Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial.
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.



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.



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.



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.



Chiesi Farmaceutici SpA.
Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, UK. Electronic address: dsingh@meu.org.uk.
Dave
D
Singh
Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy.
Alberto
A
Papi
Department of Clinical and Experimental Medicine, University of Parma, Italy.
Massimo
M
Corradi
Odborny Plicni Lekar, Poliklinika Moravsky Krumlov, Moravsky Krumlov, Czech Republic.
Ilona
I
Pavlišová
Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
Isabella
I
Montagna
Global Clinical Development, Chiesi SAS, Courbevoie, France.
Catherine
C
Francisco
Global Clinical Development, Chiesi SAS, Courbevoie, France.
Géraldine
G
Cohuet
Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
Stefano
S
Vezzoli
Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
Mario
M
Scuri
Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, UK.
Jørgen
J
Vestbo
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000368:Aged; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004417:Dyspnea / Q000139:chemically induced; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D009330:Nebulizers and Vaporizers; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D018727:Muscarinic Antagonists