Efficacy and safety of four doses of glycopyrrolate/formoterol fumarate delivered via a metered dose inhaler compared with the monocomponents in patients with moderate-to-severe COPD

Colin Reisner, James Pearle, Edward M Kerwin, Earl St Rose, Patrick Darken, Colin Reisner, James Pearle, Edward M Kerwin, Earl St Rose, Patrick Darken

Abstract

Purpose: To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 µg) using innovative co-suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 µg and formoterol fumarate (FF) MDI 9.6 µg, in patients with moderate-to-severe COPD.

Methods: In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0-12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7. Safety was assessed.

Results: All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 µg (all P≤0.0137). For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 µg. No significant differences were observed between GFF MDI and FF MDI 9.6 µg for primary and secondary endpoints. The incidence of adverse events was similar between treatments.

Conclusion: While all doses of GFF MDI were superior to GP MDI 36 µg for the primary end-point, in this study neither superiority of GFF MDI to FF MDI 9.6 µg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings.

Keywords: LAMA/LABA; bronchodilator; chronic obstructive pulmonary disease; co-suspension delivery technology; fixed-dose combination; long-acting muscarinic antagonist; long-acting β2-agonist.

Conflict of interest statement

Disclosure CR is Chief Executive Officer of Pearl – a member of the AstraZeneca Group, and an employee of AstraZeneca. JP has received speaking fees from AstraZeneca, Genentech, Pfizer, and others, and has conducted trials on behalf of Boehringer Ingelheim, Forest, GlaxoSmithKline, Merck, Novartis, Sunovion, Teva, and others. EMK has served on advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, Forest, Mylan, Novartis, Oriel, Pearl – a member of the AstraZeneca Group, Sunovion, Teva, and Theravance. He has conducted multicenter clinical trials for ~40 pharmaceutical companies. ESR and PD are employees of Pearl – a member of the AstraZeneca Group. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study design. Abbreviations: PFT, pulmonary function test; Rx, treatment.
Figure 2
Figure 2
Patient disposition. Note: Data presented as n (%). Abbreviations: FEV1, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; MDI, metered dose inhaler.
Figure 3
Figure 3
(A) FEV1 AUC0–12 on Day 7a,b (B) Change from baseline in FEV1 over time on Day 7c (mITT population). Notes: *.<0.05, **.<0.01, ***.<0.001, #P<0.0001. aPairwise treatment comparisons. bThe geometric means are plotted, which are the exponentiated values of the LSMs for FEV1 AUC0–12 on the log scale. Error bars represent 95% CIs. The GMRs reported below the graph are shown for the comparisons with GP MDI 36 µg and FF MDI 9.6 µg. cError bars represent SE. Abbreviations: AUC0–12, area under the curve from 0 to 12 hours; CI, confidence interval; FEV1, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GMR, geometric mean ratio; GP, glycopyrrolate; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable; SE, standard error.
Figure 4
Figure 4
(A) Peak change from baseline in FEV1 through 2 hours on Day 1a,b (B) Peak change from baseline in IC on Day 1a,b (mITT population). Notes: *.<0.05, **.<0.01, ***.<0.001. aPairwise treatment comparisons. bError bars represent 95% CIs. Data shown below the graph are treatment differences for the comparisons with GP MDI 36 µg and FF MDI 9.6 µg. Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable.
Figure 5
Figure 5
(A) Peak change from baseline in FEV1 through 6 hours on Day 7a,b (B) Peak change from baseline in IC on Day 7a,b (mITT population). Notes: *.<0.05, **.<0.01, #P<0.0001. aPairwise treatment comparisons. bError bars represent 95% CIs. Data shown below the graph are treatment differences for the comparisons with GP MDI 36 µg and FF MDI 9.6 µg. Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; IC, inspiratory capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; N/A, not applicable.

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