Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease

Figures & data

Figure 1 Role of ACh and muscarinic receptors in the lung.

Notes: Data from these studies.^11,17 In large airways, ACh released from cholinergic nerves activates M₃ receptors on ASM, causing bronchoconstriction. In peripheral airways, where cholinergic nerves are absent, inflammatory cells stimulate epithelial cells to release ACh, activating M₃ receptors on ASM and causing bronchoconstriction. M₃ muscarinic receptors are shown as solid blue circles. For simplicity, other types of muscarinic receptor are not shown.
Abbreviations: ACh, acetylcholine; ASM, airway smooth muscle; CNS, central nervous system.

Table 1 Preclinical studies comparing the pharmacological profile of glycopyrrolate with other LAMAs and ipratropium

Study	Characteristic	Glycopyrrolate	Aclidinium	Tiotropium	Ipratropium
In vitro calcium assay^Citation13	Equilibrium binding constant, mean ± SE:		–		–
	M2	8.70±0.04		10.05±0.03
	M3	9.59±0.05		10.37±0.04
	Drug binding t½ (minutes) at M3 vs M2 receptors (kinetic selectivity ratio)	11.4 vs 1.07 (10.7)	–	46.2 vs 10.8 (4.3)	–
In vitro study of recombinant human receptors^Citation16	Muscarinic receptor-binding affinity (Ki, nM), mean ± SE:
	M2	1.77±0.06	0.14±0.04	0.13±0.04	1.12±0.13
	M3	0.52±0.04	0.14±0.02	0.19±0.04	1.24±0.08
Ex vivo binding in rat lungs^Citation18	Binding to muscarinic receptors in lung	Binding lasted 24 hours	–	Binding lasted 24 hours	Binding observed at 2 hours, but not at 12 hours
In vitro study of recombinant human receptors^Citation16	M3 vs M2 receptors, dissociation t½ in hours (kinetic selectivity ratio)	8.1 vs 1.1 (7.3)	29.2 vs 4.7 (6.2)	62.2 vs 15.1 (4.1)	0.5 vs 0.1 (5.9)
In vivo study in guinea pigs^Citation16	Onset of action (hours) postadministration	2	2	4	2
Ex vivo study in human airways^Citation19	Onset of action of 1 µM dose, minutes ± SEM	3.4a±0.4	6.4±0.5	8.4±1.1	–
In vitro study in guinea pig trachea^Citation16	Duration of action (t½ offset of electrically stimulated contractions) at M3 receptors	>8 hours	>8 hours	>8 hours	42 minutes
In vivo study in guinea pigs^Citation16	Duration of bronchodilator action, in hours (t½ offset of maximal inhibitory effect)	13	29	64	8
In vivo rat salivation study^Citation16	ED50 (µg/kg) for inhibition of salivation	0.74	38	0.88	–
In vitro human plasma study^Citation16	Hydrolysis t½ in plasma (hours)	6	0.04	1.6	33

Notes:

a P<0.05 vs both aclidinium and tiotropium at equal concentrations. “–” indicates data not available.

Abbreviations: ED₅₀, dose required to inhibit salivation in 50% of rats; K_i, antagonist dissociation constant; LAMAs, long-acting muscarinic antagonists; SE, standard error; SEM, standard error of the mean; t_½, half-life.

