Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study

Abstract

We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium, tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). This was a multicentre, randomised, double-blind, placebo- and active-controlled, 26-week trial. Patients (n = 2144) were randomised (2:2:2:2:1) to receive once-daily QVA149 (indacaterol 110 μg/glycopyrronium 50 μg), indacaterol 150 μg, glycopyrronium 50 μg, open-label tiotropium 18 μg or placebo. The primary end-point was trough forced expiratory volume in 1 s (FEV1) at week 26 for QVA149 versus its monocomponents. Secondary end-points included dyspnoea, health status, rescue medication use and safety. Trough FEV1 at week 26 was significantly improved (p<0.001) with QVA149 compared with indacaterol and glycopyrronium (least squares mean (LSM) differences 0.07 L and 0.09 L, respectively), tiotropium and placebo (LSM differences 0.08 L and 0.20 L, respectively); these beneficial effects were sustained throughout the 26-week study. QVA149 significantly improved dyspnoea and health status versus placebo (p<0.001 and p = 0.002, respectively) and tiotropium (p = 0.007 and p = 0.009, respectively) at week 26. All treatments were well tolerated. Dual bronchodilation with once-daily QVA149 demonstrated superior and clinically meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator, with a safety and tolerability profile similar to placebo, supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist combinations for the treatment of COPD.

Figure 1–

The SHINE study design.

Figure 2–

Flow diagram for disposition of patients. Data are presented as n (%), unless otherwise stated. ^#: nine patients were randomised but did not receive the study drug (n = 5: major protocol deviation for an inclusion/exclusion criteria (did not meet electronic diary inclusion criteria); n = 1: patient did not meet spirometry criteria; n = 1: patient withdrew consent; n = 1: patient took tiotropium during visit 3; n = 1: site had issues with the MasterScope^® (eResearch Technology, Inc, Philadelphia, PA, USA) and could not continue); ^¶: for each treatment group, the full analysis and safety sets comprised the same patients.

Figure 3–

Trough forced expiratory volume in 1 s (FEV₁) a) at week 26 and b) over the entire 26-week treatment period. a) Data are presented as least squares mean±se. One-sided adjusted p-values are presented for comparisons in the statistical gatekeeping procedure and two-sided p-values are presented for all other comparisons. b) QVA149 was superior to all active treatments and placebo at all timepoints (all p<0.001). n: number per treatment group in the full analysis set.

Figure 4–

Serial spirometry on a) day 1 and b) week 26. a) QVA149 was superior to placebo and tiotropium at all assessed timepoints (p<0.001); superior to indacaterol at all assessed timepoints (p<0.01), except at 5 min post-dose; superior to glycopyrronium at all assessed timepoints (p<0.05), except 1 h post-dose. b) QVA149 superior to placebo (p<0.001) and indacaterol (p<0.05) at all assessed timepoints; superior to glycopyrronium at all assessed timepoints (p<0.05), except 23 h 45 min post-dose; superior to tiotropium at all assessed timepoints (p<0.05), except 22 h and 23 h 45 min post-dose. n: number per treatment group in the serial spirometry subset of the full analysis set. FEV₁: forced expiratory volume in 1 s.