Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD

Figures & data

Figure 1 Inhaled, long-acting muscarinic antagonists, showing the molecular structure of glycopyrronium bromide compared with other anticholinergics.

Table 1 Glycopyrronium monotherapy studies and the outcome measures assessed in each study

Reference	Patients (n)	Study duration	Comparator	Primary endpoint	Secondary endpoint
GLOW-1^Citation24	822	26 weeks	• Placebo	Trough FEV1 at week 12	• TDI score • SGRQ score • Time to first moderate or severe COPD exacerbation • Mean daily rescue medication use
GLOW-2^Citation25	1,066	52 weeks	• OL tiotropium 18 μg • Placebo	Trough FEV1 at week 12	• Dyspnea (TDI at week 26) • Health status (SGRQ at week 52) • Time to first moderate or severe exacerbation • Mean daily rescue medication use
GLOW-3^Citation27	108	3 weeks	• Placebo	Exercise tolerance	• Peak and trough FEV1 • FVC • IC • TDI • Dyspnea under exercise • Leg discomfort
GLOW-4^Citation28	163	52 weeks	• OL tiotropium 18 μg	Safety and tolerability	• Efficacy – predose FEV1
GLOW-5^Citation29	657	12 weeks	• OL tiotropium 18 μg	Trough FEV1 at week 12 (noninferiority)	• FEV1 AUC0–4 h • TDI score • SGRQ score • Rescue medication use • Exacerbation rate • Safety • Tolerability
GLOW-6^Citation30	449	12 weeks	• Indacaterol monotherapy	Mean trough FEV1 of GB-indacaterol combination	• FEV1 AUC30 min–4 h • FVC • TDI • Mean daytime respiratory symptom score

Abbreviations: AUC, area under the curve; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GB, glycopyrronium bromide; GLOW, GLycopyrronium bromide in chronic Obstructive pulmonary disease airWays study; IC, inspiratory capacity; OL, open-label; TDI, Transition Dyspnea Index; SGRQ; St George’s Respiratory Questionnaire; h, hours; min, minutes.

Table 2 Studies using glycopyrronium in combination with indacaterol and outcome measures assessed in each study

Reference	Patients (n)	Study duration	Comparator	Primary endpoint	Secondary endpoint
SHINE^Citation32	2,144	26 weeks	• Indacaterol 150 μg • Glycopyrronium 50 μg • OL tiotropium 18 μg • Placebo	Trough FEV1	• TDI focal score • SGRQ total score • Daily rescue medication use • Safety and tolerability • Cardiovascular safety
SPARK^Citation33	2,224	64 weeks	• Glycopyrronium 50 μg • OL tiotropium 18 μg	Rate of moderate to severe exacerbations	• Adverse events
BEACON^Citation37	193	4 weeks	• Indacaterol 150 μg • Glycopyrronium 50 μg	Trough FEV1	• FEV1 AUC0–4 h • Symptom scores • Rescue medication use • Safety and tolerability
BRIGHT^Citation35	85	3 weeks	• OL tiotropium 18 μg • Placebo	Exercise endurance time (cycle ergometry)	• Dynamic IC • Trough IC • Trough FEV1 • Trough FVC
ENLIGHTEN^Citation36	339	52 weeks	• Placebo	Safety and tolerability	• Pre-dose FEV1 • Safety based on ECG, vital signs, and laboratory evaluation
BLAZE^Citation34	247	6 weeks	• OL tiotropium 18 μg • Placebo	Improvement in dyspnea via SAC version of the BDI and TDI	• Lung function • Rescue medication use • Safety
ILLUMINATE^Citation31	523	26 weeks	• Salmeterol-fluticasone 50/500 μg	FEV1 AUC0–12 h	• Pre-dose trough FEV1 • Peak FEV1 • FVC AUC0–12 h • Pre-dose trough FVC • TDI score • SGRQ total score • Rescue medication use

Abbreviations: AUC, area under the curve; BDI, Basal Dyspnea Index; ECG, electrocardiogram; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GB, glycopyrronium bromide; IC, inspiratory capacity; OD, once daily; OL, open-label; SAC, self-administered computerized version; SFC, salmeterol-fluticasone combination; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; h, hours.

