Patients with severe COPD are likely to suffer frequent disease exacerbations and a reduced quality of life. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend dual agent therapy consisting of an inhaled corticosteroid (ICS) plus either a long acting beta agonist (LABA) or a long acting anticholinergic medication (LAMA) for patients with severe disease. The GOLD guidelines also offer alternative recommendations for patients who do not respond adequately to dual inhaler therapy—including adding both LABA and LAMA medications with an ICS. But this strategy has not been well studied and the need for additional inhalers could decrease patient compliance and ultimately not lead to improved care.
The “Single Inhaler Triple Therapy Versus Inhaled Corticosteroid Plus Long-acting β-agonist Therapy for Chronic Obstructive Pulmonary Disease (TRILOGY)” trial investigated the use of triple drug therapy in a novel single inhaler in patients with severe COPD. TRILOGY
was a double-blind parallel group study that randomized 1368 subjects across 159 study sites in 14 countries. Eligible patients had FEV1 of less than 50%, one or more COPD exacerbations in the previous 12 months, a COPD Assessment Test score of 10 or more, along with a Baseline Dyspnea Index score of 10 or less.
Patients in the control group received a combination inhaler containing beclomethasone dipropionate (100 µg) and formoterol fumerate (6 µg) (BDP/FF). The study group received a newly designed triple therapy inhaler containing beclomethasone dipropionate (100 µg), formoterol fumerate (6 µg) and glycopyrronium bromide (12.5 µg) (BDP/FF/GB). Each group also received a salbutamol inhaler as a rescue medication. The between group comparison included three primary endpoints assessed at 26 weeks:
. Change from baseline pre-dose morning FEV1
. Change from baseline in 2 hour post-dose FEV1
. Transitional Dyspnea Index (TDI) focal score
Secondary endpoints included time to first exacerbation, exacerbation frequency, rescue inhaler use, TDI focal score at all clinic visits, and St George’s Respiratory Questionnaire (SGRQ) total score.
The primary findings included a statistically significant improvement in pre-dose FEV1 in the BDP/FF/GB group of 0.081L (p<0.001) and 2 hour post dose FEV1 by 0.117L (p<0.001). The difference in the TDI focal score at the end of 26 weeks was not significant between the two groups—but was at various points throughout the study (weeks 4 and 12). Other differences between groups included a 23% decrease in COPD exacerbations in the treatment group, as well as a decrease in use of rescue treatment.
Compliance was very good—at 95.6% of doses in the triple therapy group and 95% in the BDP/FF study population.
Adverse events were similar between the groups. Most were classified as mild or moderate in severity. Only one serious adverse event occurred: atrial fibrillation in a BDP/FF/GB recipient resolved and did not lead to study drug discontinuation.
The authors concluded that in patients with COPD and severe to very severe airflow limitation, symptoms and exacerbation history, BDP/FF/GB single-inhaler triple therapy has greater efficacy, reduced exacerbations and a greater effect on health-related quality of life than duel BDP/FF treatment. However, the lack of a statistically significant difference at 26 weeks in TDI focal score and SGRQ calls into question whether the patients experienced a difference in day to day symptoms. The TDI measures dyspnea in 3 categories: functional impairment, magnitude of task, and magnitude of effort. The St George’s Respiratory Questionnaire measures the quality of life impact of COPD on overall health, daily life, and perceived well-being. Lacking improvement in these relatively subjective measurements of efficacy could lead to reluctance among patients to accept therapy with an additional medication.
The TRILOGY trial demonstrated the ability of a single inhaler to deliver triple (ICS, LAMA, and LABA) therapy to improve outcomes in patients with severe COPD. At a minimum, this new three-drug inhaler would simplify the medication regimen of patients needing this level multi-respiratory agent care.
Michael L. Smith, PharmD, BCPS, CACP, is the pharmacy clinical manager, East Region, Hartford Healthcare, Hartford, Conn., and adjunct clinical professor, University of Connecticut School of Pharmacy, Storrs, Conn.