Table 2 Available glycopyrrolate and other LAMA formulations

Formulation	Brand name	Delivery method	Regions approved	Approved dosage
Glycopyrrolate formulations
Monotherapy^Citation6,Citation33	Seebri Neohaler	DPI	US	15.6 µg BID
	Seebri Breezhaler	DPI	Europe	50 µg QD (glycopyrronium moiety in capsule)
Monotherapy^Citation78	Lonhala Magnair	Nebulized	US	25 µg BID
Glycopyrrolate–formoterol^Citation34	Bevespi Aerosphere	pMDI	US	18/9.6 µg BID (as glycopyrrolate–formoterol fumarate)
Glycopyrrolate–indacaterol^Citation35,Citation36	Utibron Neohaler	DPI	US	15.6/27.5 µg BID
	Ultibro Breezhaler	DPI	Europe	50/110 µg QD (in capsule, as glycopyrronium/indacaterol)
Glycopyrrolate–beclomethasone–formoterol^Citation37	Trimbow	pMDI	Europe	12.5/100/6 µg BID (metered dose, as glycopyrronium bromide–beclomethasone dipropionate–formoterol fumarate dihydrate)
Tiotropium formulations
Monotherapy^Citation79,Citation80	Spiriva HandiHaler	DPI	US	18 µg QD (as tiotropium bromide)
	Spiriva Respimat	SMI	US	5 µg QD (as tiotropium bromide)
Tiotropium–olodaterol^Citation81,Citation82	Stiolto Respimat	SMI	US	5/5 µg QD
	Spiolto Respimat	SMI	Europe	5/5 µg QD (delivered dose, as tiotropium bromide monohydrate–olodaterol hydrochloride)
Umeclidinium formulations
Monotherapy^Citation83,Citation84	Incruse Ellipta	DPI	US	62.5 µg QD
	Incruse Ellipta	DPI	Europe	62.5 µg QD (predispensed dose, as umeclidinium)
Umeclidinium–vilanterol^Citation85,Citation86	Anoro Ellipta	DPI	US	62.5/25 µg QD
	Anoro Ellipta	DPI	Europe	62.5/25 µg QD (predispensed dose, as umeclidinium–vilanterol trifenatate)
Umeclidinium–fluticasone furoate–vilanterol^Citation87	Trelegy Ellipta	DPI	US	62.5/100/25 µg QD (as umeclidinium–fluticasone furoate–vilanterol)
Aclidinium formulations
Monotherapy^Citation88–Citation90	Eklira Genuair	DPI	Europe	400 µg BID (as aclidinium bromide)
	Bretaris Genuair	DPI	Europe	400 µg BID (as aclidinium bromide)
	Tudorza Pressair	DPI	US	400 µg BID (as aclidinium bromide)
Aclidinium–formoterol^Citation91	Duaklir Genuair	DPI	Europe	400/12 µg BID (as aclidinium bromide–formoterol fumarate dihydrate)
Revefenacin formulation
Monotherapy^Citation92	TBCa	Nebulized	Completed Phase III trials	NA

Note:

a Theravance Biopharma and Mylan submitted a new drug application for revefenacin use in patients with COPD in November 2017 and were waiting for a response at the time of submission of this review article.⁹³

Abbreviations: BID, bis in die (twice daily); DPI, dry-powder inhaler; LAMA, long-acting muscarinic antagonist; NA, not applicable; pMDI, pressurized metered dose inhaler; QD, quaque die (once daily); SMI, soft-mist inhaler; TBC, to be confirmed.

Table 3 Clinical evidence of the efficacy of glycopyrrolate monotherapy in patients with COPD

