 (14.5)
Reversibility to albuterol
Mean post-albuterol FEV1 – pre-albuterol FEV1, mL (SD)	179.9 (117.0)	174.1 (120.3)	170.5 (147.9)	162.1 (119.4)
Reversible^b, n (%)	55 (39.6)	51 (37.0)	24 (34.3)	26 (37.7)
Use of ICS at screening, n (%)	42 (30.2)	46 (33.3)	21 (30.0)	22 (31.9)
BDI focal score
N	133	126	64	64
Mean (SD)	7.5 (1.8)	7.5 (1.8)	7.7 (2.1)	7.6 (1.8)
SGRQ total score
N	133	126	65	64
Mean (SD)	35.6 (14.4)	37.0 (13.8)	32.7 (13.7)	34.2 (14.7)
Mean CAT total score (SD)	15.4 (4.9)	15.4 (4.6)	14.3 (4.0)	13.9 (3.9)
Rescue medication use^c
N	139	138	70	68
Mean (SD)	0.8 (1.3)	0.7 (1.7)	0.5 (1.2)	0.5 (1.4)
Median (range), puffs/day	0.0 (0.0–6.6)	0.0 (0.0–12.1)	0.0 (0.0–6.9)	0.0 (0.0–8.0)

Notes: ^aNumber of pack-years smoked = (number of cigarettes each day/20) x number of years smoked. ^bReversible is defined as improvement in FEV₁ post-albuterol administration compared with pre-albuterol of ≥12% and ≥200 mL. ^cAssessed during the last seven days of the screening period.

Abbreviations: BDI, Baseline Dyspnea Index; BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 s; GFF, glycopyrrolate/formoterol fumarate; ICS, inhaled corticosteroid; MDI, metered dose inhaler; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.

Figure 1 Patient disposition.

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

Table 2 Primary and Secondary Lung Function Endpoints (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
Primary Endpoint
Change from baseline in morning pre-dose trough FEV1 (Weeks 12–24), mL
Japan
n  LSM (SE)	134 123 (12.6)	126 85 (12.8)	65 56 (17.7)	65 87 (17.6)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	37 (3, 72) 0.0337	67 (25, 109) 0.0020	35 (–7, 77) 0.0996
Global
n  LSM (SE)	592 138 (7.0)	559 118 (7.1)	278 61 (9.9)	288 76 (9.8)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	20 (1, 39) 0.0424	77 (53, 100) <0.0001	62 (38, 85) <0.0001
Secondary Endpoint
Change from baseline in morning pre-dose trough FEV1 (over 24 weeks), mL
Japan
n  LSM (SE)	137 130 (11.7)	134 96 (11.9)	68 68 (16.4)	68 97 (16.4)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	34 (2, 66) 0.0368	62 (23, 101) 0.0020	33 (–6, 72) 0.1014
Global^a
n  LSM (SE)	622 147 (6.5)	601 125 (6.6)	300 73 (9.2)	301 88 (9.1)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	22 (4, 39) 0.0139	74 (52, 95) <0.0001	59 (38, 80) <0.0001

Notes: ^aData from Ferguson et al.¹⁵

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CI, confidence interval; FEV₁, forced expiratory volume in 1 s; GFF, glycopyrrolate/formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; NA, not applicable; SE, standard error.

Figure 2 Change from baseline in morning pre-dose trough FEV₁ over 24 weeks (efficacy estimand; Japanese mITT population).

Note: Error bars represent standard error.
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; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat.

Table 3 Symptom and Quality of Life Endpoints (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
TDI focal score over Weeks 12–24
Japan
n  LSM (SE)	133 0.42 (0.12)	126 0.25 (0.12)	64 0.19 (0.17)	64 0.07 (0.17)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	0.17 (–0.17, 0.50) 0.3279	0.22 (–0.18, 0.63) 0.2804	0.34 (–0.06, 0.75) 0.0952
Global
n  LSM (SE)	585 1.21 (0.10)	544 1.13 (0.10)	274 1.06 (0.14)	280 0.72 (0.14)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	0.07 (–0.20, 0.35) 0.5928	0.15 (–0.18, 0.48) 0.3729	0.49 (0.16, 0.82) 0.0037
Change from baseline in SGRQ total score over Weeks 12–24
Japan
n  LSM (SE)	133 –4.1 (0.75)	126 –2.6 (0.77)	65 –4.3 (1.06)	64 –3.4 (1.06)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	–1.52 (–3.60, 0.55) 0.1495	0.20 (–2.33, 2.73) 0.8766	–0.73 (–3.26, 1.81) 0.5724
Global
n  LSM (SE)	592 –7.9 (0.50)	553 –6.8 (0.51)	277 –7.4 (0.67)	284 –6.5 (0.67)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	–1.10 (–2.29, 0.10) 0.0717	–0.52 (–1.99, 0.95) 0.4893	–1.42 (–2.88, 0.04) 0.0570
Change from baseline in E-RS total score over Weeks 12–24
Japan
n  LSM (SE)	134 –0.9 (0.35)	127 0.0 (0.35)	65 –0.4 (0.49)	66 –0.3 (0.49)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	–0.89 (–1.86, 0.07) 0.0701	–0.52 (–1.70, 0.66) 0.3899	–0.60 (–1.78, 0.58) 0.3204
Global
n  LSM (SE)	596 –1.1 (0.16)	560 –0.8 (0.16)	278 –1.0 (0.23)	292 –0.9 (0.22)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	–0.29 (–0.72, 0.15) 0.1965	–0.05 (–0.59, 0.48) 0.8445	–0.16 (–0.69, 0.37) 0.5538
Change from baseline in average daily rescue medication use over 24 weeks, puffs/day
Japan
n  LSM (SE)	139 –0.2 (0.07)	138 0.0 (0.07)	70 –0.1 (0.10)	68 –0.3 (0.10)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	–0.13 (–0.32, 0.06) 0.1831	–0.09 (–0.33, 0.14) 0.4439	0.12 (–0.12, 0.35) 0.3358
Global
n  LSM (SE)	638 –0.5 (0.06)	621 –0.4 (0.06)	313 –0.4 (0.08)	313 –0.7 (0.08)
Treatment difference for BGF MDI vs. comparators
LSM (95% CI)  P-value	NA	–0.12 (–0.28, 0.04) 0.1543	–0.14 (–0.34, 0.06) 0.1793	0.16 (–0.04, 0.36) 0.1198

