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Clinically important deterioration (CID) is a novel composite end-point (lung function, health status, exacerbations) for assessing disease stability in patients with chronic obstructive pulmonary disease (COPD). We prospectively analysed CID in the FULFIL study. FULFIL (ClinicalTrials.gov NCT02345161; randomised, double-blind, double-dummy, multicentre study) compared 24 weeks of once daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg with twice daily budesonide/formoterol (BUD/FOR) 400/12 μg in patients aged ≥40 years with symptomatic advanced COPD (Global Initiative for Chronic Obstructive Lung Disease group D). A subset of patients received study treatment for up to 52 weeks. Time to first CID event was assessed over 24 and 52 weeks using two approaches for the health status component: St George's Respiratory Questionnaire and COPD assessment test. FF/UMEC/VI significantly reduced the risk of a first CID event by 47-52% versus BUD/FOR in the 24- and 52-week populations using both CID definitions (p<0.001). The median time to first CID event was ≥169 days and ≤31 days with FF/UMEC/VI and BUD/FOR, respectively. Only stable patients with no CID at 24 weeks demonstrated sustained clinically important improvements in lung function and health status at 52 weeks versus those who had experienced CID. Once daily, single-inhaler FF/UMEC/VI significantly reduced the risk of CID versus twice daily BUD/FOR with a five-fold longer period without deterioration., Competing Interests: Conflict of interest: I. Naya is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: C. Compton is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: A.S. Ismaila is an employee of GSK and holds stocks/shares in GSK and is an unpaid faculty member at McMaster University, Canada. Conflict of interest: R. Birk is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: N. Brealey is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: M. Tabberer is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: C-Q. Zhu is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: D.A. Lipson is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: G. Criner reports grants from Boehringer Ingelheim, Novartis, AstraZeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx and Pulmonx, as well as equity interest from HGE Health Care Solutions, Inc, and consultation fees from Amirall, Boehringer Ingelheim and Holaira, outside the submitted work.

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear. FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1 s (FEV 1 ), St George's Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency). In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV 1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV 1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups. These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making., Competing Interests: Conflict of interest: D.M.G. Halpin reports receiving personal fees from GSK during the conduct of the study, and personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim and Novartis; and personal fees from Pfizer and Chiesi, outside the submitted work. R. Birk is an employee of GSK and holds shares in that company. N. Brealey is an employee of GSK and holds shares in that company. G. Criner reports receiving consulting fees from GSK and performing a contracted clinical trial for the company during the conduct of the study. He reports receiving grants from the US NIH and the Dept of Defense; receiving consulting fees from and performing contracted clinical trials for AstraZeneca, Boehringer Ingelheim, Avisa, Mereo, PneumRx/BTG, Pulmonx, Broncus and Lungpacer; receiving consulting fees from Holaira, Third Pole, Pearl, Amirall and CSA Medical; and performing contracted clinical trials for Novartis and Yungjin, all outside the submitted work. M.T. Dransfield reports receiving consulting fees from GSK and performing a contracted clinical trial for the company during the conduct of the study. He reports receiving grants from the US National Institutes of health and the Dept of Defense; receiving consulting fees from and performing contracted clinical trials for AstraZeneca, Boehringer Ingelheim and Boston Scientific; receiving consulting fees from Genentech; and performing contracted clinical trials for Novartis, Pulmonx, PneumRx/BTG and Yungjin, all outside the submitted work. E. Hilton is an employee of GSK and holds shares in that company. D.A. Lomas reports receiving grants, personal fees and nonfinancial support from GSK during the conduct of the study; personal fees and grants from GSK; and personal fees from Griffols, all outside the submitted work. C-Q. Zhu is an employee of GSK and holds shares in that company. D.A. Lipson is an employee of GSK and holds shares in that company.

Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017., (Copyright ©ERS 2016.)