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 μg 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 FEV1 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). In post-hoc analyses, 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/μL (49-73%, statistically significant for CHF6001 800 and 1600 μg 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. TRIAL REGISTRATION ClinicalTrials.gov ( NCT02986321 ). Registered 8 Dec 2016.