Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD

Figures & data

Figure 1 Patient disposition (all patients randomized in China).

Abbreviations: FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; MDI, metered dose inhaler.

Table 1 Patient Demographics And Characteristics (China ITT Population)

Parameter	GFF MDI 18/9.6 µg n=146	GP MDI 18 µg n=122	FF MDI 9.6 µg n=135	Placebo MDI n=63
Mean age, years (SD)	64.1 (6.4)	63.5 (8.0)	63.0 (7.6)	63.5 (6.2)
Male, n (%)	140 (95.9)	116 (95.1)	130 (96.3)	60 (95.2)
Race, n (%)
Asian	146 (100)	122 (100)	135 (100)	63 (100)
Mean BMI, kg/m^2 (SD)	22.9 (3.3)	23.3 (3.3)	22.8 (3.3)	23.2 (3.4)
Smoking status, n (%)
Current	50 (34.2)	42 (34.4)	43 (31.9)	20 (31.7)
Former	96 (65.8)	80 (65.6)	92 (68.1)	43 (68.3)
Mean number of pack-years smoked^a (SD)	37.0 (23.8)	34.7 (21.0)	39.7 (22.6)	34.9 (19.8)
COPD severity^b, n (%)
Mild^c	3 (2.1)	7 (5.7)	3 (2.2)	4 (6.3)
Moderate	78 (53.4)	66 (54.1)	72 (53.3)	29 (46.0)
Severe	59 (40.4)	45 (36.9)	56 (41.5)	29 (46.0)
Very severe	6 (4.1)	4 (3.3)	4 (3.0)	1 (1.6)
Mean COPD duration, years (SD)	n=141	n=122	n=132	n=62
	4.2 (5.5)	3.7 (5.0)	3.5 (4.2)	4.3 (5.5)
Mean post-bronchodilator FEV1, % predicted (SD)	53.33 (14.76)	54.45 (14.81)	53.55 (14.01)	53.62 (15.84)
Reversibility to salbutamol
Reversible^d, n (%)	76 (52.1)	60 (49.2)	63 (46.7)	32 (50.8)
Mean reversibility post-bronchodilator, % (SD)	20.9 (16.1)	20.4 (14.7)	19.8 (13.9)	20.6 (15.3)
Prior use of ICS^e, n (%)	49 (33.6)	39 (32.0)	56 (41.5)	27 (42.9)
Mean BDI score (SD)	n=142	n=119	n=129	n=59
	7.0 (2.1)	7.1 (2.0)	7.3 (2.1)	6.4 (2.3)
Mean baseline SGRQ total score (SD)	n=129	n=110	n=116	n=53
	36.0 (15.5)	33.2 (15.3)	32.6 (14.0)	34.9 (12.0)
Mean CAT total score^f (SD)	n=145	n=121	n=135	n=63
	12.0 (6.0)	12.3 (6.8)	11.7 (6.0)	11.0 (5.9)
Mean rescue medication use^g at baseline, puffs/day (SD)	n=45	n=39	n=44	n=16
	3.6 (3.1)	3.5 (2.4)	3.2 (2.3)	4.4 (4.4)

Notes: ^aNumber of pack-years smoked = (number of cigarettes each day/20) × number of years smoked. ^bSeverity of COPD was based on the non-missing post-salbutamol assessment at screening. ^cThese patients were characterized as having mild COPD due to the application of an Asian correction factor to baseline lung function assessments at the time of analysis. ^dReversible is defined as improvement in FEV₁ post-salbutamol administration compared to pre-salbutamol of ≥12% and ≥200 mL. ^eDefined as using ICS on the day of the first dose of study medication. ^fCAT total score is the sum of eight CAT item scores (range: 0–40). ^gRescue medication use was analyzed in the China rescue medication user population, defined as all patients in the China ITT population with mean baseline rescue salbutamol use of ≥1 puff/day.

Abbreviations: BDI, Baseline Dyspnea Index; BMI, body mass index; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ICS, inhaled corticosteroid; ITT, intent-to-treat; MDI, metered dose inhaler; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.