Clinical trial	Treatment duration			Treatments	Key findings
GLOW trials: double-blind, randomized, placebo-controlled studies in patients with moderate–severe COPD
Phase III GLOW1^Citation41			26 weeks	Glycopyrrolate 50 µg QD (n=552), placebo (n=270)		Glycopyrrolate significantly increased trough FEV1 vs placebo at week 12 (LSM treatment difference 0.108 L, P<0.001), increase maintained at week 26 (LSM treatment difference 0.113 L, P<0.001) Significant improvements in dyspnea (TDI focal score 1.84 vs 0.80 points, P<0.001) and time to first moderate/severe exacerbation (P=0.023) vs placebo at week 26
Phase III GLOW2^Citation42			52 weeks	Glycopyrrolate 50 µg QD (n=529), placebo (n=269), open-label tiotropium 18 µg QD (n=268)		Glycopyrrolate significantly increased trough FEV1 vs placebo at week 12 (LSM treatment difference 97 mL, P<0.001) Glycopyrrolate significantly increased trough FEV1 vs tiotropium at week 26 (LSM treatment difference 50 mL, P<0.01), while trough FEV1 was similar at weeks 12 and 52 (LSM treatment difference 14 and 19 mL, respectively) Significant improvements in dyspnea at week 26 (TDI focal score 2.13 vs 1.32, P=0.002) and risk of exacerbations at week 52 (P=0.001) vs placebo
Phase III GLOW3 crossover^Citation43			3 weeks	Glycopyrrolate 50 µg QD, then placebo (n=55); placebo, then glycopyrrolate 50 µg QD (n=53)		Glycopyrrolate significantly improved submaximal exercise endurance time vs placebo on day 1 (P<0.001), and this improvement increased at day 21 (P<0.001)
Phase III GLOW5^Citation45			12 weeks	Glycopyrrolate 50 µg QD (n=327), tiotropium 18 µg QD (n=330)		Glycopyrrolate was noninferior to tiotropium for trough FEV1 at week 12 (LSM treatment difference 0 L, P<0.001) Glycopyrrolate had a significantly faster onset of action on day 1 than tiotropium (postdose FEV1 at 0- to 4-hour time points, all P<0.001)
GLOW7^Citation46			26 weeks	Glycopyrrolate 50 µg QD (n=306), placebo (n=154)		Glycopyrrolate significantly improved trough FEV1 vs placebo at week 12 (LSM treatment difference 141 mL, P<0.001) Glycopyrrolate significantly improved SGRQ scores (LSM treatment difference −4.92 points, P<0.001) and dyspnea severity (LSM treatment difference 1 point, P<0.001) at week 26 vs placebo
SPRING trial: randomized, blinded study in patients with moderate–severe COPD
SPRING crossover^Citation47			4 weeks	Glycopyrrolate 50 µg QD, then tiotropium 18 µg QD; tiotropium 18 µg QD, then glycopyrrolate 50 µg QD (n=126)		On day 1, glycopyrrolate 50 µg treatment significantly improved FEV1 AUC0–4 after the first dose compared with tiotropium 18 µg (LSM treatment difference 0.030 L, P=0.025) Improvements in morning symptoms of COPD were similar between treatments
GEM trials: Phase III, double-blind, randomized, placebo-controlled studies in patients with COPD and moderate–severe airflow limitation
GEM1^Citation48		12 weeks		Glycopyrrolate 15.6 µg BID (n=222), placebo (n=219)			Glycopyrrolate significantly improved FEV1 AUC0–12 vs placebo at week 12 (LSM treatment difference 0.139 L, P<0.001) Glycopyrrolate significantly improved TDI (LSM treatment difference 0.92 points, P=0.003) and SGRQ scores (LSM treatment difference −2.8 points, P=0.016) vs placebo at week 12
