New developments in optimizing bronchodilator treatment of COPD: a focus on glycopyrrolate/formoterol combination formulated by co-suspension delivery technology

Figures & data

Table 1 LAMAs, LABAs, and LAMA/LABA FDCs commonly used for maintenance treatment of COPDa

Drug	Doseb,c	Actuations	Posology	Inhaler type
LAMAs
Aclidinium bromide^Citation17,Citation18	400 µg	1	BID	DPI
Glycopyrrolate^Citation19,Citation20	15.6 µg	1	BID	DPI
	63 µg	1	QD
Tiotropium^Citation21,Citation22	5 µg	2	QD	SMI
Umeclidinium^Citation23,Citation24	62.5 µg	1	QD	DPI
LABAs
Formoterol fumarate^Citation25,Citation26	11.5 µg	1	BID	DPI
Indacaterol^Citation27,Citation28	75 µg	1
	150 µg	1	All QD	DPI
	300 µg	1
Olodaterol^Citation29,Citation30	5 µg	2	QD	SMI
Salmeterol^Citation31	50 µg	1	BID	DPI
LAMA/LABA FDCs
Aclidinium bromide/formoterol fumarate^Citation57	400/11.5 µg	1	BID	DPI
Glycopyrrolate/formoterol fumarate^Citation58	18/9.6 µg	2	BID	MDI
Glycopyrrolate/indacaterol^Citation59,Citation60	15.6/27.5 µg	1	BID	DPI
	63/110 µg	1	QD
Tiotropium/olodaterol^Citation61	5/5 µg	2	QD	SMI
Umeclidinium/vilanterol^Citation62	62.5/25 µg	1	QD	DPI

Notes:

a Not all doses available in all countries;

b DPI doses represent predispensed amount, whereas SMI and MDI doses are amount dispensed from mouthpiece;

c Doses of glycopyrronium and formoterol fumarate dihydrate expressed as equivalent doses of glycopyrrolate and formoterol fumarate, respectively.

Abbreviations: BID, twice daily; DPI, dry powder inhaler; FDC, fixed-dose combination; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MDI, metered dose inhaler; QD, once daily; SMI, soft mist inhaler.

