A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease

Abstract

Background: Long-acting muscarinic antagonist/long-acting β₂-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI).

Methods: This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV₁ AUC_0-12) on Day 7 relative to baseline FEV₁. Secondary endpoints included pharmacokinetics and safety.

Results: GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV₁ AUC_0-12 after 7 days' treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated.

Conclusions: GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD.

Trial registration: ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Keywords: Bronchodilators; COPD; COPD maintenance; Co-Suspension™ Delivery Technology; LABA; LAMA; Lung function; Metered dose inhaler.

Fig. 1

Patient disposition. In Part A, patients were randomized to receive any of the eight treatments in each of the four periods of the study in an incomplete block crossover design. In Part B, patients were randomized to receive all three formoterol doses and placebo in each of the four periods of the study in a full crossover design. ^aFive patients met multiple criteria for exclusion from randomization (not meeting inclusion criteria and/or meeting exclusion criteria). ^bPatients randomized to treatment, who received at least one dose of study drug. ^cPatients who completed at least two treatment periods with at least 2 h of post-dose data on Day 7, with no more than one missing data-point from 15 min to 2 h post-dose, inclusive. COPD, chronic obstructive pulmonary disease; CT, computed tomography; ITT, intent-to-treat; LRTI, lower respiratory tract infection; mITT, modified ITT

Fig. 2

FEV₁ AUC_0–12 on Day 7 efficacy endpoint. a LSM change (95% CI) in FEV₁ over 0–12 h on Day 7 by treatment; b LSM (95% CI) FEV₁ AUC_0–12 difference from placebo on Day 7 by treatment (mITT population). ^aForadil^® Aerolizer^{® . b}LSM allows for any imbalances in baseline covariates that relate to responses to be adjusted for in order to avoid bias in treatment effect estimates. AUC_0–12, area under the curve from 0 to 12 h post-dose; DPI, dry powder inhaler; FEV₁, forced expiratory volume in 1 s; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat

Fig. 3

Ratio of geometric LSMs and 90% CIs. a GFF MDI 36/9.6 μg versus GP MDI 36 μg (b) GFF MDI 36/9.6 μg versus FF MDI 9.6 μg (c) FF MDI 9.6 μg versus FF DPI (PK-mITT population). ^aLSM allows for any imbalances in baseline covariates that relate to responses to be adjusted for in order to avoid bias in treatment effect estimates. ^bForadil^® Aerolizer^{® .} AUC_0–inf, area under the curve from time 0 to infinity; AUC_0–12, area under the curve from 0 to 12 h post-dose; CI, confidence interval; C_max, maximum observed plasma concentration; DPI, dry powder inhaler; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; LSM, least squares mean; MDI, metered dose inhaler; PK-mITT, pharmacokinetic modified intent-to-treat