Bremner et al. Respiratory Research (2018) 19:19 DOI 10.1186/s12931-018-0724-0 RESEARCH Open Access Single-inhaler fluticasone furoate/ umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: a randomized non- inferiority study Peter R. Bremner1, Ruby Birk2, Noushin Brealey2, Afisi S. Ismaila3,4, Chang-Qing Zhu2 and David A. Lipson5,6* Abstract Background: Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg has been shown to improve lung function and health status, and reduce exacerbations, versus budesonide/formoterol in patients with chronic obstructive pulmonary disease (COPD). We evaluated the non-inferiority of single-inhaler FF/ UMEC/VI versus FF/VI + UMEC using two inhalers. Methods: Eligible patients with COPD (aged ≥40 years; ≥1 moderate/severe exacerbation in the 12 months before screening) were randomized (1:1; stratified by the number of long-acting bronchodilators [0, 1 or 2] per day during run-in) to receive 24-week FF/UMEC/VI 100/62.5/25 μg and placebo or FF/VI 100/25 μg + UMEC 62.5 μg; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning. Primary endpoint: change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 24. The non-inferiority margin for the lower 95% confidence limit was set at − 50 mL. Results: A total of 1055 patients (844 [80%] of whom were enrolled on combination maintenance therapy) were randomized to receive FF/UMEC/VI (n = 527) or FF/VI + UMEC (n = 528). Mean change from baseline in trough FEV1 at Week 24 was 113 mL (95% CI 91, 135) for FF/UMEC/VI and 95 mL (95% CI 72, 117) for FF/VI + UMEC; the between-treatment difference of 18 mL (95% CI -13, 50) confirmed FF/UMEC/VI’s was considered non-inferior to FF/ VI + UMEC. At Week 24, the proportion of responders based on St George’s Respiratory Questionnaire Total score was 50% (FF/UMEC/VI) and 51% (FF/VI + UMEC); the proportion of responders based on the Transitional Dyspnea Index focal score was similar (56% both groups). A similar proportion of patients experienced a moderate/severe exacerbation in the FF/UMEC/VI (24%) and FF/VI + UMEC (27%) groups; the hazard ratio for time to first moderate/ severe exacerbation with FF/UMEC/VI versus FF/VI + UMEC was 0.87 (95% CI 0.68, 1.12). The incidence of adverse events was comparable in both groups (48%); the incidence of serious adverse events was 10% (FF/UMEC/VI) and 11% (FF/VI + UMEC). (Continued on next page) * Correspondence: [email protected] 5GSK, 709 Swedeland Road, UW2531, King of Prussia, PA 19406, USA 6Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bremner et al. Respiratory Research (2018) 19:19 Page 2 of 10 (Continued from previous page) Conclusions: Single-inhaler triple therapy (FF/UMEC/VI) is non-inferior to two inhalers (FF/VI + UMEC) on trough FEV1 change from baseline at 24 weeks. Results were similar on all other measures of efficacy, health-related quality of life, and safety. Trial registration: GSK study CTT200812; ClinicalTrials.gov NCT02729051 (submitted 31 March 2016). Keywords: COPD, Exacerbations, FEV1, Lung function, Fluticasone furoate/umeclidinium/vilanterol, Randomized controlled trial, Single-inhaler triple therapy Background regimen using two inhalers (FF/VI + UMEC) on trough The Global Initiative for Chronic Obstructive Lung Disease FEV1 after 24 weeks of treatment. To our knowledge, this (GOLD) strategy document recommends escalating to is the first study to specifically evaluate the same individual combination triple therapy with a long-acting β2-agonist component molecules administered using either a single (LABA), a long-acting muscarinic antagonist (LAMA) and inhalerormultipleinhalers. an inhaled corticosteroid (ICS) for patients with advanced chronic obstructive pulmonary disease (COPD) and persist- Methods ent symptoms (GOLD Group D) who experience further Study design symptoms or exacerbations on dual LABA/LAMA or This was a phase III, 24-week, randomized, double-blind, LABA/ICS therapy [1]. Although triple therapy for COPD parallel group, multicenter non-inferiority study (GSK study using multiple inhalers is common in current clinical prac- CTT200812; ClinicalTrials.gov identifier NCT02729051) tice [2, 3], the comparative benefits of COPD treatment that assessed the efficacy of once-daily FF/UMEC/VI regimens using single or multiple inhalers are not well 100 μg/62.5 μg/25 μg using a single ELLIPTA