Table 2 Primary And Secondary Lung Function Endpoints (China ITT Population)

	GFF MDI 18/9.6 µg	GP MDI 18 µg	FF MDI 9.6 µg	Placebo MDI
Primary endpoint
Change from baseline in morning pre-dose trough FEV1 at Week 24, mL
n	126	110	116	54
LSM (SE)	133 (17.3)	35 (18.7)	29 (18.1)	−39 (−26.6)
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	98 (48, 148)	104 (55, 153)	173 (110, 235)
P-value	NA	0.0001	<0.0001	<0.0001
Secondary endpoints
Change from baseline in morning pre-dose trough FEV1 over 24 weeks^a, mL
n	143	121	131	60
LSM (SE)	143 (13.3)	64 (14.5)	50 (13.9)	−20 (20.6)
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	79 (40, 118)	93 (55, 131)	163 (115, 212)
P-value	NA	<0.0001	<0.0001	<0.0001
Peak change from baseline in FEV1 within 2 hrs post-dosing at Week 24, mL
n	128	110	116	54
LSM (SE)	377 (19.7)	195 (21.3)	226 (20.7)	72 (30.3)
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	182 (125, 239)	151 (95, 207)	305 (234, 376)
P-value	NA	<0.0001	<0.0001	<0.0001
Onset of action on Day 1 (change from baseline in FEV1), mL
Difference vs placebo MDI at 5 mins post-dose
n	119	104	118	52
LSM (95% CI)	184 (150, 219)	34 (−1, 70)	169 (135, 204)	NA
P-value	<0.0001	0.0557	<0.0001	NA
Difference vs placebo MDI at 15 mins post-dose
n	143	117	132	62
LSM (95% CI)	225 (189, 262)	76 (38, 113)	193 (156, 230)	NA
P-value	<0.0001	<0.0001	<0.0001	NA

Note: ^aMorning pre-dose trough FEV₁ over 24 weeks was based on assessments at Weeks 2, 4, 8, 12, 16, 20, and 24. All p-values <0.05 should only be interpreted in terms of nominal significance as the analyses in the Chinese subgroup were considered exploratory.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler; NA, not applicable; SE, standard error.

Figure 2 Least squares mean change (±SE) from baseline in morning pre-dose trough FEV₁ over 24 weeks (China ITT population).

Note: Morning pre-dose trough FEV₁ over 24 weeks was based on assessments at Weeks 2, 4, 8, 12, 16, 20, and 24.
Abbreviations: FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler; SE, standard error.

Table 3 Secondary Patient-Reported Outcome Endpoints (China ITT Population/China Symptomatic Population)

	China ITT Population				China Symptomatic Population^a
	GFF MDI 18/9.6 µg	GP MDI 18 µg	FF MDI 9.6 µg	Placebo MDI	GFF MDI 18/9.6 µg	GP MDI 18 µg	FF MDI 9.6 µg	Placebo MDI
TDI focal score over 24 weeks^b
n	142	119	129	59	43	37	39	15
LSM (SE)	2.5 (0.16)	2.0 (0.18)	2.3 (0.17)	1.4 (0.25)	2.2 (0.32)	1.7 (0.34)	2.1 (0.33)	1.0 (0.54)
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM	NA	0.42	0.20	1.11	NA	0.46	0.10	1.22
95% CI	NA	−0.05, 0.89	−0.26, 0.66	0.52, 1.69	NA	−0.46, 1.38	−0.81, 1.01	−0.02, 2.45
P-value	NA	0.0780	0.3924	0.0002	NA	0.3234	0.8267	0.0543
Change from baseline in SGRQ total score at Week 24
n	129	110	116	53	38	34	35	13
LSM (SE)	−8.5 (0.97)	−7.3 (1.05)	−9.4 (1.02)	−5.3 (1.51)	−12.0 (2.17)	−12.3 (2.33)	−13.7 (2.28)	−7.0 (3.75)
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM	NA	−1.21	0.87	−3.24	NA	0.26	1.70	−5.04
95% CI	NA	−4.02, 1.61	−1.90, 3.64	−6.76, 0.28	NA	−6.05, 6.57	−4.54, 7.94	−13.66, 3.58
P-value	NA	0.3996	0.5373	0.0714	NA	0.9352	0.5894	0.2489

Notes: ^aThe China symptomatic population was defined as patients in the China ITT population with a CAT score ≥15 at screening. ^bTDI focal score over 24 weeks was based on assessments at Weeks 4, 8, 12, 16, 20, and 24. All p-values <0.05 should only be interpreted in terms of nominal significance as the analyses in the Chinese subgroup were considered exploratory.