Table 2 Pivotal studies with LAMA/LABA FDCs

Druga	Trough FEV1 (L)	FEV1 AUC (L)	Peak FEV1 (L)	Rescue medication use (puffs/day)	SGRQ score
	Treatment difference vs placebo
NCT1437397, AUGMENT, 24 weeks, n=1,692, placebo-controlled^Citation63
ACL/FF 400/11.5 µg (n=338)	0.129*,b	–	0.285*	−1.11*	−4.36*,b
ACL/FF 400/5.8 µg (n=338)	0.111*,b	–	0.259*	−1.10*	−3.73*,b
ACL 400 µg (n=340)	0.101*,b	–	0.174*	−0.68*	−4.23*,b
FF 11.5 µg (n=339)	0.085*,b	–	0.182*	−0.90*	−2.49*,b
NCT1462942, ACLIFORM-COPD, 24 weeks, n=1,729, placebo-controlled^Citation64
ACL/FF 400/11.5 µg (n=385)	0.143*	0.221*,c	0.299*,b	−0.66*	−0.65
ACL/FF 400/5.8 µg (n=381)	0.111*	0.189*,c	0.253*,b	−0.73*	−1.83
ACL 400 µg (n=385)	0.117*	–	0.178*,b	–	0.71
FF 11.5 µg (n=384)	0.058*	–	0.161*,b	–	0.93
NCT1854645, PINNACLE-1, 24 weeks, n=2,103, placebo-controlled^Citation65
GFF MDI 18/9.6 µg (n=527)	0.150*	0.237*,c,d	0.291*	−1.08*	−2.52*
GP MDI 18 µg (n=451)	0.090*,b	–	0.158b	−0.8b	−0.2b
FF MDI 9.6 µg (n=452)	0.086*,b	–	0.198b	−1.1b	−1.9b
NCT1854658, PINNACLE-2, 24 weeks, n=1,615, placebo-controlled^Citation65
GFF MDI 18/9.6 µg (n=512)	0.103*	0.209*,c,d	0.267*	−1.04*	−1.72
GP MDI 18 µg (n=440)	0.050*,b	–	0.140b	−0.4b	−1.0b
FF MDI 9.6 µg (n=439)	0.048*,b	–	0.185b	−0.7b	−1.1b
NCT1970878, PINNACLE-3, 52 weeks, n=892e,^Citation66
GFF MDI 18/9.6 µg (n=1,035)	0.133	–	0.363	–	–
GP MDI 18 µg (n=888)	0.076	–	0.234	–	–
FF MDI 9.6 µg (n=884)	0.068	–	0.275	–	–
NCT1202188, SHINE, 26 weeks, n=2,144, symptomatic entry criteria (eDiary score), placebo-controlled^Citation67
GP/IND 63/110 µg (n=475)	0.20*	0.33*,c	0.33*	−0.96*	−3.01*
GP 63 µg (n=475)	0.12*	0.21*,c	0.20*	−0.30	−1.83
IND 150 µg (n=477)	0.13*	0.20*,c	0.21*	−0.65*	−1.92
NCT1727141, FLIGHT-1, 12 weeks, n=1,042, symptomatic entry criteria (mMRC ≥2), placebo-controlled^Citation68
GP/IND 15.6/27.5 µg (n=260)	0.213*	0.231*,c	0.260*	−1.22*	−3.8*
GP 15.6 µg (n=261)	0.103b	0.133b,c	0.160b	−0.64b	−2.1b
IND 27.5 µg (n=260)	0.132b	0.137b,c	0.151b	−0.72b	−1.9b
NCT1712516, FLIGHT-2, 12 weeks, n=1,001, symptomatic entry criteria (mMRC ≥2), placebo-controlled^Citation68
GP/IND 15.6/27.5 µg (n=250)	0.233*	0.262*,c	0.290*	−1.16*	−6.4*
GP 15.6 µg (n=251)	0.146b	0.183b,c	0.204b	−0.75b	−5.0b
IND 27.5 µg (n=251)	0.155b	0.150b,c	0.151b	−1.02b	−4.9b
NCT1431274, TOnado 1, 52 weeks, n=2,624e,f,^Citation69
TIO/OLO 5/5 µg (n=522)	0.136	0.256g	–	–	−6.84b,h
TIO/OLO 2.5/5 µg (n=522)	0.111	0.241g	–	–	−6.18b,h
TIO 5 µg (n=527)	0.065	0.139g	–	–	−5.61b,h
TIO 2.5 µg (n=525)	0.083	0.148g	–	–	−5.72b,h
OLO 5 µg (n=528)	0.054	0.133g	–	–	−5.15b,h
NCT1431287, TOnado 2, 52 weeks, n=2,539e,f,^Citation69
TIO/OLO 5/5 µg (n=507)	0.145	0.268g	–	–	See above
TIO/OLO 2.5/5 µg (n=508)	0.125	0.256g	–	–	See above
TIO 5 µg (n=506)	0.096	0.165g	–	–	See above
TIO 2.5 µg (n=507)	0.062	0.125g	–	–	See above
OLO 5 µg (n=510)	0.057	0.136g	–	–	See above
NCT1313650, 24 weeks, n=1,536, symptomatic entry criteria (mMRC ≥2), placebo-controlled^Citation70
UMEC/VIL 62.5/25 µg (n=413)	0.167*	–	0.224*	−0.8*	−5.51*
UMEC 62.5 µg (n=418)	0.115*	–	0.130*	−0.3	−4.69*
VIL 25 µg (n=421)	0.072*	–	0.108*	−0.9*	−5.19*
NCT1316900, 24 weeks, n=846, symptomatic entry criteria (mMRC ≥2)e,^Citation71
UMEC/VIL 125/25 µg (n=216)	0.209	–	0.333	−2.0	−9.03
UMEC/VIL 62.5/25 µg (n=212)	0.211	–	0.345	−2.0	−6.87
VIL 25 µg (n=209)	0.121	–	0.257	−1.8	−8.29
NCT1316913, 24 weeks, n=872, symptomatic entry criteria (mMRC ≥2)e,^Citation71
UMEC/VIL 125/25 µg (n=217)	0.223	–	0.349	−3.2	−10.52
UMEC/VIL 62.5/25 µg (n=218)	0.208	–	0.349	−2.7	−9.95
UMEC 125 µg (n=222)	0.186	–	0.282	−2.1	−8.40
NCT1313637, 24 weeks, n=1,493, symptomatic entry criteria (mMRC ≥2), placebo-controlled^Citation72
UMEC/VIL 125/25 µg (n=403)	0.238*	–	0.280*	−1.5*	−3.60*
UMEC 125 µg (n=407)	0.160*	–	0.180*	−0.8*	−0.31
VIL 25 µg (n=404)	0.124*	–	0.138*	−0.8*	−0.87