GEM2^Citation49		12 weeks		Glycopyrrolate 15.6 µg BID (n=216), placebo (n=216)			Glycopyrrolate significantly improved FEV1 AUC0–12 vs placebo at day 1 (LSM treatment difference 0.119 L, P<0.001), improvement maintained at week 12 (LSM treatment difference 0.123 L, P<0.001) Glycopyrrolate significantly improved SGRQ scores (LSM treatment difference −5.2 points, P<0.001) vs placebo at week 12
GOLDEN trials: Phase III, randomized studies of nebulized glycopyrrolate in patients with moderate–very severe COPD
Double-blind, placebo-controlled GOLDEN 3 and GOLDEN 4^Citation38		12 weeks		Glycopyrrolate 25 µg BID (n=431), glycopyrrolate 50 µg BID (n=432), placebo (n=430)			At week 12, treatment with glycopyrrolate 25 and 50 µg BID resulted in significant and clinically important improvements in trough FEV1 vs placebo (GOLDEN 3 [LSM difference 0.105 and 0.126 L, respectively] and GOLDEN 4 [LSM difference 0.084 and 0.082 L, respectively], all P≤0.0001) At week 12, glycopyrrolate 25 and 50 µg BID significantly improved trough FVC vs placebo (GOLDEN 3 [LSM difference 0.149 and 0.167 L, respectively; both P<0.001], GOLDEN 4 [LSM difference 0.130 and 0.113 L, respectively; P<0.01]) At week 12/end of study, glycopyrrolate 25 and 50 µg BID significantly increased SGRQ scores vs placebo (GOLDEN 3 [LSM difference −3.072, P<0.05 and −1.848 points, P=NS, respectively]; GOLDEN 4 [LSM difference −3.585 and −3.557 points, respectively; P<0.01])
Open-label, active-controlled GOLDEN 5^Citation51		48 weeks		Glycopyrrolate 50 µg BID (n=621), tiotropium 18 µg QD (n=466)			Glycopyrrolate treatment improved trough FEV1 from baseline, which was maintained until week 48 (LSM change from baseline at week 48 0.069 L) Change from baseline in FEV1 at 48 weeks did not differ significantly between glycopyrrolate and tiotropium
Randomized, double-blind studies of glycopyrrolate delivered using co-suspension delivery technology in patients with moderate–severe COPDa
Chronic-dosing, Phase II, crossover trial^Citation52		2 weeks		Glycopyrrolate 18, 9, 4.6, 2.4, 1.2, 0.6 µg BID (n=64, 64, 62, 64, 57, 59, respectively), open-label tiotropium 18 µg QD (n=62), placebo BID (n=62)			After 14 days’ treatment, glycopyrrolate at doses 18, 9, 4.6, and 2.4 µg BID resulted in significant and clinically relevant improvements in FEV1 AUC0–12 compared with placebo (LSM difference from baseline 126–158 mL, P<0.0001) Glycopyrrolate 18 µg BID was noninferior to open-label tiotropium 18 µg QD for peak change in FEV1 on day 1 (LSM change from baseline 0.231 vs 0.270 L) and morning predose trough FEV1 on day 14 (LSM change from baseline 0.089 vs 0.126 L) and was the most appropriate dose for further evaluation
Chronic-dosing, Phase IIB, incomplete block, crossover trial^Citation57		7 days		Glycopyrrolate (as glycopyrronium) 28.8, 14.4, 7.2, 3.6 µg BID (n=192), placebo BID (n=48), open-label ipratropium 34 µg QID (n=48)b			At day 7, all glycopyrrolate doses were superior to placebo for improvement from baseline in FEV1 AUC0–12 (LSM treatment differences vs placebo 0.121–0.191 L, all P<0.0001) All glycopyrrolate doses were noninferior to ipratropium (data not shown) Glycopyrrolate 28.8 and 14.4 µg were the most effective doses for improving all secondary efficacy end points

