ACTIVATE: the effect of aclidinium/formoterol on hyperinflation, exercise capacity, and physical activity in patients with COPD

Abstract

The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 μg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD. Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair^® dry powder inhaler for 8 weeks. From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals). The primary end point was trough functional residual capacity (FRC) at Week 4. Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI). Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise. After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690). However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P<0.0001). AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 (P<0.01 and P<0.0001, respectively) and Week 8 (P<0.05 and P<0.0001, respectively). AB/FF achieved higher step counts (P<0.01) with fewer inactive patients (P<0.0001) at Week 4 versus placebo. Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo. AB/FF 400/12 μg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI. A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF.

Keywords: COPD; aclidinium; exercise capacity; formoterol; hyperinflation; physical activity.

Figure 1

Study design. Abbreviations: BI, behavioral intervention; b.i.d., twice daily; V, visit; W, week.

Figure 2

Patient flow. Abbreviations: AB, aclidinium bromide; AE, adverse event; FF, formoterol fumarate.

Figure 3

Change from baseline in trough FRC at Week 4 (ITT population). Note: Data are LSMs (95% CI). Abbreviations: AB, aclidinium bromide; CI, confidence interval; FF, formoterol fumarate; FRC, functional residual capacity; ITT, intent-to-treat; LSM, least squares mean.

Figure 4

Change from baseline in (A) EET at Week 4 (after pharmacotherapy only) and at Week 8 (after pharmacotherapy and BI), and (B) IC during constant work rate cycle ergometry at Week 8 (ITT population). Notes: ^aFor each individual patient, isotime was defined as the minimum EET among the constant work rate exercise tests at 75% W_max performed on Visits 2, 3, 4, and 5. Data are LSMs (95% CI). Abbreviations: AB, aclidinium bromide; BI, behavioral intervention; CI, confidence interval; EET, exercise endurance time; FF, formoterol fumarate; IC, inspiratory capacity; ITT, intent-to-treat; LSM, least squares mean; W_max, peak work rate.

Figure 5

(A) Percentage of inactive patients (<6,000 steps per day) over 8 weeks (ITT population) and (B) absolute number of steps per day over 8 weeks (ITT population). Note: Steps per day data are LSM ± SE. Abbreviations: AB, aclidinium bromide; BI, behavioral intervention; CI, confidence interval; FF, formoterol fumarate; ITT, intent-to-treat; LSM, least squares mean; OR, odds ratio; SE, standard error.

Figure 6

Change from baseline in D-PPAC total score and amount and difficulty domains at Weeks 4 and 8 (ITT population). Note: Data are LSMs (95% CI). Abbreviations: AB, aclidinium bromide; BI, behavioral intervention; CI, confidence interval; D-PPAC, Daily PROactive Physical in COPD; FF, formoterol fumarate; ITT, intent-to-treat; LSM, least squares mean.