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

Int J Chron Obstruct Pulmon Dis. 2022 Mar 8:17:517-533. doi: 10.2147/COPD.S308600. eCollection 2022.

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Forced Expiratory Volume
  • Formoterol Fumarate
  • Humans
  • Male
  • Muscarinic Antagonists
  • Pulmonary Disease, Chronic Obstructive* / chemically induced
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Tropanes

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Drug Combinations
  • Muscarinic Antagonists
  • Tropanes
  • Formoterol Fumarate

Associated data

  • ClinicalTrials.gov/NCT02424344

Grants and funding

The ACTIVATE study was sponsored by Menarini Group through its affiliates Berlin-Chemie and AstraZeneca. No specific funding was received regarding this manuscript.