Efficacy and safety of four doses of glycopyrrolate/formoterol fumarate delivered via a metered dose inhaler compared with the monocomponents in patients with moderate-to-severe COPD

Figures & data

Figure 1 Study design.

Abbreviations: PFT, pulmonary function test; Rx, treatment.

Figure 2 Patient disposition.

Note: Data presented as n (%).
Abbreviations: FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; MDI, metered dose inhaler.

Table 1 Baseline demographics and clinical characteristics (safety population)

Parameter	GFF MDI 36/9.6 µg N=56	GFF MDI 36/7.2 µg N=58	GFF MDI 18/9.6 µg N=57	GFF MDI 9/9.6 µg N=57	GP MDI 36 µg N=61	GF MDI 9.6 µg N=61	Gll patients N=185
Mean age, years (SD)	61.2 (8.8)	63.7 (9.3)	62.3 (9.1)	61.6 (9.1)	62.5 (9.4)	62.3 (9.8)	62.1 (9.2)
Mean BMI, kg/m^2 (SD)a	29.7 (6.4)	28.4 (6.2)	28.8 (6.7)	30.3 (6.2)	28.0 (6.0)	28.5 (6.1)	28.9 (6.3)
Gender, % male	60.7	67.2	56.1	49.1	55.7	59.0	57.8
Race/ethnicity, %
Caucasian	94.6	91.4	89.5	96.5	88.5	95.1	91.9
Black or African	0	3.4	10.5	3.5	8.2	3.3	5.4
Other	5.4	5.2	0	0	3.3	1.6	2.7
Smoking status, % current	55.4	44.8	50.9	54.4	59.0	54.1	53.0
Mean smoking history, pack-years (SD)	56.2 (33.5)	55.2 (25.3)	51.5 (26.1)	55.9 (28.8)	57.7 (26.6)	50.2 (29.0)	54.3 (28.5)
Mean duration of COPD at baseline, years (SD)	7.4 (6.3)	7.3 (6.4)	7.2 (8.4)	8.2 (7.9)	7.3 (5.4)	7.6 (6.2)	7.5 (6.7)
COPD severity,b % severe	45.5	43.1	45.6	42.1	41.0	41.0	42.7
Mean screening % predicted FEV1 (SD)c
Prebronchodilator	44.8 (13.2)	48.3 (13.5)	45.2 (13.3)	45.6 (12.9)	45.6 (13.5)	46.4 (13.0)	46.0 (13.2)
Postbronchodilator	51.1 (13.2)	54.3 (12.5)	52.7 (12.6)	53.8 (13.0)	53.3 (13.5)	53.4 (12.9)	53.2 (12.9)
Mean screening FEV1, L (SD)c
Prebronchodilator	1.371 (0.484)	1.517 (0.592)	1.364 (0.566)	1.341 (0.449)	1.362 (0.498)	1.432 (0.541)	1.398 (0.524)
Postbronchodilator	1.574 (0.529)	1.704 (0.581)	1.583 (0.581)	1.589 (0.487)	1.605 (0.570)	1.641 (0.555)	1.617 (0.549)
Mean reversibility postbronchodilator for FEV1, % (SD)c	16.4 (16.2)	15.5 (16.2)	19.4 (17.1)	20.2 (15.9)	19.4 (15.7)	17.0 (14.6)	18.0 (15.9)
Mean baseline inspiratory capacity, L (SD)d	2.154 (0.627)	2.208 (0.659)	2.058 (0.587)	2.040 (0.544)	2.037 (0.595)	2.103 (0.623)	NA

Notes:

a N=53, N=55, N=57, N=55, N=61, N=61, N=181.

b ITT population; N=55, N=58, N=57, N=57, N=61, N=61, N=185.

c mITT population; N=43, N=50, N=45, N=52, N=51, N=51, N=146.

d mITT population; N=43, N=48, N=45, N=52, N=51, N=51.

Abbreviations: BMI, body mass index; 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; mITT, modified intent-to-treat; NA, not available; SD, standard deviation.

Figure 3 (A) FEV₁ AUC_0–12 on Day 7^a,b (B) Change from baseline in FEV₁ over time on Day 7^c (mITT population).