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; E-RS, Evaluating Respiratory Symptoms in COPD Total score; GFF, glycopyrrolate/formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; NA, not applicable; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 4 CID^a and COPD Exacerbations (Efficacy Estimand; Japanese mITT Population)

	BGF MDI 320/18/9.6 µg N=139	GFF MDI 18/9.6 µg N=138	BFF MDI 320/9.6 µg N=70	BUD/FORM DPI 400/12 µg N=69
Time to CID^a
Patients with CID, n (%)	91 (65.5)	92 (66.7)	48 (68.6)	51 (73.9)
Treatment difference for BGF MDI vs. comparators
Hazard ratio (95% CI)  P-value	NA	0.93 (0.70, 1.25) 0.6461	0.89 (0.63, 1.27) 0.5348	0.81 (0.57, 1.14) 0.2270
Rate of moderate or severe COPD exacerbations, model-estimated rate per year
Patients with exacerbations, n (%) Rate	20 (14.4) 0.32	28 (20.3) 0.82	7 (10.0) 0.23	9 (13.0) 0.28
Treatment difference for BGF MDI vs. comparators
Rate ratio (95% CI)  P-value	NA	0.40 (0.19, 0.83) 0.0142	1.39 (0.47, 4.13) 0.5556	1.16 (0.43, 3.16) 0.7644

Notes: ^aCID was defined as a ≥100 mL decrease from baseline in trough FEV₁; a ≥4 point increase from baseline in SGRQ total score; a TDI focal score of –1 point or less; or a treatment-emergent moderate or severe COPD exacerbation occurring up to Week 24.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; CI, confidence interval; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 s; GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler; mITT, modified intent-to-treat; NA, not applicable; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 5 Summary of Adverse Events (Japanese Safety Population)

	BGF MDI 320/18/9.6 µg N=139	GFF MDI 18/9.6 µg N=138	BFF MDI 320/9.6 µg N=70	BUD/FORM DPI 400/12 µg N=69
TEAEs, n (%)
Patients with ≥1 TEAE	93 (66.9)	92 (66.7)	51 (72.9)	41 (59.4)
Patients with TEAEs related^a to study treatment	29 (20.9)	11 (8.0)	12 (17.1)	4 (5.8)
Patients with serious TEAEs	11 (7.9)	14 (10.1)	7 (10.0)	6 (8.7)
Patients with serious TEAEs related^a to study treatment	1 (0.7)	4 (2.9)	0	0
Patients with TEAEs that led to early discontinuation	6 (4.3)	6 (4.3)	2 (2.9)	2 (2.9)
Patients with confirmed^b MACE	0	1 (0.7)	0	2 (2.9)
Patients with confirmed^b,c pneumonia	7 (5.0)	1 (0.7)	0	0
Deaths (all causes)	0	1 (0.7)	1 (1.4)	0
TEAEs occurring in ≥3% of patients in any treatment arm, preferred term, n (%)
Nasopharyngitis	29 (20.9)	23 (16.7)	14 (20.0)	16 (23.2)
Bronchitis	6 (4.3)	6 (4.3)	7 (10.0)	3 (4.3)
Dysphonia	9 (6.5)	1 (0.7)	8 (11.4)	3 (4.3)
Muscle spasms	12 (8.6)	2 (1.4)	5 (7.1)	2 (2.9)
Upper respiratory tract infection	7 (5.0)	5 (3.6)	1 (1.4)	1 (1.4)
Upper respiratory tract inflammation	4 (2.9)	6 (4.3)	3 (4.3)	0
COPD^d	4 (2.9)	5 (3.6)	2 (2.9)	1 (1.4)
Influenza	1 (0.7)	4 (2.9)	1 (1.4)	4 (5.8)
Eczema	1 (0.7)	2 (1.4)	2 (2.9)	3 (4.3)
Pneumonia^c,e	6 (4.3)	1 (0.7)	1 (1.4)	0

Notes: ^aPossibly, probably, or definitely related in the opinion of the investigator. ^bConfirmed by clinical endpoint committee. ^cOne confirmed case of pneumonia in the BGF MDI group was reported under the preferred term of interstitial lung disease, and therefore was not categorized as a TEAE of pneumonia. ^dWorsening of COPD. ^eSpontaneously reported as adverse events; not confirmed by clinical endpoint committee.

Abbreviations: BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; BUD/FORM DPI, budesonide/formoterol fumarate dry powder inhaler; COPD, chronic obstructive pulmonary disease; GFF, glycopyrrolate/formoterol fumarate; MACE, major adverse cardiovascular events; 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)30327-830232048

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