Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology.

Background: Glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting beta(2)-agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI. Methods: The thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere (R)), GFF MDI 144/38.4 and GP MDI 144 mu g, compared with placebo MDI and open-label moxifloxacin 400 mg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6 mu g compared with open-label FF dry powder inhaler (DPI; Foradil (R) Aerolizer (R)) 12 mu g, in patients with moderate-to-severe COPD (PT003003 [NCT01349803]). Results: Seventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144 mu g all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6 mu g did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12 mu g. Conclusions: No clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4 mu g. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD.