BACKGROUND: Few data are available for the efficacy of "triple therapy" with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We designed this study to assess efficacy of single-inhaler combination of an extra fine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB) in COPD compared with beclometasone dipropionate and formoterol fumarate (BDP/FF) treatment. METHODS: TRILOGY was a randomised, parallel group, double-blind, active-controlled study done in 159 sites across 14 countries. The sites were a mixture of primary, secondary, and tertiary care providers, and specialist investigation units. Eligible patients with COPD had post-bronchodilator forced expiratory volume in 1 s (FEV1) of lower than 50%, one or more moderate-to-severe COPD exacerbation in the previous 12 months, COPD Assessment Test total score of 10 or more, and a Baseline Dyspnea Index focal score of 10 or less. Patients who met the inclusion and exclusion criteria at screening entered a 2-week open-label run-in period where they received beclometasone dipropionate (100 μg) and formoterol fumarate (6 μg) in two actuations twice daily. Patients were then randomly assigned (1:1) with an interactive response technology system to either continue BDP (100 μg) and FF (6 μg) or step-up to BDP (100 μg), FF (6 μg), and GB (12·5 μg) in two actuations twice daily for 52 weeks via pressurised metered-dose inhaler. The three co-primary endpoints were pre-dose FEV1, 2-h post-dose FEV1, and Transition Dyspnea Index (TDI) focal score, all measured at week 26 in the intention-to-treat population (all patients who were randomly assigned and received at least one dose of study drug and had at least one post-baseline efficacy assessment). Safety outcomes were measured in the safety population (all patients who were randomly assigned and received at least one dose of study drug). Secondary endpoints included moderate-to-severe COPD exacerbation rate over 52 weeks. This study is registered with ClinicalTrials.gov number NCT01917331. FINDINGS: Between March 21, 2014, and Jan 14, 2016, 1368 patients received either BDP/FF/GB (n=687) or BDP/FF (n=681). At week 26, BDP/FF/GB improved pre-dose FEV1 by 0·081 L (95% CI 0·052-0·109; p<0·001) and 2-h post-dose FEV1 by 0·117 L (0·086-0·147; p<0·001) compared with BDP/FF. Mean TDI focal scores at week 26 were 1·71 for BDP/FF/GB and 1·50 for BDP/FF, with a difference of 0·21 (95% CI -0·08 to 0·51; p=0·160). Adjusted annual moderate-to-severe exacerbation frequencies were 0·41 for BDP/FF/GB and 0·53 for BDP/FF (rate ratio 0·77 [95% CI 0·65-0·92]; p=0·005), corresponding to a 23% reduction in exacerbations with BDP/FF/GB compared with BDP/FF. Adverse events were reported by 368 (54%) patients with BDP/FF/GB and 379 (56%) with BDP/FF. One serious treatment-related adverse event occurred (atrial fibrillation) in a patient in the BDP/FF/GB group. INTERPRETATION: We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β2-agonist combination treatment to triple therapy using a single inhaler. FUNDING: Chiesi Farmaceutici SpA.

Centre for Respiratory Medicine and Allergy University of Manchester Manchester UK

Department of Clinical and Experimental Medicine University of Parma Italy

Global Clinical Development Chiesi Farmaceutici SpA Parma Italy

Global Clinical Development Chiesi SAS Courbevoie France

Odborny Plicni Lekar Poliklinika Moravsky Krumlov Moravsky Krumlov Czech Republic

Research Centre on Asthma and COPD University of Ferrara Ferrara Italy

Lancet. 2016 Sep 3;388(10048):936. doi: 10.1016/S0140-6736(16)31522-7. PubMed

Lancet. 2016 Sep 3;388(10048):937-8. doi: 10.1016/S0140-6736(16)31464-7. PubMed

Ann Intern Med. 2016 Dec 20;165(12):JC67. doi: 10.7326/ACPJC-2016-165-12-067. PubMed

Am J Respir Crit Care Med. 2018 Apr 1;197(7):944-946. doi: 10.1164/rccm.201704-0833RR. PubMed

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Dose-response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT)

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ClinicalTrials.gov
NCT01917331