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.MethodsA 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.ResultsAB/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).ConclusionsAB/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 registrationClinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011.Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0583-0) contains supplementary material, which is available to authorized users.

Umeclidinium/Vilanterol Versus Tiotropium/Olodaterol in Maintenance-Naïve Patients with Moderate Symptomatic Chronic Obstructive Pulmonary Disease: A Post Hoc Analysis

“…However, LAMA/LABA bronchodilation appear to be similarly beneficial compared with LAMA monotherapy in symptomatic patients who have or have not previously received a COPD maintenance treatment, which questions the rationale for a delayed stepwise approach in managing persistent symptoms [16,17]. There is also evidence that early use of LAMA/LABA combinations may improve disease stability compared with LAMA monotherapy by protecting symptomatic patients, including maintenance-naïve (MN) patients, from further disease deterioration [16,[18][19][20]. Dual therapy could therefore provide the opportunity for maximal bronchodilation, with a view to minimizing daily symptoms, improving quality of life (QoL), and preventing further disease deterioration.…”

Reduced risk of clinically important deteriorations by ICS in COPD is eosinophil dependent: a pooled post-hoc analysis

“…Most previous publications on CID in COPD evaluate the effect of bronchodilators [1,[3][4][5][6] and, due to the study designs and patient populations, FEV 1 deterioration is then the most frequent event type reported [9][10][11][12]. If FEV 1 is assessed at all visits, but not SGRQ, this can give an imbalance in the number of individual CID components.…”

“…Studies using CID have focused primarily on long-acting bronchodilator effects [1,[3][4][5][6], mostly in COPD populations without increased exacerbation risk, often leading to a predominance of CID events triggered by lung function deteriorations, and a relatively small contribution of exacerbations to the composite index. Recently, higher blood eosinophil counts have been shown to be associated with increased exacerbation risk in COPD patients not treated with inhaled corticosteroids (ICS) [7,8].…”

<p>Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD</p>

“…The reduction in risk of CID relative to monocomponents and placebo is consistent with those reported in studies of the LAMA/LABA FDCs umeclidinium/vilanterol and aclidinium/formoterol, although there were slight differences in the definition of a CID event. 21,22 As CID is a composite endpoint encompassing lung function, symptoms, and exacerbations, it provides a more comprehensive assessment of disease status than individual outcomes. Limiting disease progression is a major objective of COPD management, 23 and therefore identifying treatments that prevent deterioration is an important clinical goal.…”