Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial

Abstract

IntroductionExercise limitation, dynamic hyperinflation, and exertional dyspnea are key features of symptomatic chronic obstructive pulmonary disease (COPD). We assessed the effects of glycopyrronium bromide (NVA237), a once-daily, long-acting muscarinic antagonist, on exercise tolerance in patients with moderate to severe COPD.MethodsPatients were randomized to a cross-over design of once-daily NVA237 50 μg or placebo for 3 weeks, with a 14-day washout. Exercise endurance, inspiratory capacity (IC) during exercise, IC and expiratory volumes from spirometry, plethysmographic lung volumes, leg discomfort and dyspnea under exercise (Borg scales), and transition dyspnea index were measured on Days 1 and 21 of treatment. The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test on Day 21.ResultsA total of 108 patients were randomized to different treatment groups (mean age, 60.5 years; mean post-bronchodilator, forced expiratory volume in 1 second [FEV1] 57.1% predicted). Ninety-five patients completed the study. On Day 21, a 21% difference in endurance time was observed between patients treated with NVA237 and those treated with placebo (P < 0.001); the effect was also significant from Day 1, with an increase of 10%. Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 of treatment that were maintained throughout the study. This was accompanied by inverse decreases in residual volume and functional residual capacity. NVA237 was superior to placebo (P < 0.05) in decreasing leg discomfort (Borg CR10 scale) on Day 21 and exertional dyspnea on Days 1 and 21 (transition dyspnea index and Borg CR10 scale at isotime). The safety profile of NVA237 was similar to that of the placebo.ConclusionNVA237 50 μg once daily produced immediate and significant improvement in exercise tolerance from Day 1. This was accompanied by sustained reductions in lung hyperinflation (indicated by sustained and significant improvements in IC at isotime), and meaningful improvements in trough FEV1 and dyspnea. Improvements in exercise endurance increased over time, suggesting that mechanisms beyond improved lung function may be involved in enhanced exercise tolerance. (ClinicalTrials.gov Identifier: NCT01154127).

Does the Term “Deflators” Reflect More Accurately the Beneficial Effects of Long-acting Bronchodilators in COPD?

“…In clinical trials, once-daily LABD have consistently improved not only airflow limitation, but also to a greater extent hyperinflation (as expressed by IC), both at rest and during exercise and these effects are translated into improvements in dyspnea and exercise capacity (18)(19)(20). Moreover, by deflating the lungs, bronchodilators effectively improve ventilatory muscle performance and lung mechanics, resulting in improvement of neuromechanical coupling, leading to alleviation of dyspnea (21).…”

Cardiovascular safety of new inhaled medications for asthma and chronic obstructive pulmonary disease: a critical review from pharmacist perspective

“…86 The rate of AEs observed in short-duration clinical trials is about 5%, and not significantly different to placebo controls. 87,88 A series of GLOW trials has investigated the use of glycopyrronium in extended duration of up to 52 weeks, either as monotherapy or in combination with LABAs. Most studies have found low incidences of extra-pulmonary effects among subjects without significant cardiovascular co-morbidity.…”

Addressing unmet needs in the treatment of COPD

“…Significant improvements have been observed with glycopyrronium versus placebo in lung function and clinical end-points, such as health status, dyspnoea, rescue medication use, daily symptoms, exercise endurance time and rate of exacerbations in three major clinical trials [23,[71][72][73].…”

“…Triple therapy (the combination of a LABA/LAMA with an ICS, or an ICS/LABA with a LAMA) is a treatment option for patients in GOLD group D. The improvements in lung function and clinical end-points observed with glycopyrronium [71][72][73][74] suggest that the LAMA may be a suitable candidate for use in a loose triple combination with an ICS/LABA. To study the efficacy of glycopyrronium in this approach, the GLISTEN trial investigated the efficacy (non-inferiority) of glycopyrronium compared with blinded tiotropium when added to twice-daily SFC [75].…”