Reduction in clinically important deterioration in chronic obstructive pulmonary disease with aclidinium/formoterol

Abstract

Background: 'Clinically important deterioration' (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations. ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 μg/formoterol fumarate (FF) 12 μg. This pooled post-hoc analysis assessed the effects of AB/FF 400/12 μg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD.

Methods: A first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in ≥1 of the following: trough forced expiratory volume in 1 second (FEV₁; ≥100 mL), Transition Dyspnea Index (TDI) focal score (≥1 unit), or St George's Respiratory Questionnaire (SGRQ) total score (≥4 units). A 'sustained' CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time. CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV₁ was also measured at weeks 1 and 18.

Results: AB/FF 400/12 μg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p < 0.001), 18% versus FF 12 μg (HR 0.82, p < 0.01), and 15% versus AB 400 μg (HR 0.85, p < 0.05). Similarly, AB/FF 400/12 μg reduced the risk of a sustained CID event by 48% versus placebo (HR 0.52, p < 0.001) and 22% versus FF 12 μg (HR 0.78, p < 0.01). AB/FF 400/12 μg reduced the risk of a first or sustained CID event for all four components versus placebo (trough FEV₁ and TDI, first and sustained CID, all p < 0.001; SGRQ first CID p < 0.001; SGRQ sustained CID, p < 0.01; exacerbations first and sustained CID, both p < 0.05) and TDI and SGRQ versus FF 12 μg (TDI, first and sustained CID both p < 0.05; SGRQ first CID p < 0.01), and SGRQ versus AB 400 μg (first CID, p < 0.05).

Conclusions: AB/FF 400/12 μg BID may provide greater airway stability and fewer exacerbations or deteriorations in lung function, health status, or dyspnea compared with placebo or monotherapies.

Trial registration: Clinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011. Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011.

Keywords: Bronchodilation; COPD; Chronic respiratory disease; LABA; LAMA.

Fig. 1

Analysis of time to first CID event (ITT population). *p < 0.05, **p < 0.01, ***p < 0.001. The risk of a first CID event was analyzed using a Cox-Proportional Hazard model including study, treatment group, and smoking status as covariates. AB, aclidinium bromide; CID, clinically important deterioration; FF, formoterol fumarate; HR, hazard ratio

Fig. 2

Analysis of first CID events by individual components over 24 weeks (ITT population). *p < 0.05, **p < 0.01, ***p < 0.001. The risk of a first CID event was analyzed using a Cox-Proportional Hazard model including study, treatment group, and smoking status as covariates. AB, aclidinium bromide; CID, clinically important deterioration; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; HR, hazard ratio; ITT, intent-to-treat; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index

Fig. 3

Analysis of sustained CID events overall and by individual components over 24 weeks (ITT population). *p < 0.05, **p < 0.01, ***p < 0.001 HR vs placebo. The risk of a sustained CID event was analyzed using a Cox-Proportional Hazard model including study, treatment group, and smoking status as covariates. AB, aclidinium bromide; CID, clinically important deterioration; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; HR, hazard ratio; ITT, intent-to-treat; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index

Fig. 4

Analysis of time to first CID event in patients who (a) received treatment with a LABA and / or LAMA and (b) did not receive treatment with a LABA and / or LAMA prior to the study (ITT population). *p < 0.05, **p < 0.01, ***p < 0.001. The risk of a first CID event was analyzed using a Cox-Proportional Hazard model including study, treatment group, and smoking status as covariates. AB, aclidinium bromide; CID, clinically important deterioration; FF, formoterol fumarate; HR, hazard ratio; ITT, intent-to-treat; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist

Fig. 5

Analysis of time to first CID event in patients with (a) moderate and (b) severe COPD at baseline (ITT population). *p < 0.05, **p < 0.01, ***p < 0.001. ^aPatients with ≥50% predicted post-bronchodilator FEV₁; ^bPatients with <50% predicted post-bronchodilator FEV₁. The risk of a first CID event was analyzed using a Cox-Proportional Hazard model including study, treatment group, and smoking status as covariates. AB, aclidinium bromide; CID, clinically important deterioration; FF, formoterol fumarate; HR, hazard ratio; ITT, intent-to-treat