The Effect of Aclidinium on Symptoms Including Cough in Chronic Obstructive Pulmonary Disease: A Phase 4, Double-Blind, Placebo-controlled, Parallel-Group Study

Abstract

To the Editor: Cough and sputum production are very common and troublesome symptoms for patients with chronic obstructive pulmonary disease (COPD) (1), and those symptoms are associated with lung function decline, increased exacerbation risk, and poor prognosis (2–4). To date, few clinical studies have investigated the efficacy of a long-acting muscarinic antagonist (LAMA) on cough (5, 6). Aclidinium is a LAMA approved as a twice-daily maintenance bronchodilator treatment for patients with COPD (7). This study assessed the efficacy of aclidinium on symptoms, including cough, in patients with moderate COPD. This was a phase 4, double-blind, placebo-controlled, parallel-group study (clinical trial registered with www.clinicaltrials.gov: NCT02375724) in 30 centers across five European countries between March 23, 2015, and November 17, 2015. Patients were randomly assigned 1:1 to receive twice-daily aclidinium 400 μg or placebo, administered via a multidose, dry powder inhaler (Genuair/Pressair, a registered trademark of the AstraZeneca group of companies, for use within the United States as Pressair and as Genuair within all other licensed territories). The study comprised a 1- to 2-week run-in period followed by an 8-week treatment period. Efficacy endpoints were measured at Week 4 and Week 8; the data over the course of 8 weeks are shown as an average of the scores measured at Week 4 and Week 8. Patients were aged at least 40 years with moderate COPD (post-bronchodilator FEV1 ≥50% and <80% predicted; FEV1/FVC <70%). The primary endpoint was change from baseline in Evaluating Respiratory Symptoms in COPD (E-RS:COPD, formerly the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]-Respiratory Symptoms Scale [E-RS; http://www.exactproinitiative.com/instrument-descriptions/], is owned by Evidera; permission to use this instrument may be obtained from Evidera [http://www.exactproinitiative.com/instrument-descriptions/[e-mail]]) total score over the course of 8 weeks (minimal clinically important difference [MCID], 2.0) (8). Secondary efficacy endpoints were change from baseline in E-RS cough and sputum domain score over the course of 8 weeks (MCID, 0.7) (8) and change from baseline in Leicester Cough Questionnaire (LCQ; MCID, 1.3) (9) at Week 8. Exploratory endpoints included change from baseline in COPD Assessment Test (CAT) score (MCID, 2.0) (10), cough severity visual analog scale (VAS) score, E-RS total score, and E-RS cough and sputum domain score at Week 4 and Week 8, and E-RS breathlessness (MCID, 0.1) and chest domain scores (MCID, 0.7) (8) at Week 4 and Week 8 and over the course of 8 weeks. A post hoc analysis stratified patients by baseline cough severity (VAS; >30 mm, more severe; ≤30 mm, less severe) to assess the effect of aclidinium on cough-related endpoints. All patients provided written informed consent; study protocols and amendments were approved by local ethics committees. The primary endpoint was analyzed using a mixed model for repeated measures. Overall, 269 patients were randomized; all had chronic bronchitis, 135 received aclidinium, and 134 received placebo. Sixty percent of patients were male, 64% were current smokers, and mean age was 62 years, with mean post-bronchodilator FEV1 64.2% predicted. In addition, patients had previously received short-acting β2-agonist (74%) and LAMA (26%). Mean baseline E-RS breathlessness, cough and sputum, and chest domain scores were 6.0, 3.7, and 2.9, respectively, and total E-RS was 12.5. Baseline CAT and LCQ scores were 19.4 and 14.5, respectively. Significant improvements in E-RS total score were observed with aclidinium versus placebo (Figure 1). Aclidinium significantly improved E-RS cough and sputum domain scores versus placebo at Week 8 but not at Week 4 or over the course of 8 weeks (Table 1). For E-RS breathlessness domain score, aclidinium provided statistically significant improvements versus placebo at all time points (Table 1). Changes in LCQ total score for aclidinium versus placebo were not statistically significant at any time point (Table 1). Improvements in CAT and E-RS chest domain scores were numerical only (Table 1), as were changes in cough severity (VAS; at Week 4, −0.7; at Week 8, −1.1; over the course of 8 weeks, −0.9). In total, 264 patients were stratified by cough severity (more severe, 123 patients; less severe, 141 patients). In patients with more severe cough, significant improvements were observed in E-RS total score at Week 4, and cough and sputum domain scores at each time point (Table 1). Numerical differences versus placebo were observed in LCQ and E-RS breathlessness and chest domain scores, at Weeks 4 or 8, in