The Effect of Inhaled Corticosteroid Withdrawal and Baseline Inhaled Treatment on Exacerbations in the IMPACT Study. A Randomized, Double-Blind, Multicenter Clinical Trial

Abstract

Rationale: In the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.Objectives: To understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization.Methods: Exacerbations and change from baseline in trough FEV₁ and St. George's Respiratory Questionnaire results were analyzed by prior ICS use. Exacerbations were also analyzed while excluding data from the first 30 days.Measurements and Main Results: FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction; P < 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction; P = 0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%; P < 0.001) compared with UMEC/VI. The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction; P < 0.001; non-ICS users, 35% reduction; P = 0.018), and overall when excluding the first 30 days (29%; P < 0.001). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV₁ and St. George's Respiratory Questionnaire, regardless of prior ICS use.Conclusions: These data support the important treatment effects of FF/UMEC/VI combination therapy on exacerbation reduction, lung function, and quality of life that do not appear to be related to abrupt ICS withdrawal.Clinical trial registered with www.clinicaltrials.gov (NCT02164513).

Keywords: chronic obstructive pulmonary disease; step down; triple therapy.

Figure 1.

Cumulative number of moderate/severe exacerbations (A) overall, for (B) inhaled corticosteroid (ICS) use at screening, and for (C) no ICS use at screening and time to the first moderate/severe exacerbations (D) overall, for (E) ICS use at screening, and for (F) no ICS use at screening. (A) In this study, 4,151 subjects were randomly assigned to fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI), 4,134 were randomly assigned to FF/VI, and 2,070 were randomly assigned to UMEC/VI. (B) As shown, 2,971 and 1,180 subjects were randomly assigned to FF/UMEC/VI in the ICS-use and no-ICS-use groups, respectively; 2,908 and 1,226 were randomly assigned to FF/VI; and 1,481 and 589 were randomly assigned to UMEC/VI. In the cumulative plots (A–C), events have been adjusted to account for the different randomized population sizes and withdrawal from treatment by scaling the plot on all three arms to represent the number of events per 1,000 patients on each arm and by further adjusting to account for the proportion of patients left on treatment. The figure in D was reprinted by permission from Reference .

Figure 2.

On-treatment moderate/severe and severe exacerbations overall and by inhaled corticosteroid (ICS) use at screening for fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus UMEC/VI (primary analysis). Throughout, n represents the number of patients on FF/UMEC/VI and UMEC/VI, excluding those with missing covariates (overall: FF/UMEC/VI, n = 6; FF/VI, n = 1; UMEC/VI, n = 1; ICS use at screening: FF/UMEC/VI, n = 4; FF/VI, n = 1; no ICS use at screening: FF/UMEC/VI, n = 2; UMEC/VI, n = 1). CI = confidence interval.

Figure 3.

Forest plot of on-treatment moderate/severe chronic obstructive pulmonary disease (COPD) exacerbation rates by prior COPD medication class: fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus UMEC/VI. Throughout, n represents the number of patients on FF/UMEC/VI and UMEC/VI, excluding those with missing covariates (inhaled corticosteroid [ICS] + long-acting muscarinic antagonist [LAMA] + long-acting β₂-agonist [LABA]: FF/UMEC/VI, n = 1; ICS + LABA: FF/UMEC/VI, n = 3; FF/VI, n = 1; LAMA + LABA: FF/UMEC/VI, n = 2; UMEC/VI, n = 1). CI = confidence interval.

Figure 4.

On-treatment moderate/severe and severe exacerbations overall and in patients on ICS treatment at screening for fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus UMEC/VI, examining only after Day 30 data. Throughout, n represents the number of patients on FF/UMEC/VI and UMEC/VI, excluding those with missing covariates and patients who are no longer at risk of an exacerbation after the first 30 days. CI = confidence interval; ICS = inhaled corticosteroid.