Once-daily triple therapy in a single inhaler showed a significant reduction in moderate-to-severe exacerbation of chronic obstructive pulmonary disease (COPD) compared with dual inhaled therapy, according to data from a phase 3 trial published in the American Journal of Respiratory and Critical Care Medicine.
David A. Lipson, MD, from GSK, King of Prussia, Pennsylvania, and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues sought to compare the effects of once-daily inhaled triple therapy (dual inhaled corticosteroid [ICS]/long-acting-β2 agonist [LABA]/long-acting muscarinic antagonist [LAMA] vs twice-daily dual inhaled ICS/LABA therapy in patients with COPD; FULFIL; A Comparison Study Between the Fixed Dose Triple Combination of Fluticasone Furoate/Umeclidinium/Vilanterol Trifenatate [FF/UMEC/VI] With Budesonide/Formoterol in Subjects With Chronic Obstructive Pulmonary Disease [COPD]; ClinicalTrials.gov identifier: NCT02345161).
In the randomized, double-blind, double-dummy study, patients with COPD aged ≥40 years received either once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; n=911) or twice-daily therapy with budesonide/formoterol (BUD/FOR; n=899). The coprimary endpoints were change from baseline in trough forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ) total score at week 24. A subset of patients (n=430) was followed-up in a 52-week study extension.
At week 24, the mean change in the FF/UMEC/VI and BUD/FOR groups from baseline in FEV1 was 142 mL (95% CI, 126-158 mL) and −29 mL (95% CI, −46 to −13 mL), respectively; mean change from baseline SGRQ was −6.6 units (95% CI, −7.4 to −5.7 units) and −4.3 units (95% CI, −5.2 to −3.4 units), respectively. The differences between the groups were statistically significant (P <.001). The 35% reduction in moderate to severe exacerbation rate with triple vs ICS/LABA therapy was significant (95% CI, 14%-51%; P =.002).
Comparable results were observed in the extension study. The mean change in the FF/UMEC/VI and BUD/FOR groups from baseline in FEV1 was 126 mL (95% CI, 92-159 mL) and −53 mL (95% CI, −87 to −20 mL), respectively; mean change from baseline SGRQ was −4.6 units (95% CI, −6.5 to −2.6 units) and −1.9 units (95% CI, −3.9 to 0.1 units), respectively. The between-treatment difference was similar to the difference reported in the intent-to-treat population; however, it did not reach statistical significance.
On-treatment adverse events (AEs) were 38.9% in the FF/UMEC/VI group and 37.7% in the BUD/FOR group. The most common AEs in the FF/UMEC/VI and BUD/FOR groups were nasopharyngitis (7% and 5%, respectively) and headache (5% and 6%, respectively).
Serious AEs in the FF/UMEC/VI and BUD/FOR groups included COPD exacerbation (1.3% and 2.3%, respectively) and pneumonia (1.0% and 0.3%, respectively). Each group had 6 on-treatment deaths, which were not unexpected, given the patient population with advanced COPD and multiple comorbidities.
“The FULFIL study provided important evidence of the benefits of ICS/LAMA/LABA therapy compared to ICS/LABA therapy,” noted Dr Lipson in an email interview with Pulmonology Advisor. “Although not yet approved in any market worldwide, we were very pleased that the study demonstrated statistically significant, compelling, and clinically meaningful benefits in lung function, health related quality of life, symptoms, and reduction in COPD exacerbations with a once-daily single inhaler triple therapy (FF/UMEC/VI) compared to twice-daily [BUD/FOR], in symptomatic patients with COPD who are at risk of exacerbation.”
Although the study included patients with comorbid hypertension, diabetes mellitus, and coronary heart disease, it excluded patients with current asthmas, unresolved pneumonia, and severe COPD.
Study funding was provided by GSK. The researchers report financial relationships with GSK.
Lipson DA, Barnacle H, Birk R, et al. FULFIL trial: once-daily triple therapy in patients with chronic obstructive pulmonary disease [published online April 4, 2017]. Am J Respir Crit Care Med. doi: 10.1164/rccm.201703-0449OC