Efficacy and Safety of Inhaled Glycopyrronium Bromide in COPD: A Randomized, Parallel Group, Dose-Ranging Study (GLIMMER)

Figures & data

Figure 1. Subject disposition.

*The protocol permitted subjects to be screened multiple times. ^†One subject randomized to GB 25 µg BID withdrew prior to receiving study medication, and so was excluded from the safety and ITT populations. GB, glycopyrronium bromide; BID, twice daily; QD, once daily; ITT, intention-to-treat.

Table 1. Subject demographics and disease characteristics at screening (ITT population).

	GB				Placebo N = 121	Tiotropium 18 µg QD N = 123	Overall N = 732
	6.25 μg BID N = 121	12.5 μg BID N = 123	25 μg BID N = 121	50 μg BID N = 123
Age (years), mean (SD)	64.1 (9.1)	65.3 (9.1)	65.3 (8.2)	64.9 (9.1)	64.9 (9.3)	63.8 (9.6)	64.7 (9.1)
Range	45, 90	41, 85	43, 84	46, 86	45, 90	43, 88	41, 90
Age category, n (%)
<65 years	59 (48.8)	53 (43.1)	56 (46.3)	62 (50.4)	60 (49.6)	62 (50.4)	352 (48.1)
65–84 years	60 (49.6)	68 (55.3)	65 (53.7)	60 (48.8)	58 (47.9)	59 (48.0)	370 (50.5)
≥85 years	2 (1.7)	2 (1.6)	0	1 (0.8)	3 (2.5)	2 (1.6)	10 (1.4)
Sex, male, n (%)	63 (52.1)	55 (44.7)	54 (44.6)	58 (47.2)	69 (57.0)	66 (53.7)	365 (49.9)
Race, n (%)
Black or African American	13 (10.7)	10 (8.1)	10 (8.3)	14 (11.4)	12 (9.9)	10 (8.1)	69 (9.4)
White	107 (88.4)	110 (89.4)	107 (88.4)	108 (87.8)	104 (86.0)	110 (89.4)	646 (88.3)
Other	1 (0.8)	0	0	0	4 (3.3)	1 (0.8)	6 (0.8)
Unknown or not reported	0	3 (2.4)	4 (3.3)	1 (0.8)	1 (0.8)	2 (1.6)	11 (1.5)
BMI (kg/m²), mean (SD)	28.7 (7.1)	29.1 (6.0)	28.5 (6.8)	29.6 (6.7)	29.3 (6.5)	28.1 (5.5)	28.9 (6.5)
Time since first COPD diagnosis (years), mean (SD)	9.2 (5.6)	9.8 (6.1)	9.9 (6.5)	8.6 (5.4)	9.8 (5.9)	8.2 (5.8)	9.2 (5.9)
COPD maintenance medication on study entry, n (%)
LAMA	24 (19.8)	22 (17.9)	31 (25.6)	22 (17.9)	25 (20.7)	27 (22.0)	151 (20.6)
ICS + LABA	80 (66.1)	89 (72.4)	74 (61.2)	93 (75.6)	78 (64.5)	83 (67.5)	497 (67.9)
ICS + LAMA	0	1 (0.8)	2 (1.7)	1 (0.8)	2 (1.7)	2 (1.6)	8 (1.1)
LABA + LAMA	6 (5.0)	8 (6.5)	3 (2.5)	1 (0.8)	3 (2.5)	3 (2.4)	24 (3.3)
ICS + LABA + LAMA	11 (9.1)	3 (2.4)	11 (9.1)	6 (4.9)	13 (10.7)	8 (6.5)	52 (7.1)
Smoking status n (%)
Current smoker	61 (50.4)	59 (48.0)	59 (48.8)	68 (55.3)	55 (45.5)	67 (54.5)	369 (50.4)
Ex-smoker	60 (49.6)	64 (52.0)	62 (51.2)	55 (44.7)	66 (54.5)	56 (45.5)	363 (49.6)
Number of pack-years, mean (SD)	50.8 (25.1)	54.6 (27.3)	49.2 (27.4)	48.6 (24.3)	50.5 (25.9)	46.9 (24.3)	50.1 (25.8)
FEV1 % predicted, mean (SD)*	59.1 (8.5)	59.6 (10.0)	60.8 (10.5)	59.4 (9.7)	58.9 (9.0)	58.7 (9.0)	59.4 (9.5)
≥80% predicted (n, %)	0	0	0	1 (0.8)	0	0	1 (0.1)
≥50 to < 80% (n, %)	110 (90.9)	109 (88.6)	105 (86.8)	111 (90.2)	107 (88.4)	112 (91.1)	654 (89.3)
≥30 to < 50% (n, %)	11 (9.1)	14 (11.4)	16 (13.2)	11 (8.9)	14 (11.6)	11 (8.9)	77 (10.5)
FEV1/FVC, mean (SD)*	0.55 (0.09)	0.54 (0.09)	0.56 (0.09)	0.55 (0.08)	0.55 (0.08)	0.54 (0.08)	0.55 (0.08)
Reversibility FEV1 (%), mean (SD)	19.2 (13.0)	18.9 (12.1)	19.4 (11.1)	20.2 (13.3)	20.9 (12.8)	20.3 (13.3)	19.8 (12.6)

