INCRUSE ELLIPTA Rx

The safety and efficacy of umeclidinium 62.5 mcg were evaluated in 3 dose-ranging trials, 2 placebo-controlled clinical trials (one 12-week trial and one 24-week trial), and a 12-month long-term safety trial. The efficacy of Incruse Ellipta is based primarily on the dose-ranging trials and the 2 placebo-controlled confirmatory trials in patients with COPD, including chronic bronchitis and/or emphysema.

In the dose-ranging trials, dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover study evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 patients with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV₁ over 24 hours compared with the lower doses of 15.6 and 31.25 mcg.

The differences in trough FEV₁ from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively. Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response.

The clinical development program for Incruse Ellipta included 2 randomized, double-blind, placebo-controlled, parallel-group confirmatory trials in patients with COPD designed to evaluate the efficacy of Incruse Ellipta on lung function. Trial 1 (NCT #01313650) was a 24-week placebo-controlled trial, and Trial 2 (NCT #01772147) was a 12-week placebo-controlled trial. These trials treated patients that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking ≥10 pack-years, had a post-albuterol FEV₁ ≤70% of predicted normal values, had a ratio of FEV₁/FVC of <0.7, and had a Modified Medical Research Council (mMRC) score ≥2. The majority of subjects (72%) reported not having a COPD exacerbation in the prior 12 months.

Patient demographics: (n=1738)

• Mean age: 63 years

• Average smoking history: 46 pack-years (with 50% identified as current smokers)

• Mean FEV₁ (predicted): 47% (range: 13 to 74%)

• Mean FEV₁/FVC ratio: 0.47 (range: 0.20 to 0.74)

• Mean percent reversibility: 15% (range: -35 to 109%)

Trial 1 (n=418) evaluated umeclidinium 62.5 mcg and placebo. The primary endpoint was change from baseline in trough (predose) FEV₁ at Day 169 (defined as the mean of the FEV₁ values obtained at 23 and 24 hours after the previous dose on Day 168) compared with placebo. Incruse Ellipta 62.5 mcg demonstrated a larger increase in mean change from baseline in trough (predose) FEV₁ relative to placebo (n=280; difference from placebo:  115 [95% CI: 76, 155]). Similar results were obtained from Trial 2. 

The safety and efficacy of Incruse Ellipta in combination with an ICS/LABA were also evaluated in 4 randomized, double-blind, parallel-group trials involving 1,637 patients with COPD. These trials had similar study design and were of 12-weeks’ treatment duration. Patients were randomized to Incruse Ellipta 62.5 mcg + ICS/LABA or placebo + ICS/LABA. The primary endpoint for these trials was change from baseline in trough (predose) FEV₁ at Day 85 (defined as the mean of the FEV₁ values obtained at 23 and 24 hours after the previous dose on Day 84). Baseline FEV₁ was measured while patients were on background ICS/LABA.

In the combination with Fluticasone Furoate + Vilanterol (Trial 4 [NCT #01957163] and Trial 5 [NCT #02119286]):

• Patients were randomly assigned to Incruse Ellipta 62.5 mcg + FF/VI 100 mcg/25 mcg given once daily or placebo + FF/VI 100 mcg/25 mcg given once daily.

• Results in trial 4 (n=206), showed that Incruse Ellipta + FF/VI demonstrated a larger mean change from baseline in trough (predose) FEV₁ relative to placebo + FF/VI (n=206; difference from placebo: 124 [95% CI: 93, 154]). Trial 5 results were similar.

In the combination with Fluticasone Propionate + Salmeterol (Trial 6 [NCT #01772134] and Trial 7 [NCT #01772147]): 

• Patients were randomly assigned to Incruse Ellipta 62.5 mcg + FP/SAL 250 mcg/50 mcg or placebo + FP/SAL 250 mcg/50 mcg. The treatments with Incruse Ellipta and placebo were given once daily, while the FP/SAL treatment was given twice daily. 

• Results in trial 6 (n=204), showed that Incruse Ellipta + FP/SAL demonstrated a larger mean change from baseline in trough (predose) FEV₁ relative to placebo + FP/SAL (n=205; difference from placebo: 147 [107, 187]). Results for Trial 7 were similar.