Notes: *.<0.05, **.<0.01, ***.<0.001, ^#P<0.0001. ^aPairwise treatment comparisons. ^bThe geometric means are plotted, which are the exponentiated values of the LSMs for FEV₁ AUC_0–12 on the log scale. Error bars represent 95% CIs. The GMRs reported below the graph are shown for the comparisons with GP MDI 36 µg and FF MDI 9.6 µg. ^cError bars represent SE.
Abbreviations: AUC_0–12, area under the curve from 0 to 12 hours; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GMR, geometric mean ratio; GP, glycopyrrolate; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable; SE, standard error.

Table 2 Summary of secondary efficacy endpoints on Day 1 (mITT population)

Proportion of patients achieving ≥12% improvement in FEV1
Treatment	Proportion of patients achieving ≥12% improvement in FEV1, %	Differences between treatments, % (n [%]/n [%])a
		GP MDI 36 µg	FF MDI 9.6 µg
GFF MDI 36/9.6 µg	81.4	30.0	−14.3
N=43		(8 [80.0]/5 [50.0])	(5 [71.4]/6 [85.7])
GFF MDI 36/7.2 µg	80.0	25.0	8.3
N=50		(6 [75.0]/4 [50.0])	(11 [91.7]/10 [83.3])
GFF MDI 18/9.6 µg	82.2	0	22.2
N=45		(8 [80.0]/8 [80.0])	(9 [100.0]/7 [77.8])
GFF MDI 9/9.6 µg	84.6	27.3	−9.1
N=52		(11 [100.0]/8 [72.7])	(9 [81.8]/10 [90.9])
GP MDI 36 µg	66.7	N/A	−16.7
N=51			(9 [75.0]/11 [91.7])
FF MDI 9.6 µg	86.3	Shown above	N/A
N=51
Time to onset of action (≥10% improvement from baseline in FEV1)
Treatment	Proportion of patients achieving ≥10% improvement in FEV1 within 2 hours, %	Difference in expected time to onset, hours (95% CI)
		GP MDI 36 µg	FF MDI 9.6 µg
GFF MDI 36/9.6 µg	81.4	−0.18	0.12
N=43		(−0.39, 0.04)	(−0.08, 0.31)
GFF MDI 36/7.2 µg	92.0	−0.30*	−0.01
N=50		(−0.50, −0.09)	(−0.18, 0.16)
GFF MDI 18/9.6 µg	86.7	−0.18	0.11
N=45		(−0.40, 0.03)	(−0.07, 0.28)
GFF MDI 9/9.6 µg	88.5	−0.27*	0.02
N=52		(−0.48, −0.07)	(−0.15, 0.18)
GP MDI 36 µg	76.5	N/A	0.29*
N=51			(0.10, 0.48)
FF MDI 9.6 µg	90.2	Shown above	N/A
N=51

Notes:

* P<0.01.

a Pairwise treatment comparisons, (n [%]/n [%] is n [%] responding to treatment/n [%] responding to comparator for patients with non-missing data for both treatment and comparator).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat, N/A, not applicable.

Figure 4 (A) Peak change from baseline in FEV₁ through 2 hours on Day 1^a,b (B) Peak change from baseline in IC on Day 1^a,b (mITT population).

Notes: *.<0.05, **.<0.01, ***.<0.001. ^aPairwise treatment comparisons. ^bError bars represent 95% CIs. Data shown below the graph are treatment differences for the comparisons with GP MDI 36 µg and FF MDI 9.6 µg.
Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable.

Table 3 Summary of secondary efficacy endpoints on Day 7 (mITT population)