Notes:

* Significant versus placebo. Numbers indicate patients randomized, intent-to treat population, or patients treated, depending on population data presented in the source.

a Doses of glycopyrronium and formoterol fumarate dihydrate expressed as equivalent doses of glycopyrrolate and formoterol fumarate;

b Approximate value calculated based on data presented in source, so no statistical analysis available;

c FEV₁ AUC_0–12;

d At week 12;

e Reported as change from baseline, as study did not include placebo control;

f End points presented at week 24;

g FEV₁ AUC_0–3;

h Data reported for pooled studies.

Abbreviations: ACL, aclidinium bromide; AUC, area under curve; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IND, indacaterol; MDI, metered dose inhaler; OLO, olodaterol; SGRQ, St George’s Respiratory Questionnaire; TIO, tiotropium; UMEC, umeclidinium; VIL, vilanterol.

Table 3 Definitions of CID and sustained CID

Source	CID definition	Sustained CID definition
Rabe et al^Citation128	• Decrease of ≥100 mL from baseline in trough FEV1, or • ≥4-unit increase from baseline in SGRQ total score, or • Occurrence of moderate-to-severe COPD exacerbation	• FEV1 or SGRQ event occurring on two consecutive visits, or • FEV1 or SGRQ event occurring for ≥50% of all subsequent visits, or • Incidence of any moderate-to-severe exacerbation
Singh et al^Citation129	• Decrease of ≥100 mL from baseline in trough FEV1, or • ≥4-unit increase from baseline in SGRQ total score, or • Occurrence of moderate-to-severe COPD exacerbation on treatment	• CID occurring on two or more consecutive visits 4 weeks apart, or • CID occurring for ≥50% of all available subsequent visits • Incidence of any moderate-to-severe exacerbation
Anzueto et al^Citation127	Definition 1 • Decrease of ≥100 mL from baseline in trough FEV1, or Definition 2 • ≥1 unit decrease in TDI, or Both definitions • ≥4-unit increase from baseline in SGRQ total score, or • Occurrence of moderate-to-severe COPD exacerbation after first dose of study medication	Definition 1 • FEV1 event occurring on two consecutive visits at least 4 weeks apart or for >50% of all available subsequent visits, or Definition 2 • TDI event occurring on two consecutive visits at least 4 weeks apart or for >50% of all available subsequent visits, or Both definitions • SGRQ event occurring on two consecutive visits at least 4 weeks apart or for >50% of all available subsequent visits, or • Incidence of any moderate-to-severe exacerbation after first dose of study medication
Buhl et al^Citation131	• Decrease of ≥100 mL from baseline in trough FEV1, or • ≥4-unit increase from baseline in SGRQ total score, or • Severe (hospitalized) exacerbation • Death	Not reported
Singh et al^Citation130	• Decrease of ≥100 mL from baseline in trough FEV1, or • ≥4-unit increase from baseline in SGRQ total score, or • Occurrence of moderate-to-severe COPD exacerbation, or • ≥1 unit decrease in TDI focal score	• FEV1, SGRQ, or TDI event maintained at all subsequent visits from appearance to week 24, or • Incidence of any moderate-to-severe exacerbation

Abbreviations: CID, clinically important deterioration; FEV₁, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnea index.

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