Notes:

a Phase II studies included, as Phase III trial data have not yet been published for this product;

b each patient received three treatments of two doses of glycopyrrolate and either placebo or ipratropium.

Abbreviations: AUC, area under curve; BID, bis in die (twice daily); FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; LSM, least squares mean; NS, not significant; QD, quaque die (once daily); QID, quater in die (four times daily); SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 4 Recent clinical evidence (2015 to present) of efficacy of glycopyrrolate combinations in patients with COPD

Clinical trial	Treatment duration	Treatments		Key findings
Glycopyrrolate–formoterol FDC delivered using co-suspension delivery technology via a pMDI
Phase III, randomized, double-blind, PINNACLE-1 and -2 studies in moderate–very severe COPD^Citation60	24 weeks	Glycopyrrolate–formoterol 18/9.6 µg BID (n=1,039), glycopyrrolate 18 µg BID (n=891), formoterol 9.6 µg BID (n=891), placebo BID (n=444), open-label tiotropium 18 µg (PINNACLE-1 only, QD; n=453)	At week 24, the change in predose trough FEV1 for glycopyrrolate–formoterol was significantly greater than for glycopyrrolate, formoterol, and placebo (LSM difference in change from baseline vs comparators, PINNACLE-1, 0.059–0.150 L, P<0.0001; PINNACLE-2, 0.054–0.103 L, P<0.001) Change in predose trough FEV1 for glycopyrrolate–formoterol did not differ significantly from tiotropium in PINNACLE-1, but did in PINNACLE-2 (LSM difference in change from baseline 0.021, P=NS and 0.103, P<0.001, respectively)
Phase III, randomized, double-blind trial (PINNACLE-3 [a PINNACLE-1 and -2 extension study])^Citation61	28 weeks	Glycopyrrolate–formoterol 18/9.6 µg BID (n=290), glycopyrrolate 18 µg BID (n=218), formoterol 9.6 µg BID (n=213), open-label tiotropium 18 µg QD (n=171)	At week 52, the change in predose trough FEV1 for glycopyrrolate–formoterol was significantly greater than that for all other treatments (LSM difference in change from baseline 0.025–0.065 L, P≤0.0117)
Two Phase IIIB, double-blind, crossover studies (PT03011 and PT03012) in moderate–very severe COPD^Citation62	4 weeks	Glycopyrrolate–formoterol 18/9.6 µg BID (n=115), placebo (n=112), open-label tiotropium 5 µg QD (PT03011 only, n=73)	By day 29, glycopyrrolate–formoterol had significantly improved FEV1 AUC0–24 vs placebo (LSM treatment difference, PT03011, 0.265 L; PT03012, 0.249 L; both P<0.0001) In PT03011, glycopyrrolate–formoterol treatment resulted in significantly improved FEV1 AUC0–12 vs tiotropium (LSM treatment difference 0.080 L, P=0.0001) FEV1 AUC12–14 improvements with glycopyrrolate–formoterol were also greater than for placebo (LSM treatment difference for FEV1 AUC0–12, PT03011 0.251 and PT03012 0.255; for AUC0–24, PT03011 0.277 and PT03012 0.242)
Glycopyrrolate–indacaterol FDC via a DPI
Randomized, double-blind, noninferiority FLAME trial in patients with high exacerbation risk^Citation67	52 weeks	Glycopyrrolate–indacaterol 50/110 µg QD (n=1,680), fluticasone propionate–salmeterol 500/50 µg BID (n=1,682)	The glycopyrrolate–indacaterol combination was found to be superior to fluticasone propionate–salmeterol in reducing annual COPD exacerbations (P=0.003) and increasing time to first exacerbation (P<0.001)
Randomized, double-blind, LANTERN study in moderate–severe COPD with a history of exacerbations^Citation68	26 weeks	Glycopyrrolate–indacaterol 50/110 µg QD (n=372), fluticasone propionate–salmeterol 500/50 µg BID (n=372)	At week 26, glycopyrrolate–indacaterol was significantly superior at improving trough FEV1 to fluticasone propionate–salmeterol (LSM treatment difference 0.075, P<0.001) At week 26, the glycopyrrolate–indacaterol group showed a significantly greater improvement in FEV1 AUC0–4 than the fluticasone propionate–salmeterol group (LSM treatment difference 0.122 L, P<0.001) Glycopyrrolate–indacaterol treatment reduced moderate/severe exacerbations to a significantly greater extent than fluticasone propionate–salmeterol (P=0.048)
