Efficacy and Safety of Once-daily NVA237 in COPD
Efficacy and Safety of Once-daily NVA237 in COPD
Background: NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD). The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.
Methods: Patients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ≥ 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled. Patients were randomized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry. The primary outcome measure was trough FEV1 at Week 12.
Results: A total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270). Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001). Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26. FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints. Transition dyspnoea index focal scores and St. George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and-2.81 (p = 0.004), respectively. NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo. NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.
Conclusions: Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation, results in breathlessness and reduced exercise capacity, and is a leading cause of morbidity and mortality. The main goals of pharmacotherapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status, and increase exercise tolerance. Symptomatic treatment relies to a large extent on the use of bronchodilators, including long-acting muscarinic antagonists (LAMAs).
Tiotropium is the most frequently used LAMA worldwide and is an effective bronchodilator. Some patients taking tiotropium may experience adverse events (AEs) such as dry mouth, urinary problems and constipation. Tiotropium has a slow onset of action, with peak effects on lung function achieved after up to 3 hours. NVA237 is a once-daily dry-powder formulation of the LAMA glycopyrronium bromide that is currently in development for the treatment of COPD. In common with other LAMAs, the bronchodilatory effects of NVA237 result from blockade of muscarinic type 1 (M1) and type 3 (M3) receptors, which are involved in transmission of nerve impulses (M1) and promotion of contraction (M3) in airway smooth muscle.
Among patients with moderate-to-severe COPD, once-daily NVA237 provides sustained 24-hour bronchodilation, has a rapid onset of action and is safe and well tolerated. All evaluated doses of NVA237 (up to 200 μg) were well tolerated, with doses of 50 or 100 μg once daily having greater efficacy than lower doses.
The objective of the Phase III glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) was to evaluate the efficacy, safety and tolerability of oncedaily NVA237 50 μg, compared with placebo, in patients with moderate-to-severe COPD.
Abstract and Introduction
Abstract
Background: NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD). The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.
Methods: Patients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ≥ 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled. Patients were randomized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry. The primary outcome measure was trough FEV1 at Week 12.
Results: A total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270). Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001). Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26. FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints. Transition dyspnoea index focal scores and St. George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and-2.81 (p = 0.004), respectively. NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo. NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.
Conclusions: Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation, results in breathlessness and reduced exercise capacity, and is a leading cause of morbidity and mortality. The main goals of pharmacotherapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status, and increase exercise tolerance. Symptomatic treatment relies to a large extent on the use of bronchodilators, including long-acting muscarinic antagonists (LAMAs).
Tiotropium is the most frequently used LAMA worldwide and is an effective bronchodilator. Some patients taking tiotropium may experience adverse events (AEs) such as dry mouth, urinary problems and constipation. Tiotropium has a slow onset of action, with peak effects on lung function achieved after up to 3 hours. NVA237 is a once-daily dry-powder formulation of the LAMA glycopyrronium bromide that is currently in development for the treatment of COPD. In common with other LAMAs, the bronchodilatory effects of NVA237 result from blockade of muscarinic type 1 (M1) and type 3 (M3) receptors, which are involved in transmission of nerve impulses (M1) and promotion of contraction (M3) in airway smooth muscle.
Among patients with moderate-to-severe COPD, once-daily NVA237 provides sustained 24-hour bronchodilation, has a rapid onset of action and is safe and well tolerated. All evaluated doses of NVA237 (up to 200 μg) were well tolerated, with doses of 50 or 100 μg once daily having greater efficacy than lower doses.
The objective of the Phase III glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) was to evaluate the efficacy, safety and tolerability of oncedaily NVA237 50 μg, compared with placebo, in patients with moderate-to-severe COPD.