proximately 1500 times the MRHDID on a mg/m2 basis). No effect on fertility was detected in female rats at doses up to 15 mg/kg (approximately 7600 times the MRHDID on a mg/m2 basis).
14 CLINICAL STUDIES
The safety and efficacy of BEVESPI AEROSPHERE was eva luated in a clinical development program that included 8 dose-ranging trials and two placebo-controlled lung function trials of 24-weeks duration that included a 28-week extension study to eva luate safety over 1 year. The efficacy of BEVESPI AEROSPHERE is based on the dose ranging trials in 822 subjects with COPD and the 2 placebo-controlled confirmatory trials in 3,705 subjects with COPD.
14.1. Dose-Ranging Trials
Dose selection for BEVESPI AEROSPHERE for COPD was primarily based on data for the individual components, glycopyrrolate and formoterol fumarate, in COPD patients. Based on the findings from these studies, glycopyrrolate/formoterol fumarate 18/9.6 mcg administered twice-daily was eva luated in the confirmatory COPD trials.
Glycopyrrolate
Dose selection for glycopyrrolate was supported by a 14-day, randomized, double-blind, placebo-controlled, incomplete-block crossover trial eva luating 6 doses of glycopyrrolate (GP MDI 18 to 0.6 mcg) administered twice daily and an open-label active control in 140 subjects with COPD. A dose ordering was observed, with the glycopyrrolate 18 mcg demonstrating larger improvements in FEV1 over 12 hours compared with glycopyrrolate 9, 4.6, 2.4, 1.2, and 0.6 mcg (Figure 1).
Figure 1 - Mean Change from Baseline in FEV1 over Time on Day 14 (MITT Population)
Figure 1 - Mean Change from Baseline in FEV1 over Time on Day 14 (MITT Population)
The difference from placebo in change from baseline in trough FEV1 after 14 days for the 18, 9, 4.6, 2.4, 1.2, and 0.6 mcg doses were 97 mL (95% CI: 45, 149), 88 mL (95% CI: 37, 139), 75 mL (95% CI: 24, 125), 84 mL (95% CI: 33, 135), 76 mL (95% CI: 22, 129), and 37 mL (95% CI: -17, 91), respectively. Two additional dose ranging trials (single-dose and 7-day trials) in subjects with COPD demonstrated minimal additional benefit at doses above 18 mcg of glycopyrrolate. The results supported the selection of 18 mcg of glycopyrrolate twice daily in the confirmatory COPD trials.
eva luations of the appropriate dosing interval for glycopyrrolate were conducted by comparing to open-label ipratropium bromide inhalation aerosol administered four times daily. The results supported the selection of a twice-daily dosing interval for further eva luation in the confirmatory COPD trials.
Formoterol Fumarate
Dose selection for formoterol fumarate was supported by a single-dose, randomized, double-blind, placebo-controlled, crossover trial eva luating 3 doses of formoterol fumarate (FF MDI 9.6, 4.8 and 2.4 mcg), an open-label active control, and placebo in 34 subjects with COPD. A dose ordering was observed with the formoterol fumarate 9.6 mcg dose demonstrating larger improvements in FEV1 over 12 hours compared with the lower doses of 4.8 and 2.4 mcg (Figure 2).
Figure 2 - Mean Change from Baseline in FEV1 over Time on Day 1
Figure 2 - Mean Change from Baseline in FEV1 over Time on Day 1
The differences in mean change from baseline in normalized FEV1 AUC0-12 for formoterol fumarate 9.6, 4.8, and 2.4 mcg compared to placebo were 176 mL (95% CI: 138, 214), 103 (95% CI: 66, 140), and 81 (95% CI: 45, 118), respectively. These results provided support for the selection of 9.6 mcg of formoterol fumarate twice daily in the confirmatory C
