Differential Outcomes Following 4 Weeks of Aclidinium/Formoterol in Patients with COPD: A Reanalysis of the ACTIVATE Study

Abstract

Rationale: It is difficult to predict the effects of long-acting bronchodilators (LABD) on lung function, exercise capacity and physical activity in patients with chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD.

Methods: In the ACTIVATE study, patients were randomized to aclidinium bromide/formoterol fumarate (AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered representation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups.

Results: A total of 250 patients were randomized to AB/FF (n = 126) or placebo (n = 124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in clusters 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients.

Conclusion: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and is non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy.

Clinical trial registration: The original ACTIVATE study was registered on ClinicalTrials.gov, registration number NCT02424344.

Keywords: COPD; hyperinflation; physical activity.

Conflict of interest statement

Maud Koopman reports no real or perceived conflict of interest. Frits M.E. Franssen reports grants and personal fees from AstraZeneca and Novartis; personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and TEVA, outside the submitted work. Swetlana Gaffron works at Viscovery. Viscovery provides analysis services to Ciro+. Henrik Watz reports personal fees from AZ, during the conduct of the study; grants and/or personal fees from AZ, GSK, Chiesi, Boehringer Ingelheim Novartis, and Menarini, outside the submitted work. Thierry Troosters reports personal fees from AstraZeneca, Boehringer Ingelheim, and Chiesi, outside the submitted work. Judith Garcia-Aymerich reports consulting and lecture fees from AstraZeneca (outside the submitted work) and lecture fees from Esteve and Chiesi (outside the submitted work). Pierluigi Paggiaro reports grants and/or personal fees from ALK, AstraZeneca, Chiesi, GSK, Novartis, Sanofi, Guidotti, Menarini, and Mundipharma, outside the submitted work. Eduard Molins, Miguel Moya, Lindy van Burk, and Esther Garcia Gil are AstraZeneca employees. Dieter Maier works at Biomax. Biomax provides data management and analysis services to CIRO+. Emiel F.M. Wouters reports no real or perceived conflict of interest. Lowie E.G.W. Vanfleteren reports grants and/or personal fees from AstraZeneca, Novartis, GSK, Chiesi, Menarini, Pulmonx, Fisher&Paykel, and Boehringer, outside the submitted work. Martijn A. Spruit reports grants from the Netherlands Lung Foundation, Stichting Astma Bestrijding, GSK, Boehringer Ingelheim, AstraZeneca, TEVA, and Chiesi, outside the submitted work. The authors report no other conflicts of interest in this work.

© 2022 Koopman et al.

Figures

Figure 1

Weighted attributes (improvements) and their baseline values in the AB/FF group. Panels generated using Viscovery (Viscovery Software GmbH, Vienna, Austria). The Viscovery program placed all patients on a specific position in the map based on their multidimensional outcome profile. The more subjects resemble in terms of their response to AB/FF after four weeks, the closer they are on the map, and the more they differ, the further they are away from each other. When looking at an outcome measure, an area is coloured red when the outcome was very good, yellow when the outcome was good, green when there was no major change, and blue when the outcome was negative/towards the worse. The panels in the first row illustrate the percentage of improvement after four weeks of treatment with AB/FF in pre-dose functional respiratory capacity (FRC), pre-dose forced expiratory volume in the first second (FEV1), inspiratory capacity (IC) at isotime during constant work rate cycle ergometry (CWRT), cycle endurance time (CWRT), the amount of self-reported activity by Daily PROactive Physical Activity in COPD (D-PPAC), the number of steps per day, and the percentage of the day patients were very physically active (>3 metabolic equivalents [METs]). The second row shows the same outcomes at baseline of the AB/FF-treated patients.

Figure 2

Overall improvement following 4 weeks of AB/FF. The overall improvement of the AB/FF-treated patients. The overall improvement is based on the weighted standardized improvements between initial and 4-week assessment of the seven outcome indicators, as shown in Figure 1. Using the colour scale shown below the overall improvement picture, colours can be matched to the corresponding values. Values below 0 (green towards blue) indicate a deterioration, whereas values above 0 (green towards red) indicate an overall improvement in the outcomes.