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.

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.