14.2. Confirmatory Trials
The clinical development program for BEVESPI AEROSPHERE included two (Trial 1 and Trial 2) 24-week, randomized, double-blind, placebo-controlled, parallel-group trials in subjects with moderate to very severe COPD designed to eva luate the efficacy of BEVESPI AEROSPHERE on lung function. The 24-week trials included 3,699 subjects that had a clinical diagnosis of COPD, were between 40 and 80 years of age, had a history of smoking greater than or equal to 10 pack-years, had a post-albuterol FEV1 less than 80% of predicted normal values, and had a ratio of FEV1/FVC of less than 0.7. The majority of patients were male (56%) and Caucasian (91%) with a mean age of 63 years and an average smoking history of 51 pack-years (54% current smokers). During screening, mean post-bronchodilator percent predicted FEV1 was 51% (range: 19% to 82%) and mean percent reversibility was 20% (range: -32% to 135%).
Trial 1 and Trial 2 eva luated BEVESPI AEROSPHERE (glycopyrrolate/formoterol fumarate) 18 mcg/9.6 mcg, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg, and placebo administered twice daily (BID). Trial 1 also included an open-label active control. The primary endpoint was change from baseline in trough FEV1 at Week 24 compared with placebo, glycopyrrolate 18 mcg BID, and formoterol fumarate 9.6 mcg BID. The comparison of BEVESPI AEROSPHERE with glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg was assessed to eva luate the contribution of the individual components to BEVESPI AEROSPHERE. In both trials, BEVESPI AEROSPHERE demonstrated a larger increase in mean change from baseline in trough FEV1 at Week 24 relative to placebo, glycopyrrolate 18 mcg, and formoterol fumarate 9.6 mcg (Table 2).
Table 2 – Least Square (LS) Mean Change from Baseline in Morning Pre-dose Trough
FEV1 (mL) at Week 24 in Trial 1 and Trial 2 (Intent-to-Treat Population)

Trough FEV1 (mL) at Week 24

Difference from

Treatment

N

Placebo*
LS Mean
(95% CI)

Glycopyrrolate
18 mcg BID*
LS Mean
(95% CI)

Formoterol Fumarate
9.6 mcg BID*
LS Mean
(95% CI)

Trial 1

BEVESPI AEROSPHERE

429

N=161
  
150 mL
(114, 186)

N=344
   
59 mL
(31, 88)

N=367
  
64 mL
(36, 92)

Trial 2

BEVESPI
AEROSPHERE

433

N=170
  
103 mL
(67, 140)

N=367
  
54 mL
(25, 83)

N=350
  
56 mL
(27, 85)

N = Number in the intent to treat population
*The placebo, glycopyrrolate and formoterol fumarate comparators used the same inhaler and excipients as BEVESPI AEROSPHERE.

With the limited data available, there were consistent improvements in trough FEV1 with respect to age, sex, degree of airflow limitation, GOLD stage, smoking status, or inhaled corticosteroid use.

In Trials 1 and 2, serial spirometric eva luations were performed throughout the 12-hour dosing interval in a subset of subjects (n=718 and n=585, respectively) at Day 1 and Week 12. Results from Trial 1 are shown in Figure 3. In Trial 2, the results for BEVESPI AEROSPHERE in FEV1 AUC0-12h were similar to those observed in Trial 1.

Figure 3 - Mean Change from Baseline in FEV1 over Time at Day 1 and Week 12 (Trial 1)

Day 1

 Figure 3 - Mean Change from Baseline in FEV1 over Time at Day 1 and Week 12 (Trial 1) Day 1
Week 12

 Week 12
In both trials, peak FEV1 w