inhaler understood. versus once-daily FF/VI 100 μg/25 μgplusUMEC62.5μg Triple therapy with a LAMA plus ICS/LABA adminis- using two ELLIPTA inhalers (Fig. 1). Prior to the beginning tered using multiple inhalers has been shown to improve of the 24-week treatment period, there was a 2-week run-in forced expiratory volume in 1 s (FEV1) and health status, period, during which patients continued their existing and reduce exacerbations and rescue medication use, in COPD medications. At randomization following the run-in patients with COPD compared with ICS plus LABA dual period, all existing COPD medications were discontinued therapy or LAMA monotherapy [4–9]. Several recent and patients started their assigned study treatment, with large randomized controlled trials have also assessed the short-acting albuterol/salbutamol provided as rescue medi- efficacy and safety of triple ICS/LABA/LAMA therapy cation throughout the study. Study clinic visits occurred at using a single fixed-dose combination inhaler for patients pre-screening (visit 0), screening (visit 1), randomization with COPD at increased exacerbation risk [10–12]. (Week 0, visit 2), Week 4 (visit 3), Week 12 (visit 4), and The FULFIL study demonstrated improvements in Week 24 (visit 5). A safety follow-up telephone contact or trough FEV1, health status, and reductions in moderate/ clinic visit was conducted a week after study completion, or severe exacerbation rate, with once-daily, single-inhaler in the event of an early withdrawal. fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/ VI) versus twice-daily budesonide/formoterol (FOR) Patients [10]. Similarly, the TRILOGY study showed improve- Patients aged ≥40 years with COPD and who were current/ ments in lung function and exacerbation frequency with former smokers with a ≥ 10-pack-year smoking history a twice-daily, single-inhaler ICS/LABA/LAMA combin- were eligible for enrollment. Other key inclusion criteria in- ation of beclomethasone dipropionate (BDP)/FOR/gly- cluded: COPD Assessment Test™ (CAT) score ≥ 10 [13, 14]; copyrronium bromide (GB) compared with BDP/FOR a post-albuterol/salbutamol FEV1/forced vital capacity ratio alone [11]. Furthermore, results from the TRINITY < 0.70; and a post-bronchodilator FEV1 <50%ofpredicted study confirmed that the twice-daily, single-inhaler and ≥1 moderate/severe exacerbation in the previous BDP/FOR/GB combination was non-inferior to twice- 12 months or a post-bronchodilator FEV1 ≥ 50% to < 80% daily BDP/FOR plus tiotropium using multiple inhalers of predicted and ≥2 moderate exacerbations or ≥1 severe on change from baseline in pre-dose FEV1 [12]. exacerbation requiring hospitalization in the previous Given that single-inhaler triple therapy is soon expected 12 months. to be widely available, the current study was specifically Exclusion criteria included: a current diagnosis of asthma designed to demonstrate the non-inferiority of the only (patients with a prior history of asthma were eligible if they currently available once-daily, single-inhaler triple therapy had a current diagnosis of COPD that was the primary cause (FF/UMEC/VI) to an alternative once-daily triple therapy of their respiratory symptoms); α1-antitrypsin deficiency; Bremner et al. Respiratory Research (2018) 19:19 Page 3 of 10 Fig. 1 Study design active tuberculosis; other respiratory disorders that were the incidence of adverse events (AEs), serious AEs (SAEs), primary cause of respiratory symptoms; lung resection sur- and AEs of special interest (AESIs). gery in the previous 12 months; risk factors for pneumonia Spirometry was performed at screening and pre-dose at (including immunosuppression and neurological disorders each scheduled study visit during the treatment period affecting control of the upper airway [e.g. Parkinson’sdisease using standardized equipment according to American or myasthenia gravis]; pneumonia and/or moderate/severe Thoracic Society–European Respiratory Society guidelines exacerbation that had not resolved at least 14 days prior to [15]. The SGRQ for COPD patients [16] was completed screening; respiratory infections; abnormal findings on chest by patients at randomization and Weeks 12 and 24. The X-ray; clinically significant comorbidities; unstable liver or Baseline Dyspnea Index was measured at randomization cardiac disease; and cancer.