patients with more severe cough. Statistically significant improvements were seen for patients with more severe cough versus placebo in CAT score at Weeks 4 and 8 (Table 1). No significant differences were observed for any outcome in patients with less severe cough. Figure 1. Change from baseline in E-RS total score for aclidinium 400 μg versus placebo (intent-to-treat population). *P < 0.05 versus placebo. Data are least squares mean ± SE. COPD = chronic obstructive pulmonary disease; E-RS = Evaluating Respiratory Symptoms in COPD (E-RS:COPD). Table 1. Summary of Efficacy for Aclidinium versus Placebo (Intent-to-Treat Population)   Baseline Cough Any VAS Baseline Cough VAS >30 mm (More Severe) Baseline Cough VAS ≤30 mm (Less Severe) E-RS total score        At Week 4 −0.9 (0.4) * −1.3 (0.6) * −0.6 (0.6)  At Week 8 −1.1 (0.6) * −1.2 (0.8) −1.1 (0.8)  Over 8 wk −1.0 (0.5) * −1.2 (0.7) −0.8 (0.6) E-RS cough and sputum domain        At Week 4 −0.1 (0.1) −0.3 (0.2) * 0.1 (0.2)  At Week 8 −0.3 (0.2) * −0.5 (0.2) * −0.2 (0.2)  Over 8 wk −0.2 (0.1) −0.4 (0.2) * −0.1 (0.2) LCQ        At Week 4 0.1 (0.3) 0.6 (0.4) −0.1 (0.4)  At Week 8 −0.1 (0.3) 0.4 (0.4) −0.4 (0.4) CAT total score        At Week 4 −0.7 (0.6) −2.2 (0.8) * † 0.5 (0.8)  At Week 8 −0.6 (0.6) −2.3 (0.9) * † 1.0 (0.9) E-RS breathlessness domain        At Week 4 −0.6 (0.2) * −0.7 (0.3) −0.5 (0.3)  At Week 8 −0.6 (0.3) * −0.5 (0.4) −0.7 (0.4)  Over 8 wk −0.6 (0.3) * −0.6 (0.4) −0.6 (0.4) E-RS chest symptoms domain        At Week 4 −0.2 (0.1) −0.3 (0.2) −0.2 (0.2)  At Week 8 −0.2 (0.2) −0.2 (0.2) −0.2 (0.2)  Over 8 wk −0.2 (0.1) −0.3 (0.2) −0.2 (0.2) Definition of abbreviations: CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; E-RS = Evaluating Respiratory Symptoms in COPD (E-RS:COPD); LCQ = Leicester Cough Questionnaire; VAS = visual analog scale. Data are least-squares mean (SE) change from baseline for aclidinium 400 μg versus placebo. Analyzed using a mixed model for repeated measures (covariates: baseline, and age; factors: treatment group, sex, smoking status, visit, and treatment-by-visit interaction). The 30-mm VAS threshold value represented the median value of VAS baseline cough severity score and provided an almost equal split in the patient population. Bold indicates data points that are statistically significant. * P < 0.05. † Treatment difference was greater than the minimal clinically important difference (10). Overall, aclidinium significantly improved a range of daily COPD symptoms (including cough and sputum) versus placebo. Improvements in respiratory-specific quality-of-life measures (LCQ and CAT) did not reach statistical significance for aclidinium versus placebo in the total patient population. Baseline LCQ values in the total population suggested that the impact of symptoms on quality of life was minimal, possibly because of the number of patients with mild cough. Safety outcomes were consistent with those previously reported (11). Post hoc analyses showed that for patients with more severe cough, aclidinium provided greater improvements versus placebo in E-RS cough and sputum domain scores and CAT score. These patients had higher baseline CAT and E-RS total and domain scores than patients with less severe cough, and a mean LCQ of 12.7, indicating prominent cough symptoms. In contrast to the total population, when patients were stratified by cough severity, there was a numerical trend toward improvement in LCQ in patients with more severe cough versus less severe cough. This suggests baseline cough severity could be an important symptomatic marker for treatment response, and VAS score may reflect some mechanisms driving cough and sputum production in COPD, and specifically those most responsive to aclidinium treatment (12). One limitation was that this study was powered for E-RS total score and E-RS cough and sputum domain, but not for CAT or LCQ scores. As the LCQ and CAT instruments are designed to capture disease effect rather than severity, these tools may not be as sensitive to symptom changes compared with those specifically designed for symptom severity, such as E-RS. In addition, only patients with moderate COPD were included; therefore, further studies in a population with more severe COPD would be beneficial. In this study, which was one of the first studies to assess the effect of a LAMA on cough outcomes in patients with COPD, aclidinium 400 μg significantly improved a range of daily symptoms, including cough, in symptomatic patients with moderate COPD compared with placebo. In addition, a subgroup of patients with more severe cough symptoms gained a distinct and early benefit from aclidinium in a number of cough-related endpoints. Therefore, routine evaluation of cough symptoms (in addition to breathlessness) may be of benefit in the treatment management of some patients with moderate COPD.