Preventing clinically important deterioration with single-inhaler triple therapy in COPD

Ian Naya, Chris Compton, Afisi S Ismaila, Ruby Birk, Noushin Brealey, Maggie Tabberer, Chang-Qing Zhu, David A Lipson, Gerard Criner, Ian Naya, Chris Compton, Afisi S Ismaila, Ruby Birk, Noushin Brealey, Maggie Tabberer, Chang-Qing Zhu, David A Lipson, Gerard Criner

Abstract

Clinically important deterioration (CID) is a novel composite end-point (lung function, health status, exacerbations) for assessing disease stability in patients with chronic obstructive pulmonary disease (COPD). We prospectively analysed CID in the FULFIL study. FULFIL (ClinicalTrials.gov NCT02345161; randomised, double-blind, double-dummy, multicentre study) compared 24 weeks of once daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg with twice daily budesonide/formoterol (BUD/FOR) 400/12 μg in patients aged ≥40 years with symptomatic advanced COPD (Global Initiative for Chronic Obstructive Lung Disease group D). A subset of patients received study treatment for up to 52 weeks. Time to first CID event was assessed over 24 and 52 weeks using two approaches for the health status component: St George's Respiratory Questionnaire and COPD assessment test. FF/UMEC/VI significantly reduced the risk of a first CID event by 47-52% versus BUD/FOR in the 24- and 52-week populations using both CID definitions (p<0.001). The median time to first CID event was ≥169 days and ≤31 days with FF/UMEC/VI and BUD/FOR, respectively. Only stable patients with no CID at 24 weeks demonstrated sustained clinically important improvements in lung function and health status at 52 weeks versus those who had experienced CID. Once daily, single-inhaler FF/UMEC/VI significantly reduced the risk of CID versus twice daily BUD/FOR with a five-fold longer period without deterioration.

Conflict of interest statement

Conflict of interest: I. Naya is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: C. Compton is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: A.S. Ismaila is an employee of GSK and holds stocks/shares in GSK and is an unpaid faculty member at McMaster University, Canada. Conflict of interest: R. Birk is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: N. Brealey is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: M. Tabberer is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: C-Q. Zhu is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: D.A. Lipson is an employee of GSK and holds stocks/shares in GSK. Conflict of interest: G. Criner reports grants from Boehringer Ingelheim, Novartis, AstraZeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx and Pulmonx, as well as equity interest from HGE Health Care Solutions, Inc, and consultation fees from Amirall, Boehringer Ingelheim and Holaira, outside the submitted work.

Figures

FIGURE 1
FIGURE 1
Time to a first composite clinically important deterioration (CID) event in a) the intent-to-treat population (24-week study duration, n=1810) and b) the extension population (52-week study duration, n=430). RR: risk reduction (based on a time-to-first-event analysis using a Cox proportional hazards model); FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol; BUD: budesonide; FOR: formoterol; SGRQ: St George's Respiratory Questionnaire; CAT: chronic obstructive pulmonary disease assessment test.
FIGURE 2
FIGURE 2
Occurrence of a clinically important deterioration (CID) by individual CID component event type in a, b) the intent-to-treat population (24-week study duration, n=1810) and c, d) the extension population (52-week study duration, n=430). CID assessment using a, c) the St George's Respiratory Questionnaire (SGRQ)-containing definitions and b, d) chronic obstructive pulmonary disease assessment test (CAT)-containing definitions. FEV1: forced expiratory volume in 1 s; FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol; BUD: budesonide; FOR: formoterol; RR: relative risk (based on a time-to-first-event analysis using a Cox proportional hazards model).
FIGURE 3
FIGURE 3
Forest plot of hazard ratios for time to first composite clinically important deterioration (CID) event segmented by baseline disease severity, exacerbation history, sex, health status and prior treatment at screening using a) the St George's Respiratory Questionnaire-containing and b) the chronic obstructive pulmonary disease assessment test (CAT)-containing CID definitions (intent-to-treat population). Hazard ratios and 95% CIs are from a Cox proportional hazards model with covariates of treatment group, smoking status at screening and geographical region, plus the specified factor and specified factor by treatment group interaction. GOLD: Global Initiative for Chronic Obstructive Lung Disease; ICS: inhaled corticosteroid; FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol; BUD: budesonide; FOR: formoterol. ***: ppost hoc sensitivity analysis).

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