Effect of Recent Exacerbation History on the Efficacy of Once-Daily Single-Inhaler Fluticasone Furoate/Umeclidinium/Vilanterol Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease in the FULFIL Trial

Abstract

Background In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy. Methods FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.5/25 mcg or BUD/FOR 400/12 mcg. In this post hoc analysis, patients were categorized by exacerbation history in the year prior to study entry (≥1 moderate/severe exacerbation [recent exacerbation] versus no recent exacerbation). Endpoints included annual rate of on-treatment moderate/severe exacerbations up to Week 24, annual rate of on-treatment severe exacerbations up to Week 24, change from baseline in trough forced expiratory volume in 1 second at Week 24, and change from baseline in health status as measured by St George’s respiratory questionnaire total score at Week 24. Results Of the 1810 patients in the intent-to-treat population, 1180 (65%) had one or more moderate/severe exacerbation in the year prior to entry, while 630 (35%) patients did not. FF/UMEC/VI versus BUD/FOR significantly reduced moderate/severe exacerbation rates in the recent exacerbation subgroup (mean annualized rate: 0.19 vs 0.29; rate ratio [95% confidence interval [CI]]: 0.64: [0.45, 0.91]; p =0.014) and numerically reduced moderate/severe exacerbation rates in the no recent exacerbation subgroup (mean annualized rate: 0.29 vs 0.43; rate ratio [95% CI]: 0.67 [0.43, 1.04]; p =0.073). Severe exacerbation rates were numerically reduced with FF/UMEC/VI versus BUD/FOR treatment across both subgroups. FF/UMEC/VI conferred significant improvements in lung function and health status versus BUD/FOR, regardless of recent exacerbation history. Conclusion FF/UMEC/VI reduced moderate/severe and severe exacerbation rates and improved lung function and health status versus BUD/FOR in patients with symptomatic COPD, regardless of recent exacerbation history.

Outcomes of Patients with COPD Treated with ICS/LABA Before and After Initiation of Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI)

“…In our observational study, we also observed a reduction in the annualized rate of any (moderate/severe) exacerbation following the initiation of FF/UMEC/VI in the BUD/FORM subgroup; a high proportion of patients had experienced ≥ 1 exacerbation in the prior year and these patients experienced a reduction in any exacerbation as well. In FULFIL, a reduction in the annualized rate of severe exacerbations was observed at 24 weeks in patients treated with FF/UMEC/VI versus BUD/FORM with an exacerbation in the year prior to study entry [ 14 ]. In our study, we also observed a significant reduction in severe exacerbations in patients with ≥ 1 exacerbation during baseline following the initiation of FF/UMEC/VI in the BUD/FORM subgroup.…”

Letter to the Editor Regarding “Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis”

“…Additionally, prior exacerbations are well-recognized as a strong predictor of future exacerbation risk [ 18 ]. KRONOS did not require patients to have an exacerbation in the previous year (74% of patients did not) [ 14 ]; FULFIL required patients to have ≥ 2 moderate exacerbations or ≥ 1 severe exacerbation in the previous year if their FEV 1 was ≥ 50–< 80%, but did not require exacerbations in the previous year if their FEV 1 was < 50% (35% of patients did not) [ 15 , 19 ]. Considering these studies are supposedly similar in other key aspects according to Ismaila et al, it is surprising and contrary to accepted scientific knowledge on the impact of prior exacerbations that the annual moderate/severe exacerbation rate was > 50% higher for BUD/FOR in KRONOS versus FULFIL (0.55 vs. 0.34), when 74% of KRONOS patients had no exacerbations in the previous year [ 14 , 15 ].…”

“…One difference was that IMPACT only included patients with recent exacerbations, and the annual moderate/severe exacerbation rate with FF/UMEC/VI was 0.91 [ 20 ]. However, in a post hoc analysis of FULFIL, the annual moderate/severe exacerbation rate in patients with recent exacerbations before study entry (aligned with IMPACT) was 0.19 with FF/UMEC/VI [ 19 ], approximately 80% lower than in IMPACT. This again highlights that FULFIL is somewhat of an outlier, with fundamental differences to its connected studies; this questions how these studies could be considered similar and why heterogeneity was not further explored.…”