Table 3 Treatment differences with glycopyrronium versus placebo and tiotropium in the GLOW studies and SHINE trial

Study	Glycopyrronium (50 μg) versus placebo			Glycopyrronium (50 μg) versus tiotropium (18 μg)
	GLOW-1	GLOW-2	SHINE	GLOW-2	GLOW-5	SHINE
Lung function (mL)a
Δ through FEV1	108*	97*	120*	14^NS	0^NS	10^NS
Dyspnea (TDI)b
Δ TDI total score	1.04*	0.81*	0.89*	−0.13^NS	−0.188^NS	0.31
Percentage of patients achieving MCIDc	61.3 versus 48.3*	55.3 versus 44.2*	63.7 versus 57.5$	55.3 versus 53.4	58.6 for both	63.7 versus 59.2
Health status (SGRQ)b
Δ SGRQ total score	−2.81*	−3.38**	−1.83^NS	0.86^NS	0.65^NS	−0.95^NS
Percentage of patients achieving MCIDd	56.8 versus 46.3*	54.3 versus 50.8^NS	60.5 versus 56.6^NS	54.3 versus 59.3	55.2 versus 54	60.5 versus 56.4
Exacerbationse
Time to first exacerbation, % risk reduction	31$	34**	NA	−5^NS	0^NS	NA
Rate of exacerbations (annual)	0.72	0.66	NA	−0.14^NS	0.03^NS	NA
Rescue medication usee
Δ puffs/day (LSM)	−0.46*	−0.37$	−0.3^NS	0.26^NS	0^NS	0.11^NS

Notes:

$ P<0.05,

* P<0.01,

** P<0.001

a at week 12 in GLOW-1, GLOW-2, and GLOW-5, and week 26 in SHINE

b at week 26 in all studies, except GLOW-5 (week 12)

c change in TDI total score ≥1 unit from baseline

d change in SGRQ total score ≥4 units from baseline

e at week 26 in GLOW-1 and SHINE, and week 52 in GLOW-2.

Abbreviations: FEV₁, forced expiratory volume in 1 second; GLOW, GLycopyrronium bromide in chronic Obstructive pulmonary disease airWays study; LSM, least square mean; MCID, minimal clinically important difference; NS, nonsignificant; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 4 Treatment differences with QVA149 versus placebo and active comparators in the Phase III IGNITE studies

Study	QVA149 (110/50 μg) versus placebo		QVA149 (110/50 μg) versus indacaterol (150 μg)	QVA149 (110/50 μg) versus glycopyrronium (50 μg)		QVA149 (110/50 μg) versus tiotropium (80 μg)			QVA149 (110/50 μg) versus SFC (50/500 μg)
	SHINE	BLAZE	SHINE	SHINE	SPARK	SHINE	BLAZE	SPARK	ILLUMINATE
Lung function (mL)a
Δ through FEV1	200**	NR	70**	90**	70**	80**	NR	60**	103**
Dyspnea (TDI)a
Δ TDI total score	1.09**	1.37**	0.26^NS	0.21^NS	NR	0.51$	0.49$	NR	0.76*
Percentage of patients achieving MCIDb	68.1 versus 57.5*	33.1 versus 16.3** (moderate COPD) 41.7 versus 21.7* (severe COPD)	68.1 versus 64.6$	68.1 versus 63.7$	NR	68.1 versus 59.2$	33.1 versus 21.8$	NR	67.5 versus 56.8$
Health status (SGRQ)a
Δ SGRQ total score	−3.01*	NR	−1.09^NS	−1.18^NS	−2.07**	−2.13*	NR	2.69$	−1.24^NS
Percentage of patients achieving MCIDc	63.7 versus 56.6$	NR	63.7 versus 63.0^NS	63.7 versus 60.5^NS	57.3 versus 51.8^NS	63.7 versus 56.4^NS	NR	57.3 versus 51.8^NS	NS
Exacerbationsa
Time to first exacerbation, % risk reduction	NR	NR	NR	NR	0.79^NS	NR	NR	1.13^NS	NR
Rate of all exacerbations (annual)	NR	NR	NR	NR	0.85*	NR	NR	0.86*	NR
Rescue medication usea (Δ puffs/day)	−0.96**	−1.43**	−0.30*	−0.66	−0.81**	−0.54*	−0.45*	−0.76**	−0.39$

Notes:

$ P<0.05,

* P<0.01,

** P<0.001

a at week 26 in SHINE and ILLUMINATE, week 6 for BLAZE, and week 64 for SPARK

b change in TDI total score ≥1 unit from baseline

c change in SGRQ total score ≥4 units from baseline.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; MCID, minimal clinically important difference; NR, not reported; NS, nonsignificant; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; SFC, salmeterol/fluticasone fixed dose combination.

Figure 2 Effect of QVA149, its monocomponents, and tiotropium on mean trough FEV₁ (A), responder analysis for improvement in TDI score (B), SGRQ score (C), and annualized rate ratio of moderate or severe COPD exacerbations (D).

Notes: SHINE trial data for (A–C) and SPARK trial data for (D). In A, the comparisons are with placebo (1.25 L) and all values are at week 26; delta values shown are the primary endpoint of the trial. In C, the mean differences shown within the bars are the differences between bronchodilator and placebo. The mean differences above the bars are between QVA149 and monotherapy. (A–C) data from Bateman ED, et al.³² (D) data from Wedzicha JA, et al.³³ *P<0.001 for comparison with placebo.
Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; NS, nonsignificant; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

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