Efficacy of Aclidinium Bromide According to Baseline Therapy: Post-Hoc Analysis of ASCENT-COPD Randomized Trial

Abstract

Introduction: Long-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs), inhaled corticosteroids (ICS), and their combinations, are recommended for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to determine whether the safety and efficacy of aclidinium bromide differs by baseline maintenance LABA and ICS therapies.

Methods: ASCENT-COPD was a phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium 400 μg or placebo twice daily, via a multidose dry-powder inhaler for up to 3 years. Outcomes included time to first major adverse cardiovascular events (MACE), all-cause mortality, change from baseline in trough forced expiratory volume in 1 s (FEV1), and COPD assessment test (CAT) total score over 3 years, and annual moderate-to-severe COPD exacerbation rate in patients receiving aclidinium or placebo with maintenance LABA monotherapy, ICS monotherapy, LABA + ICS (fixed/free), or no maintenance therapy (neither LABA nor ICS) at baseline.

Results: A total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV1 irrespective of baseline therapy and CAT total scores, except for LABA and ICS subgroups, versus placebo at several time points.

Conclusion: In patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit.

Trial registration: ClinicalTrials.gov identifier NCT01966107.

Keywords: Aclidinium bromide; Chronic obstructive pulmonary disease; Muscarinic antagonists.

© 2021. The Author(s).

Figures

Fig. 1

a Time to first adjudicated MACE and b the risk of MACE on study, by patient baseline treatment subgroup. CI confidence interval, CV cardiovascular, HR hazard ratio, ICS inhaled corticosteroid, LABA long-acting β2-agonist, n number of patients in the analysis, N number of patients in the treatment group. Data derived using the Cox proportional hazard regression model with treatment group, baseline CV risk, smoking status, and baseline treatment use as factors, and the interaction between baseline treatment use and treatment group. Baseline users include patients who took treatment within 15 days prior to the administration of the first dose study treatment, regardless of continuation

Fig. 2

a Time to death and b risk of all-cause mortality on study, by patient baseline treatment subgroup. CI confidence interval, CV cardiovascular, HR hazard ratio, ICS inhaled corticosteroid, LABA long-acting β2-agonist, n number of patients in the analysis, N number of patients in the treatment group. Data derived using the Cox proportional hazard regression model with treatment group, baseline CV risk, smoking status, and baseline treatment use as factors. Baseline users include patients who took treatment within 15 days prior to the administration of the first dose study treatment, regardless of continuation

Fig. 3

Moderate-to-severe COPD exacerbations during the first year, by patient baseline treatment subgroup (on-treatment). CI confidence interval, COPD chronic obstructive pulmonary disease, ICS inhaled corticosteroid, LABA long-acting β2-agonist, PY patient-years, RR rate ratio. Data derived using the negative binomial regression model with treatment group, baseline ICS use, baseline COPD severity, history of ≥ 1 exacerbation in the past year, and smoking status as factors, and the log of the exposure time adjusted for the time patients experience exacerbations as an offset variable. Baseline users include patients who took treatment within 15 days prior to the administration of the first dose study treatment, regardless of continuation

Fig. 4

Change from baseline in trough FEV1 over 156 weeks in a overall population, b patients receiving LABA monotherapy at baseline, c patients receiving ICS monotherapy at baseline, d patients receiving LABA + ICS at baseline, and e patients not receiving maintenance therapy at baseline. FEV1 forced expiratory volume in 1 s, ICS inhaled corticosteroid, LABA long-acting β2-agonist, MMRM mixed model for repeated measures, n number of patients in the analysis, N number of patients in the treatment group. *P < 0.05, **P < 0.01, ***P < 0.001 for aclidinium versus placebo. Data are least squares means ± standard error. The analysis was based on an MMRM for change from baseline in trough FEV1 with pre- and post-bronchodilator (albuterol/salbutamol) FEV1 at screening visit and baseline FEV1 as covariates, and treatment group, smoking status, baseline ICS use, visit, and treatment-group-by-visit interaction as fixed effect factors. Visit is fitted as a categorical variable, and the variance–covariance matrix is assumed to be unstructured. Week 156 includes assessments from patients who completed 3 years treatment or who were on-treatment when the study was stopped. Baseline users include patients who took treatment within 15 days prior to the administration of the first dose study treatment, regardless of continuation

Fig. 5

Change from baseline in CAT total score over 156 weeks in a overall population, b patients receiving LABA monotherapy at baseline, c patients receiving ICS monotherapy at baseline, d patients receiving LABA + ICS at baseline, and e patients not receiving maintenance therapy at baseline. CAT COPD assessment test, ICS inhaled corticosteroid, LABA long-acting β2-agonist, MMRM mixed model for repeated measures, n number of patients in analysis, N number of patients in the treatment group. *P < 0.05 for aclidinium versus placebo. Data are least squares means ± standard error. The analysis was based on an MMRM for change from baseline in CAT score with baseline CAT total score as a covariate, and treatment group, smoking status, baseline ICS use, visit, and treatment-group-by-visit interaction as fixed effect factors. Visit is fitted as a categorical variable, and the variance–covariance matrix is assumed to be unstructured. Week 156 includes assessments from patients who completed 3 years treatment or who were on-treatment when the study was stopped. Baseline users include patients who took treatment within 15 days prior to the administration of the first dose study treatment, regardless of continuation