Background: Currently, once-daily nebulized bronchodilator therapy is unavailable for patients with chronic obstructive pulmonary disease (COPD). Prior studies demonstrated that once-daily revefenacin (REV) doses of 88 and 175 µg produced significant bronchodilation in COPD patients. We report the pooled results of two replicate phase 3 efficacy trials.
Methods: In these double-blind, placebo-controlled, parallel-group, 12-week trials (NCT02459080, NCT02512510), 1229 randomized patients with moderate to very severe COPD received once-daily REV 88 µg (n=417), 175 µg (n=395), or placebo (n=418), administered by a standard jet nebulizer. The primary endpoint was 24-hour trough forced expiratory volume in 1 second (FEV1) change from baseline to day 85. Secondary endpoints included overall treatment effect on trough FEV1 (OTE FEV1; day 15–day 85), day 1 peak FEV1 (0–2 hours after first dose), and patient-reported outcomes (St. George’s Respiratory Questionnaire [SGRQ]). Concomitant long-acting beta agonist (LABA) or inhaled corticosteroid/LABA therapy was allowed in 40% of subjects.
Results: Baseline demographics (mean age 64 years; 50% male; 49% current smokers) and spirometry (mean postbronchodilator FEV1 54%, 1.32L) were similar across treatment groups. Compared with placebo, REV 88 and 175 µg increased trough FEV1, OTE FEV1, and peak FEV1 by >100 mL (Figure 1). REV improved total SGRQ score from baseline by >4 points (Figure 2), with the greatest improvement observed in the symptom component score. REV 88 µg and 175 µg doses were both more likely to meet 4-point, 8-point, and 12-point SGRQ improvement responder definitions compared with placebo, with higher odds of achieving the 8-point and 12-point responder thresholds with the 175 µg dose relative to the 88 µg dose.
Conclusions: In replicate 12-week phase 3 studies in patients with moderate to very severe COPD, once-daily REV (88 and 175 μg) demonstrated clinically and statistically significant improvements in peak FEV1, trough FEV1, and OTE FEV1 relative to placebo. SGRQ results suggest improvement in the health status of patients treated with REV. If approved, REV could become the first once-daily bronchodilator to be available for COPD patients who require or prefer nebulized therapy.