* Post-bronchodilator. ITT, intention-to-treat; GB, glycopyrronium bromide; BID, twice daily; QD, once daily; SD, standard deviation; BMI, body mass index; LAMA, long-acting muscarinic antagonist; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity.

Figure 2. FEV₁ AUC_0–12h on Day 1 and at Week 6 (ITT population).

Bars are adjusted mean changes from baseline, with 95% confidence intervals (*95% CI and p values adjusted for multiplicity). Values are adjusted mean treatment–placebo differences, 95% confidence intervals and p values. ^†p < 0.05 vs GB 6.25 µg BID; ^‡p < 0.05 vs GB 12.5 µg BID. Tiotropium–GB differences were not analyzed. ITT, intention-to-treat; GB, glycopyrronium bromide; BID, twice daily; QD, once daily; FEV₁, forced expiratory volume in 1 second; AUC, area under the curve.

Figure 3. Pre-dose morning FEV₁ at Weeks 3 and 6 (ITT population).

Bars are adjusted mean changes from baseline, with 95% confidence intervals. Values are adjusted mean treatment–placebo differences, 95% confidence intervals and p values. ^†p < 0.05 vs GB 6.25 µg BID. Tiotropium–GB differences were not analyzed. ITT, intention-to-treat; GB, glycopyrronium bromide; BID, twice daily; QD, once daily; FEV₁, forced expiratory volume in 1 second.

Figure 4. TDI focal score at Weeks 3 and 6 (ITT population).

Bars are adjusted mean, with 95% confidence intervals. Values are adjusted mean treatment–placebo differences, 95% confidence intervals and p values. ^†p < 0.05 vs GB 6.25 µg BID. Tiotropium–GB differences were not analyzed. ITT, intention-to-treat; GB, glycopyrronium bromide; BID, twice daily; QD, once daily; TDI, Transition Dyspnea Index.

Figure 5. E-RS total score, analyzed across the study duration (ITT population).

There were no significant differences between GB doses. Tiotropium–GB differences were not analyzed. ITT, intention-to-treat; GB, glycopyrronium bromide; BID, twice daily; QD, once daily; E-RS, Evaluating Respiratory Symptoms questionnaire.

Table 2. TDI focal score responder analysis at Weeks 3 and 6 (ITT population).

	GB				Placebo N = 121	Tiotropium 18 µg QD N = 123
	6.25 μg BID N = 121	12.5 μg BID N = 123	25 μg BID N = 121	50 μg BID N = 123
Week 3
N	121	123	121	123	119	122
Responders, n (%)	70 (57.9)	78 (63.4)	75 (62.0)	84 (68.3)	67 (56.3)	74 (60.7)
Odds ratio vs placebo (95% CI); p value	1.05 (0.62, 1.77); p = 0.848	1.35 (0.80, 2.28); p = 0.264	1.29 (0.76, 2.18); p = 0.343	1.74 (1.02, 2.98); p = 0.042		1.20 (0.71, 2.02); p = 0.503
Week 6
N	118	120	113	122	115	117
Responders, n (%)	74 (62.7)	83 (69.2)	82 (72.6)	91 (74.6)^†	55 (47.8)	80 (68.4)
Odds ratio vs placebo (95% CI); p value	1.92 (1.12, 3.30); p = 0.018	2.59 (1.50, 4.49); p < 0.001	3.08 (1.75, 5.44); p < 0.001	3.42 (1.94, 6.02); p < 0.001		2.45 (1.41, 4.26); p = 0.001

