Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study

Background: This study evaluated the efficacy, safety and tolerability of the novel inhaled phosphodiesterase-4 inhibitor CHF6001 added-on to formoterol in patients with chronic obstructive pulmonary disease (COPD). Methods: Randomised, double-blind, placebo- and active-controlled, parallel-group study. Eligible patients had symptomatic COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 30-70% predicted, and history of >= 1 moderate/severe exacerbation. Patients were randomised to extrafine CHF6001 400, 800, 1200 or 1600 mu g twice daily (BID), budesonide, or placebo for 24 weeks. Primary objectives: To investigate CHF6001 dose-response for pre-dose FEV1 after 12 weeks, and to identify the optimal dose. Moderate-to-severe exacerbations were a secondary endpoint. Results: Of 1130 patients randomised, 91.9% completed. Changes from baseline in pre-dose FEV(1)at Week 12 were small in all groups (including budesonide), with no CHF6001 dose-response, and no significant treatment-placebo differences. For moderate-to-severe exacerbations, CHF6001 rate reductions versus placebo were 13-28% (non-significant). Inpost-hocanalyses, CHF6001 effects were larger in patients with a chronic bronchitis phenotype (rate reductions versus placebo 24-37%; non-significant), and were further increased in patients with chronic bronchitis and eosinophil count >= 150 cells/mu L (49-73%, statistically significant for CHF6001 800 and 1600 mu g BID). CHF6001 was well tolerated with no safety signal (including in terms of gastrointestinal adverse events). Conclusions: CHF6001 had no effect in the primary lung function analysis, although was well-tolerated with no gastrointestinal adverse event signal. Post-hoc analyses focused on exacerbation risk indicate specific patient subgroups who may receive particular benefit from CHF6001.