Efficacy and safety of a novel, nebulized glycopyrrolate for the treatment of COPD: effect of baseline disease severity and age; pooled analysis of GOLDEN 3 and GOLDEN 4

Abstract

Background: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow® Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294).

Methods: Patients were grouped by baseline predicted post-bronchodilator FEV1 (<50%, ≥50%) and age (<65, ≥65, ≥75 years).

Results: GLY (25 and 50 μg BID) produced significant improvements in trough FEV1 in FEV1% predicted <50% (0.070 L, 0.079 L) and ≥50% (0.112 L, 0.126 L) subgroups (P<0.01 vs placebo), and in patients aged <65 (0.056 L, 0.086 L), ≥65 (0.140 L, 0.124 L), and ≥75 (0.144 L, 0.120 L) years (P<0.05 vs placebo). St George's Respiratory Questionnaire (SGRQ) total score was significantly improved with GLY 25 and 50 μg BID (P<0.05 vs placebo) in FEV1% predicted <50% (-3.237, -3.061) and ≥50% (-3.392, -2.322) and in <65 years (-3.447, -2.318) and ≥65 years (-3.053, -3.098) subgroups. In patients aged ≥75 years, GLY 25 μg reduced SGRQ total score by -6.278 units (P<0.01 vs placebo). The incidence of treatment-emergent adverse events was similar between GLY and placebo across all subgroups, and the overall incidence of cardiovascular events was low.

Conclusions: Nebulized GLY improved lung function and health status and was well tolerated over 12 weeks in patients with moderate-to-very-severe COPD, irrespective of baseline disease severity and age.

Clinical trial registration: NCT02347761, NCT02347774.

Keywords: COPD; LAMA; age; disease severity; long-acting muscarinic antagonist; nebulized glycopyrrolate; nebulizer.

Conflict of interest statement

Disclosure Jill Ohar has served on advisory boards for Sunovion Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Mylan, and Theravance, and has provided expert witness testimony for: Wallace & Graham, Levy Konigsberg, Goldenberg Heller & Antognoli, Simon Greensone Panatier Bartlett, Williams Kherkher Hart, Gori Julian & Associates, Simmons Hanley Conroy, and Elrod Pope. Robert Tosiello, Thomas Goodin, and Shahin Sanjar are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work.

Figures

Figure 1

GOLDEN 3 and GOLDEN 4 study designs: 12-week, randomized, double-blind, placebo-controlled, parallel group, multicenter, efficacy and safety studies. Notes: Data from Kerwin et al. Abbreviations: BID, twice daily; CS, closed system; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist.

Figure 2

LS mean change from baseline in trough FEV1 by (A) baseline FEV1% predicted and (B) age. Notes: *P<0.05 vs placebo; **P<0.01 vs placebo; ***P<0.001 vs placebo. aSubset of the ≥65 years subgroup. Abbreviations: LS, least squares; SE, standard error; GLY, glycopyrrolate inhalation solution; BID, twice daily.

Figure 2

LS mean change from baseline in trough FEV1 by (A) baseline FEV1% predicted and (B) age. Notes: *P<0.05 vs placebo; **P<0.01 vs placebo; ***P<0.001 vs placebo. aSubset of the ≥65 years subgroup. Abbreviations: LS, least squares; SE, standard error; GLY, glycopyrrolate inhalation solution; BID, twice daily.

Figure 3

LS mean SGRQ total score by (A) baseline FEV1% predicted and (B) age. Notes: *P<0.05 vs placebo; **P<0.01 vs placebo. aSubset of the ≥65 years subgroup. Abbreviations: LS, least squares; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; GLY, glycopyrrolate inhalation solution; BID, twice daily; MCID, minimum clinically important difference.

Figure 4

SGRQ responder (≥4-unit reduction in SGRQ total score) rates by (A) baseline FEV1% predicted and (B) age. Notes: *P<0.05 vs placebo. aSubset of the ≥65 years subgroup. Abbreviations: SGRQ, St George’s Respiratory Questionnaire; GLY, glycopyrrolate inhalation solution; BID, twice daily.