Post hoc analysis of pooled ILLUMINATE and LANTERN trials examining symptomatic (GOLD B and D)a patients with moderate–severe COPD^Citation72	26 weeks	Glycopyrrolate–indacaterol 50/110 µg QD (n=630), fluticasone propionate–salmeterol 500/50 µg BID (n=633)	At week 26, glycopyrrolate–indacaterol significantly improved lung function from baseline vs fluticasone propionate–salmeterol in symptomatic patients (LSM treatment difference in predose trough FEV1 in GOLD B and D patients 0.10 and 0.08 L, respectively [both P<0.0001]; LSM treatment difference in FEV1 AUC0–12 0.14 L [P<0.0001] in GOLD B and 0.11 L [P<0.005] in GOLD D)
Two randomized, double-blind, crossover studies (A2349 and A2350) in patients with moderate–severe COPD^Citation71	12 weeks	Glycopyrrolate–indacaterol 15.6/27.5 µg BID, umeclidinium–vilanterol 62.5/25 µg QD (A2349, n=357; A2350, n=355)	Noninferiority of glycopyrrolate–indacaterol vs umeclidinium–vilanterol for change from baseline in FEV1 AUC0–24 at week 12 was not met (lower boundary of 97.5% one-sided CI for glycopyrrolate–indacaterol below prespecified margin of −20 mL in both studies; LSM between-treatment differences −11.5 mL, 95% CI −26.9 to 3.8 [A2349] and −18.2 mL, 95% CI −34.2 to 2.3 [A2350]) Both glycopyrrolate–indacaterol and umeclidinium–vilanterol improved FEV1 AUC12–24 (208 and 203 mL [A2349], 163 and 154 mL [A2350]) and trough FEV1 levels from baseline at week 12 (189 and 201 mL [A2349], 168 and 177 mL [A2350])
Randomized, double-blind, crossover, MOVE study in patients with moderate–severe COPD^Citation73	21 days	Glycopyrrolate–indacaterol 50/110 µg QD, then placebo; placebo, then glycopyrrolate–indacaterol 50/110 µg QD (n=194)	Glycopyrrolate–indacaterol significantly improved peak IC levels (LSM treatment difference 0.202 L, P<0.0001) and activity-related energy used (P=0.040) vs placebo after 21 days’ treatment
Randomized, multicenter, blinded, QUANTIFY study in moderate–severe COPD^Citation66	26 weeks	Glycopyrrolate–indacaterol 50/110 µg QD (n=476), tiotropium 18 µg QD + formoterol 12 µg BID (n=458)	At week 26, glycopyrrolate–indacaterol was found to be noninferior to tiotropium + formoterol in improving SGRQ scores (LSM treatment difference −0.69) At week 26, significantly more patients using glycopyrrolate–indacaterol vs tiotropium + formoterol achieved a clinically relevant improvement in TDI score (49.6% vs 42.4%, P=0.033) and significantly improved predose FEV1 (LSM treatment difference 0.068 L, P<0.001) and FVC (LSM treatment difference 0.074 L, P<0.01)
Randomized, open-label, crossover, FAVOR study in symptomatic (GOLD B or D)a patients who had previously received tiotropium therapy^Citation65	4 weeks	Open-label glycopyrrolate–indacaterol 50/110 µg QD, then tiotropium 18 µg QD (n=43); tiotropium 18 µg QD, then open-label glycopyrrolate–indacaterol 50/110 µg QD (n=45)	Glycopyrrolate–indacaterol significantly increased FEV1 1 hour postdose vs tiotropium after 4 weeks’ treatment (treatment difference 0.081 L, P=0.0017)
Pooled analysis of randomized, double-blind, parallel-group, FLIGHT1 and FLIGHT2 studies in moderate–severe COPD^Citation69	12 weeks	Glycopyrrolate–indacaterol 15.6/27.5 µg BID (n=260), indacaterol 27.5 µg BID (n=260), glycopyrrolate 15.6 µg BID (n=261), placebo (n=261)	Glycopyrrolate–indacaterol improved FEV1 AUC0–12 significantly more than individual components (LSM treatment difference 0.103 L vs indacaterol and 0.088 L vs glycopyrrolate, respectively; both P<0.001) and placebo (LSM treatment difference 0.246 L, P<0.001) Compared with individual components and placebo, glycopyrrolate–indacaterol produced significantly greater and more clinically meaningful improvements in TDI total score (LSM treatment difference 0.78 points vs indacaterol, 0.73 points vs glycopyrrolate, and 1.64 points vs placebo; all P<0.001) and SGRQ score (LSM treatment difference −1.7 points vs indacaterol [P<0.05], −1.5 points vs glycopyrrolate [P<0.05], −5.0 points vs placebo [P<0.001])