Abbreviations: CAT, COPD Assessment Test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler; NA, not applicable; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 4 Exacerbations And CID^a (China ITT Population)

	GFF MDI 18/9.6 µg n=146	GP MDI 18 µg n=122	FF MDI 9.6 µg n=135	Placebo MDI n=63
Exacerbations
Patients with a moderate or severe exacerbation
n (%)	22 (15.1)	23 (18.9)	31 (23.0)	15 (23.8)
Time to first moderate or severe COPD exacerbation
GFF MDI vs monocomponents and placebo MDI
Hazard ratio	NA	0.71	0.57	0.57
95% CI	NA	0.39, 1.28	0.33, 1.00	0.29, 1.10
P-value	NA	0.2543	0.0501	0.0950
Rate of moderate or severe COPD exacerbations (per year)^b
Rate	0.44	0.47	0.62	0.65
Model-estimated rate	0.38	0.46	0.58	0.60
GFF MDI vs monocomponents and placebo MDI
Model-estimated rate ratio	NA	0.82	0.65	0.63
95% CI	NA	0.46, 1.49	0.38, 1.12	0.32, 1.22
P-value	NA	0.5200	0.1224	0.1689
CID
Patients with a CID
n (%)	73 (50.0)	80 (65.6)	77 (57.0)	51 (81.0)
Median time to CID^c (weeks)	24.1	16.3	16.1	12.0
Time to first CID
GFF MDI vs monocomponents and placebo MDI
Hazard ratio	NA	0.65	0.71	0.36
95% CI	NA	0.47, 0.90	0.52, 0.99	0.25, 0.52
P-value	NA	0.0095	0.0428	<0.0001

Notes: ^aCID is defined as the first occurrence of one of the following events: ≥100 mL decline in trough FEV₁; a treatment-emergent moderate or severe COPD exacerbation; or ≥4-unit increase in SGRQ total score. ^bRate of exacerbations per year = total number of exacerbations/total years of exposure across all patients for the treatment. ^cTime to CID (weeks) = (date of CID – first treatment administration date + 1)/7. All p-values <0.05 should only be interpreted in terms of nominal significance as the analyses in the Chinese subgroup were considered exploratory.

Abbreviations: CI, confidence interval; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MDI, metered dose inhaler; NA, not applicable; SGRQ, St George’s Respiratory Questionnaire.

Figure 3 Kaplan–Meier curves for (A) time to first moderate or severe COPD exacerbation^a and (B) time to first CID^b (both China ITT population).

Notes: ^aTime to first moderate or severe exacerbation (weeks) = (date of first COPD exacerbation – first treatment administration date + 1)/7. ^bTime to CID (weeks) = (date of CID – first treatment administration date + 1)/7.
Abbreviations: CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MDI, metered dose inhaler.

Table 5 Summary Of AEs (China Safety Population)

Parameter	GFF MDI 18/9.6 µg n=146	GP MDI 18 µg n=122	FF MDI 9.6 µg n=135	Placebo MDI n=63
Patients with ≥1 TEAE	83 (56.8)	71 (58.2)	69 (51.1)	42 (66.7)
Patients with TEAEs related^a to study treatment	18 (12.3)	18 (14.8)	17 (12.6)	7 (11.1)
Patients with serious TEAEs	15 (10.3)	10 (8.2)	13 (9.6)	7 (11.1)
Patients with serious TEAEs related^a to study treatment	1 (0.7)	2 (1.6)	3 (2.2)	2 (3.2)
Patients with TEAEs leading to early discontinuation	10 (6.8)	6 (4.9)	9 (6.7)	6 (9.5)
Deaths (all cause) during treatment period	1 (0.7)	0	1 (0.7)	0
Deaths (all cause) during treatment period + 14 days	1 (0.7)	0	1 (0.7)	0
AEs occurring in ≥4% of patients in any treatment arm (preferred term), n (%)
Upper respiratory tract infection	18 (12.3)	20 (16.4)	18 (13.3)	11 (17.5)
Viral upper respiratory tract infection	12 (8.2)	15 (12.3)	15 (11.1)	4 (6.3)
Chronic obstructive pulmonary disease^b	7 (4.8)	5 (4.1)	5 (3.7)	6 (9.5)
Blood glucose increased	2 (1.4)	4 (3.3)	2 (1.5)	4 (6.3)
Hyperlipidemia	3 (2.1)	6 (4.9)	1 (0.7)	2 (3.2)
Protein urine present	5 (3.4)	1 (0.8)	0	3 (4.8)
Blood triglycerides increased	3 (2.1)	1 (0.8)	2 (1.5)	3 (4.8)

Notes: Data are n (%). ^aRelated = possibly, probably, or definitely related in the opinion of the Investigator. ^bWorsening of COPD defined as a COPD exacerbation since the patient’s last visit. COPD exacerbations were only recorded as an AE if they were considered to be a serious TEAE.

Abbreviations: AE, adverse event; COPD, chronic obstructive pulmonary disease; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; MDI, metered dose inhaler; TEAE, treatment-emergent adverse event.

Data Availability

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.