A responder is a subject with TDI focal score ≥1. ^†p < 0.05 vs GB 6.25 µg BID. Tiotropium–GB differences were not analyzed. ITT, intention-to-treat; GB, glycopyrronium bromide; BID, twice daily; QD, once daily; TDI, Transition Dyspnea Index.

Table 3. Adverse events, overall and most common preferred terms (≥2% of subjects in any group; safety population).

	GB				Placebo N = 121	Tiotropium 18 µg QD N = 123
	6.25 μg BID N = 121	12.5 μg BID N = 123	25 μg BID N = 121	50 μg BID N = 123
Adverse events	34 (28.1)	36 (29.3)	30 (24.8)	34 (27.6)	27 (22.3)	32 (26.0)
COPD	2 (1.7)	1 (0.8)	4 (3.3)	4 (3.3)	4 (3.3)	4 (3.3)
Upper respiratory tract infection	4 (3.3)	2 (1.6)	2 (1.7)	5 (4.1)	2 (1.7)	3 (2.4)
Headache	5 (4.1)	2 (1.6)	1 (0.8)	3 (2.4)	2 (1.7)	0
Hypertension	2 (1.7)	3 (2.4)	3 (2.5)	0	1 (0.8)	2 (1.6)
Viral upper respiratory tract infection	0	5 (4.1)	1 (0.8)	1 (0.8)	3 (2.5)	0
Dyspnea	4 (3.3)	1 (0.8)	0	1 (0.8)	0	2 (1.6)
Bronchitis	1 (0.8)	4 (3.3)	1 (0.8)	1 (0.8)	0	0
Related adverse events	9 (7.4)	5 (4.1)	5 (4.1)	3 (2.4)	5 (4.1)	3 (2.4)
Dyspnea	3 (2.5)	0	0	0	0	0
Severe adverse events	1 (0.8)	5 (4.1)	0	1 (0.8)	1 (0.8)	0
Related severe adverse events	1 (0.8)	0	0	0	0	0
Serious adverse events	2 (1.7)	5 (4.1)	1 (0.8)	1 (0.8)	1 (0.8)	1 (0.8)
Related serious adverse events	1 (0.8)	0	0	0	0	0
Adverse events leading to study discontinuation	5 (4.1)	3 (2.4)	6 (5.0)	2 (1.6)	3 (2.5)	4 (3.3)
COPD	1 (0.8)	0	3 (2.5)	2 (1.6)	3 (2.5)	3 (2.4)
Dyspnea	3 (2.5)	0	0	0	0	0
Adverse events leading to death	0	0	0	0	0	0

GB, glycopyrronium bromide; BID, twice daily; QD, once daily.

Table 4. QTc (Fridericia’s correction) interval data at any post-dose timepoint (Safety population).

	GB				Placebo N = 121	Tiotropium 18 µg QD N = 123
	6.25 μg BID N = 121	12.5 μg BID N = 123	25 μg BID N = 121	50 μg BID N = 123
Change from baseline
>30 msec	19 (15.7)	20 (16.3)	21 (17.4)	20 (16.3)	16 (13.2)	18 (14.6)
>60 msec	0	1 (0.8)	0	2 (1.6)	2 (1.7)	1 (0.8)
Individual values
>450 msec (males) or > 470 msec (females)	6 (5.0)	7 (5.7)	6 (5.0)	5 (4.1)	2 (1.7)	6 (4.9)
>500 msec	0	1 (0.8)	0	0	0	0

GB, glycopyrronium bromide; BID, twice daily; QD, once daily.

Data availability

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