An overview of glycopyrrolate/eFlow® CS in COPD

Figures & data

Table 1. Summary of the efficacy outcomes for LAMA monotherapies in selected trials.

Drug	Dose	Delivery device	Pivotal trial	Trial duration	Efficacy outcomes
Aclidinium	200/400 mcg b.i.d.	Dry powder	ACCORD I [19]	12 weeks	Mean change from baseline in trough FEV1 of 0.086 and 0.124 L for 200 and 400 mcg b.i.d., respectively
bromide		inhaler
			ACCORD II [20]	12 weeks	Mean change from baseline in trough FEV1 of 0.051 and 0.072 L for 200 and 400 mcg b.i.d., respectively Mean change from baseline in SGRQ total score of –6.0 and –5.4 for 200 and 400 mcg b.i.d., respectively
			ACCLAIM/COPD I and I [21]	52 weeks	200 mcg q.d.
					Placebo-adjusted mean changes from baseline in trough FEV1 at 12 and 28 weeks were 0.061 and 0.067 L for ACCLAIM/COPD I and 0.063 and 0.059 L for ACCLAIM/COPD II (p < 0.001 compared to placebo for both studies) At 52 weeks, mean change from baseline in SGRQ total score was –4.63 units and –3.49 units for ACCLAIM/COPD I and ACCLAIM/COPD II, respectively
			LAS-MD-35 [22]	52 weeks	400 mcg b.i.d.
					Mean change from baseline in trough FEV1 of 0.072 L Mean change from baseline in SGRQ total score of –5.2 units
Tiotropium	18 mcg q.d.	HandiHaler	Combined analysis of two 6-month studies [23]	24 weeks	Mean change from baseline in trough FEV1 of 0.120 L Mean change from baseline in SGRQ total score of –4.2 units
			Combined analysis of two 1-year studies [24]	1 year	Mean change from baseline in trough FEV1 of 0.110–0.130 L (p < 0.01 compared to placebo) Mean improvement from baseline in SGRQ total score was significantly greater than placebo (p < 0.05)
			UPLIFT [25]	4 years	Placebo-adjusted mean change from baseline in FEV1 of 0.087–0.103 L before bronchodilation and 0.047–0.065 L after bronchodilation (p < 0.001 compared to placebo) Mean change from baseline in SGRQ total score ranged from −2.3 to −3.3 units (p < 0.001 compared to placebo)
Glycopyrrolate	15.6 mcg b.i.d.	Neohaler®	GEM 1 [26]	12 weeks	Superior change from baseline in FEV1 AUC0-12h compared to placebo (LSM treatment difference 0.139 L (p < 0.001) Placebo-adjusted LSM change from baseline in SGRQ total score of –2.8 units (p = 0.016 compared to placebo)
			GEM 2 [27]	12 weeks	Superior change from baseline in FEV1 AUC0-12h compared to placebo (LSM treatment difference 0.123 L (p < 0.001) Placebo-adjusted LSM change from baseline in SGRQ total score of –5.2 units
			GEM 3 [28]	52 weeks	LSM change from baseline of FEV1 was 0.056 L, and was similar to that observed with indacaterol (p = 0.902)
Umeclidinium	62.5 mcg q.d.	ELLIPTA™ dry	NCT02207829 [29]	12 weeks	Mean change from baseline in FEV1 of 0.147 L, which was greater than the change observed with TIO (p < 0.001) Mean change from baseline of SGRQ total score of –6.03, which was similar to that observed with TIO (p = 0.571)
bromide		powder inhaler
			NCT01387230 [30]	12 weeks	Placebo-adjusted LSM change from baseline in trough FEV1 of 0.127 L (p < 0.001 compared to placebo) Placebo-adjusted mean change from baseline in SGRQ total score of 7.9 units (p < 0.001 compared to placebo)
			NCT01313650 [31]	24 weeks	Statistically significant placebo-adjusted mean change from baseline in trough FEV1 of 0.115 L (p < 0.001) Mean change from baseline in SGRQ total score of –7.25 units (p ≤ 0.001 compared to placebo)
	125 mcg q.d.	ELLIPTA™ dry powder inhaler	NCT01313637 [32]	24 weeks	Statistically significant placebo-adjusted mean change from baseline in trough FEV1 of 0.160 L (p < 0.001) Mean SGRQ total score at week 24 was not statistically different from placebo
			NCT01316887 [33]	52 weeks	Placebo-adjusted mean change from baseline in trough FEV1 of 0.178 L

AUC, area under the curve; b.i.d., twice daily; FEV₁, forced expiratory volume in 1 s; LSM, least squares mean; q.d., once daily; SGRQ, St George’s Respiratory Questionnaire; TIO, tiotropium.

Table 2. Summary of phase II clinical studies.

