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.

Keywords:

• COPD
• exacerbations
• severe exacerbations
• triple therapy
• ICS/LABA

Abbreviations

AE, adverse event; AESI, adverse event of special interest; BMI, body mass index; BUD, budesonide; CAT, COPD Assessment Test; CFB, change from baseline; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; FOR, formoterol; GLY, glycopyrrolate; ICS, inhaled corticosteroid; ITT, intent-to-treat; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic receptor antagonist; LS, least squares; SAE, serious adverse event; SD, standard deviation; SGRQ, St George’s respiratory questionnaire; UMEC, umeclidinium; VI, vilanterol.

Data Sharing Statement

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Ethics Approval and Informed Consent

All patients provided written informed consent. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by the relevant national, regional, or independent ethics committees or institutional review boards. A full list of the ethics committees and institutional review boards is provided in Supplementary Table S2.

Consent for Publication

All authors contributed to the writing and reviewing of the manuscript and have given final approval for the version to be published.

Acknowledgments

Editorial support (in the form of writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors’ comments for each draft, assembling tables and figures, grammatical editing and referencing) was provided by Maria Guillermina Casabona, PhD, from Fishawack Indicia Ltd, part of Fishawack Health, UK, and was funded by GSK.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

RA Panettieri has received research support from Novartis, AstraZeneca, Genentech, Optikira, Medimmune, Maven, Evelobio, Johnson & Johnson, RIFM, Equillium, Theravance, TEVA, Origo, ACTIV-1, Janssen and Vault Health; has received consulting fees from AstraZeneca, RIFM, Equillium, Bayer and TEVA; is part of the speaking bureau for Sanofi/Regeneron, AstraZeneca, Merck & Co and Genentech; and is a member of the advisory committee for AstraZeneca, Genentech, RIFM, Equillium and Theravance. CA Camargo is a member of the scientific advisory board for AstraZeneca. T Cheema is part of the speaking bureau for BI, GSK, Regeneron and AstraZeneca, and is a consultant for Noveome Biotherapeutics. S El Bayadi is a speaker for GSK, Grifols, Sanofi Genzyme Regeneron, Mylan Theravance, Janssen, Bayer, Mallinckrodt Pharmaceuticals. S Fiel is a member of Speakers Bureau Gilead. T Vila, RG Jain, D Midwinter, DA Lipson are GSK employees and hold stock/shares at GSK. B Thomashow has taken part in advisory boards for AstraZeneca, Boehringer Ingelheim and GSK and performed consulting work for GSK. A Ludwig-Sengpiel is KLB Gesundheitsforschung Lübeck GmbH managing director. ELLIPTA is owned by or licensed to the GSK group of companies. Turbuhaler is owned by or licensed to the AstraZeneca group of companies, and BUD/FOR 400/12 mcg twice-daily is not a US Food and Drug Administration-approved formulation. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was funded by GSK (CTT116853/NCT02345161). The funders of the study had a role in the study design, data analysis, data interpretation, and writing of the report.