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 COPD60 | 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])61 | 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 (PT003011 and PT003012) in moderate–very severe COPD62 | 4 weeks | Glycopyrrolate–formoterol 18/9.6 µg BID (n=115), placebo (n=112), open-label tiotropium 5 µg QD (PT003011 only, n=73) | By day 29, glycopyrrolate–formoterol had significantly improved FEV1 AUC0–24 vs placebo (LSM treatment difference, PT003011, 0.265 L; PT003012, 0.249 L; both P<0.0001) In PT003011, 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, PT003011 0.251 and PT003012 0.255; for AUC0–24, PT003011 0.277 and PT003012 0.242) |
|
| Glycopyrrolate–indacaterol FDC via a DPI | ||||
| Randomized, double-blind, noninferiority FLAME trial in patients with high exacerbation risk67 | 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 exacerbations68 | 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 COPD72 | 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 COPD71 | 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 COPD73 | 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 COPD66 | 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 therapy65 | 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 COPD69 | 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 COPD70 | 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 COPD74 | 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 COPD75 | 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 COPD76 | 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.