Trial name	Study design	Patient population and functional criteria for study inclusion	Treatments	Primary outcomes
Leaker et al. [43]	Two-center Randomized Placebo-controlled Double-blind Dose finding Single dose Six-way crossover	N = 42 Moderate-to-severe COPD FEV1 30–70% of predicted normal At least 12% and 0.150 L reversibility to inhaled ipratropium bromide	GLY/eFlow (12.5, 25, 50, 100, and 200 mcg single dose)	Significant improvements in mean change from baseline in FEV1 at 24 h with doses ≥50 mcg Dose-response relationship for improvements in FEV1
GOLDEN 1 [41,45]	Multicenter Randomized Double-blind Placebo-controlled Seven arm Four-period crossover Incomplete block design 1 week	N = 140 Moderate-to-severe COPD FEV1 between 30–70% of predicted normal FEV1/FVC <0.70 Post-bronchodilator improvement in FEV1 ≥ 12% and ≤30%, and a minimum of 0.100 L	GLY/eFlow (25, 50, 100, and 200 mcg q.d.) Tiotropium bromide via HandiHaler® (18 mcg q.d.) Ipratropium bromide via general purpose nebulizer (500 mcg three times daily)	Dose-dependent and significant improvements in lung function, as measured by FEV1 AUC(0-24h) on day 7
GOLDEN 2 [39]	Randomized Double-blind Placebo-controlled Parallel arm 4 weeks	N = 282 Moderate-to-severe COPD FEV1 between 30–70% of predicted normal FEV1/FVC <0.70 At least 12% and 0.100 L reversibility to inhaled ipratropium bromide	GLY/eFlow CS (12.5, 25, 50, and 100 mcg b.i.d.)	Pooled analysis of GOLDEN 2 and GOLDEN 6 showed that GLY treatment resulted in clinically important and statistically significant improvements in lung function, at days 7 and 28 On day 7, placebo-adjusted changes from baseline in trough FEV1 of >0.100 L were observed with GLY 12.5, 25, and 50 mcg b.i.d. doses GLY 25 and 50 mcg b.i.d. doses were comparable to aclidinium bromide 400 mcg
GOLDEN 6 [39]	Randomized Double-blind Placebo- and active-controlled Crossover 1 week	N = 96 Moderate-to-severe COPD FEV1 between 40–70% of predicted normal FEV1/FVC <0.70 At least 12% and 0.100 L reversibility to inhaled ipratropium bromide	GLY/eFlow CS (3, 6.25, 12.5, 25, and 50 mcg b.i.d.) Aclidinium bromide 400 mcg b.i.d. via Pressair®

AUC, area under the curve; b.i.d., twice daily; FEV₁, forced expiratory volume in 1 s; GLY, glycopyrrolate; q.d., once daily.

Figure 1. Mean change from baseline in FEV₁ over time on Day 7 (pooled population) in the GOLDEN 2 and GOLDEN 6 studies [39]. Redrawn with author’s permission.

b.i.d., twice daily; FEV₁, forced expiratory volume in 1 s.

Figure 2. Least squares mean change from baseline in trough FEV₁ in subjects receiving GLY 25 or 50 mcg b.i.d. or placebo in pooled analysis of the GOLDEN 3 and GOLDEN 4 studies (a) and in subjects receiving GLY 50 mcg b.i.d. (57% of total population) or TIO 18 mcg q.d. (43% of total population) in the GOLDEN 5 study (b) [40,42]. Redrawn with author’s permission.

b.i.d., twice daily; GLY, glycopyrrolate; LSM, least squares mean; FEV₁, forced expiratory volume in 1 s; q.d., once daily; TIO, tiotropium.

Figure 3. Placebo-adjusted, least squares mean change from baseline in SGRQ total scores in subjects receiving GLY 25 or 50 mcg b.i.d. in the GOLDEN 3 (a) and GOLDEN 4 (b) studies, and in subjects receiving GLY 50 mcg b.i.d. (57% of total population) or TIO 18 mcg q.d. (43% of total population) in the GOLDEN 5 study (c) [40,42].

*p < 0.05; **p < 0.01 versus placebo.b.i.d., twice daily; CI, confidence interval; GLY, glycopyrrolate; LSM, least squares mean; MCID, minimal clinically important difference; q.d., once daily; SE, standard error; SGRQ, St George’s respiratory questionnaire; TIO, tiotropium.

Table 3. Summary of the safety profile of nebulized GLY from the GOLDEN phase III studies [40,42].

	GOLDEN 3			GOLDEN 4			GOLDEN 5
	Placebo (n = 218)	GLY 25 mcg b.i.d. (n = 217)	GLY 50 mcg b.i.d. (n = 218)	Placebo (n = 212)	GLY 25 mcg b.i.d. (n = 214)	GLY 50 mcg b.i.d. (n = 214)	GLY 50 mcg b.i.d. (n = 620)	TIO 18 mcg q.d. (n = 466)
Overall incidence of any TEAE, %	52.3	39.6	48.2	52.4	47.2	53.3	69.4	67.0
Discontinuations due to TEAEs, %	9.6	3.2	3.7	9.0	7.0	4.2	10.0	2.8

b.i.d., twice daily; GLY, glycopyrrolate; q.d., once daily; TEAE, treatment-emergent adverse event; TIO, tiotropium.

Table 4. Most common TEAEs (≥5% in any treatment group) observed in the GOLDEN phase III studies [40,42].

	GOLDEN 3			GOLDEN 4			GOLDEN 5
Preferred term, %	Placebo (n = 218)	GLY 25 mcg b.i.d. (n = 217)	GLY 50 mcg b.i.d. (n = 218)	Placebo (n = 212)	GLY 25 mcg b.i.d. (n = 214)	GLY 50 mcg b.i.d. (n = 214)	GLY 50 mcg b.i.d. (n = 620)	TIO 18 mcg q.d. (n = 466)
Cough	10.1	7.4	9.6	6.6	6.5	8.4	11.8	5.6
COPD	8.3	5.1	10.6	9.0	7.9	6.5	16.6	20.2
Bronchitis	1.4	0.9	0.9	1.4	1.4	2.3	4.5	5.2
Dyspnea	2.3	2.3	1.4	3.8	7.5	5.1	4.5	3.2
Nasopharyngitis	1.4	1.4	2.8	0.5	1.9	0.9	4.0	6.0
Upper respiratory	0.9	0.5	2.8	0.9	2.3	4.2	6.1	5.4
tract infection

b.i.d., twice daily; COPD, chronic obstructive pulmonary disease; GLY, glycopyrrolate; q.d., once daily; TEAE, treatment-emergent adverse event; TIO, tiotropium.

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