Randomized, multicenter, double-blind, parallel-group, FLIGHT3 study in moderate–severe COPD^Citation70	52 weeks	Glycopyrrolate–indacaterol 15.6/27.5 µg BID (n=204), glycopyrrolate–indacaterol 31.2/27.5 µg BID (n=204), indacaterol 75 µg QD (n=207)	Improvements in predose trough FEV1 were greater with glycopyrrolate–indacaterol 15.6/27.5 µg and 31.2/27.5 µg (LSM treatment difference 0.080 L and 0.079 L, respectively), and improvements in 1-hour postdose FEV1 were greater with glycopyrrolate–indacaterol 15.6/27.5 µg (LSM treatment difference 0.108 L) than indacaterol alone at week 52
Glycopyrrolate via DPI plus FDC fluticasone propionate–salmeterol via DPI
Randomized, blinded, GLISTEN study in moderate–severe COPD^Citation74	12 weeks	Glycopyrrolate 50 µg QD + fluticasone propionate–salmeterol 500/50 µg BID (n=258), tiotropium 18 µg QD + fluticasone propionate–salmeterol 500/50 µg BID (n=258), placebo + fluticasone propionate–salmeterol 500/50 µg BID (n=257)	At week 12, glycopyrrolate + fluticasone propionate–salmeterol significantly improved trough FEV1 from baseline vs placebo + fluticasone propionate–salmeterol (LSM treatment difference 0.101 L, P<0.001) At week 12, glycopyrrolate + fluticasone propionate–salmeterol was noninferior to tiotropium + fluticasone propionate–salmeterol (LSM treatment difference −0.007 L) At week 12, glycopyrrolate + fluticasone propionate–salmeterol significantly improved SGRQ total scores from baseline vs placebo + fluticasone propionate–salmeterol (LSM treatment difference −2.15, P=0.02)
Extrafine glycopyrrolate–beclomethasone–formoterol FDC via pMDI
Randomized, double-blind, active-comparator, TRILOGY study in patients with symptomatic COPD^Citation75	52 weeks	2-week open-label run-in period, beclomethasone–formoterol 100/6 µg; patients then randomly assigned to beclomethasone–formoterol 100/6 µg (n=681) or stepped up to glycopyrrolate–beclomethasone–formoterol 12.5/100/6 µg (n=687)	At week 26, triple FDC significantly improved predose (treatment difference 0.081 L) and 2-hour postdose FEV1 (treatment difference 0.117 L) from baseline vs the dual ICS–LABA (both P<0.001) At week 52, patients in the triple FDC group experienced 23% fewer moderate/severe exacerbations than those in the dual ICS–LABA FDC group
Randomized, double-blind, TRINITY study in patients with symptomatic COPD^Citation76	52 weeks	2-week open-label tiotropium 18 µg QD, then open-label tiotropium µg QD (n=1,075), glycopyrrolate–beclomethasone–formoterol 12.5/100/6 µg BID (n=1,078), beclomethasone–formoterol 100/6 µg BID + tiotropium 18 µg QD (n=538)	Glycopyrrolate–beclomethasone–formoterol was superior to tiotropium in reducing the rate of exacerbations (P=0.0025) and week 52 predose FEV1 (treatment difference 0.061 L, P<0.0001) Glycopyrrolate–beclomethasone–formoterol had a similar efficacy to beclomethasone–formoterol + tiotropium in terms of risk of exacerbations (P=0.890) and was noninferior for improvement in predose FEV1 at week 52 (treatment difference −0.003 L, P=0.85)

Note:

a GOLD B and D defined according to the 2013 GOLD guidelines (FAVOR), the 2010 GOLD guidelines (ILLUMINATE), or the 2009 GOLD guidelines (LANTERN).

Abbreviations: AUC, area under curve; BID, bis in die (twice daily); DPI, dry-powder inhaler; FDC, fixed-dose combination; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Pulmonary Disease; LSM, least squares mean; IC, inspiratory capacity; ICS-LABA, inhaled corticosteroid-long-acting β2-agonist; NS, not significant; pMDI, pressurized metered-dose inhaler; QD, quaque die (once daily); SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

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