Parameter	Change from baseline	Differences between treatmentsa
		GP MDI 36 µg		FF MDI 9.6 µg
Baseline-adjusted LSM change from baseline in morning predose FEV1 (95% CI), Lb
GFF MDI 36/9.6 µg	0.110		0.010		0.007
N=43	(0.061, 0.159)		(−0.052, 0.072)		(−0.057, 0.070)
GFF MDI 36/7.2 µg	0.152		0.052		0.049
N=49	(0.105, 0.199)		(−0.009, 0.114)		(−0.010, 0.108)
GFF MDI 18/9.6 µg	0.122		0.022		0.019
N=45	(0.073, 0.170)		(−0.039, 0.083)		(−0.043, 0.080)
GFF MDI 9/9.6 µg	0.131		0.031		0.028
N=52	(0.085, 0.177)		(−0.028, 0.091)		(−0.031, 0.087)
GP MDI 36 µg	0.100		N/A		−0.003
N=51	(0.053, 0.146)				(−0.062, 0.055)
FF MDI 9.6 µg	0.103		Shown above		N/A
N=51	(0.057, 0.149)
Baseline-adjusted LSM change from baseline in mean evening 12-hour postdose trough FEV1 (95% CI), Lb
GFF MDI 36/9.6 µg	0.073		−0.008		−0.047
N=43	(0.023, 0.123)		(−0.069, 0.052)		(−0.109, 0.015)
GFF MDI 36/7.2 µg	0.080		−0.001		−0.040
N=48	(0.032, 0.129)		(−0.062, 0.060)		(−0.098, 0.018)
GFF MDI 18/9.6 µg	0.105		0.023		−0.016
N=44	(0.055, 0.154)		(−0.037, 0.083)		(−0.076, 0.045)
GFF MDI 9/9.6 µg	0.112		0.030		−0.009
N=51	(0.064, 0.159)		(−0.029, 0.089)		(−0.067, 0.050)
GP MDI 36 µg	0.081		N/A		−0.039
N=49	(0.033, 0.129)				(−0.096, 0.018)
FF MDI 9.6 µg	0.120		Shown above		N/A
N=50	(0.073, 0.168)

Notes:

a Pairwise treatment comparisons.

b Data from one patient in the GFF MDI 36/7.2 µg treatment group were excluded as the patient showed a decline in lung function prior to the onset of an exacerbation.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable.

Figure 5 (A) Peak change from baseline in FEV₁ through 6 hours on Day 7^a,b (B) Peak change from baseline in IC on Day 7^a,b (mITT population).

Notes: *.<0.05, **.<0.01, ^#P<0.0001. ^aPairwise treatment comparisons. ^bError bars represent 95% CIs. Data shown below the graph are treatment differences for the comparisons with GP MDI 36 µg and FF MDI 9.6 µg.
Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable.

Table 4 Summary of AEs (safety population)

Parameter	GFF MDI 36/9.6 µg N=56	GFF MDI 36/7.2 µg N=58	GFF MDI 18/9.6 µg N=57	GFF MDI 9/9.6 µg N=57	GP MDI 36 µg N=61	FF MDI 9.6 µg N=61	Gll patients N=185
At least one TEAE, n (%)	13 (23.2)	18 (31.0)	13 (22.8)	11 (19.3)	15 (24.6)	14 (23.0)	69 (37.3)
TEAEs related to study treatment, n (%)a	7 (12.5)	12 (20.7)	6 (10.5)	9 (15.8)	9 (14.8)	10 (16.4)	44 (23.8)
TEAEs leading to early withdrawal, n (%)	4 (7.1)	1 (1.7)	4 (7.0)	0	3 (4.9)	2 (3.3)	14 (7.6)
Serious AEs, n (%)	0	1 (1.7)	0	0	2 (3.3)	0	3 (1.6)
Serious AEs leading to early withdrawal, n (%)	0	0	0	0	1 (1.6)	0	1 (0.5)
TEAEs (preferred term) reported in ≥2% of all patients, n (%)
Dry mouth	3 (5.4)	3 (5.2)	1 (1.8)	5 (8.8)	2 (3.3)	4 (6.6)	16 (8.6)
COPD	2 (3.6)	2 (3.4)	2 (3.5)	0	2 (3.3)	1 (1.6)	9 (4.9)
Tremor	0	2 (3.4)	0	2 (3.5)	0	4 (6.6)	8 (4.3)
Headache	1 (1.8)	4 (6.9)	0	0	0	0	5 (2.7)
Cough	2 (3.6)	1 (1.7)	0	0	0	1 (1.6)	4 (2.2)

Notes:

a Considered by the Investigator as possibly, probably or definitely related, based on their assessment at the time of the study.

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.