Results
Patient Population
Of 3421 randomised patients, 3394 (99.2 %) were included in the ITT population and 3398 (99.3 %) were included in the ITT-exacerbations population. In total, 573 (16.7 %) patients discontinued treatment; the primary reasons were withdrawal of consent (4.5 %), AEs (4.2 %) and protocol violation (3.2 %). Patient flow and the reasons for discontinuation are presented by treatment group in Fig. 1. Patient demographics and baseline characteristics were similar between the treatment groups (Table 1). The patient population was not enriched for exacerbations and the number of exacerbations in the previous year was low (0.3–0.5 exacerbations; Table 1). Overall, 1335 (39.3 %) patients in the ITT-exacerbations population were using ICS at baseline. At baseline, 88.3 % and 94.4 % of patients reported night-time and early-morning symptoms of COPD (Table 2), although symptoms were relatively mild (rated 1.1–1.3 units out of a maximum score of 4; Table 1). When the ITT population was stratified by GOLD group, 9.2, 45.9, 3.0 and 41.9 % of patients were in GOLD groups A, B, C and D, respectively (75 patients were missing data required for GOLD classification). Baseline GOLD data by treatment group are shown in Table 1.
(Enlarge Image)
Figure 1.
CONSORT diagram of patient flow in the pooled ACLIFORM and AUGMENT studies. Data for the 400/6 μg dose of the FDC are not reported in this paper and can be found elsewhere [23,24]; AE, adverse event; FDC, aclidinium/formoterol fixed-dose combination
Dyspnoea (TDI)
FDC 400/12 μg significantly improved TDI focal score versus placebo at all visits assessed, and these improvements exceeded the MCID of 1 unit (range of least squares [LS] means differences vs placebo: 1.32–1.43 units; all time points p < 0.001). Additionally, FDC 400/12 μg significantly improved TDI focal score versus formoterol at all visits assessed (range of LS means differences vs formoterol: 0.47–0.63 units; all visits p < 0.01) and versus aclidinium from Week 12 onwards (difference vs aclidinium: 0.39–0.44 units; Week 12 and 24 p < 0.05; Fig. 2a and b).
(Enlarge Image)
Figure 2.
TDI focal score at Week 24 (a) and over 24 weeks (b). Data are LS means ± SE for the pooled ITT population; ***p < 0.001 vs placebo, p < 0.05 vs aclidinium p < 0.01 vs formoterol; FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; LS, least squares; MCID, minimum clinically important difference; ns, not significant; SE, standard error; TDI, Transitional Dyspnoea Index
Overall, 61.9 % of patients achieved the MCID in TDI focal score with FDC 400/12 μg compared with 55.7 % for aclidinium, 57.0 % for formoterol and 40.3 % for placebo. Treatment with FDC 400/12 μg significantly increased the odds of improving by the MCID in TDI versus placebo (Table 3), and significantly reduced the odds of TDI worsening by the MCID versus placebo (Table 3). There were no significant differences in the odds of TDI improving or worsening by the MCID with FDC 400/12 μg versus either monotherapy.
When stratified by ICS use, FDC 400/12 μg significantly improved TDI versus placebo regardless of concomitant ICS use (LS mean difference vs placebo with ICS: 1.59 units, p < 0.001; without ICS: 1.36 units, p < 0.001). Significant improvements in TDI with FDC 400/12 μg versus the monotherapies were only observed in patients who were not using concomitant ICS (LS mean difference vs aclidinium with ICS: 0.02 units, p = 0.948; without ICS: 0.66, p = 0.002; LS mean difference vs formoterol with ICS: 0.45 units, p = 0.105; without ICS: 0.48, p = 0.024).
Data for improvements in TDI at Week 24 stratified by GOLD group are presented in Additional file 1 http://www.respiratory-research.com/content/16/1/92/additional.
Daily Symptoms (E-RS)
Over 24 weeks, E-RS total score was significantly improved with FDC 400/12 μg compared with placebo and both monotherapies (mean change from baseline: FDC 400/12 μg: −2.4 units [−18.6 %]; aclidinium: −1.8 units [−14.2 %]; formoterol: −1.8 units [−14.7 %]; placebo: –1.2 units [−10.0 %]; p < 0.001 vs placebo; p < 0.01 vs both monotherapies; Additional file 1: Figure S2 http://www.respiratory-research.com/content/16/1/92/additional). Overall, 48.7 % of patients had improvements in E-RS total score that exceeded the recently proposed MCID (percentage of patients achieving a reduction in E-RS total score of ≥2 units) compared with 41.3 % with aclidinium, 42.3 % with formoterol and 34.4 % with placebo. Treatment with FDC 400/12 μg significantly increased the odds of improving by the MCID versus placebo (odds ratio [OR]: 1.9; p < 0.001) and formoterol (OR: 1.3; p < 0.05) but not aclidinium (OR: 1.2; p = 0.145). Improvements in E-RS domain scores are described in an online supplement (Additional file 1 http://www.respiratory-research.com/content/16/1/92/additional).
Night-time and Early-morning Symptoms (NiSCI and EMSCI)
Over 24 weeks, FDC 400/12 μg significantly improved night-time and early-morning symptom severity compared with placebo, including both overall and individual symptom severity scores (cough, wheezing, shortness of breath and difficulty bringing up phlegm; Fig. 3a and b). Additionally, compared with placebo, FDC 400/12 μg significantly improved limitation of activities due to morning symptoms (Fig. 3b). FDC 400/12 μg had no significant effect on nocturnal awakenings compared with placebo (Fig. 3a).
(Enlarge Image)
Figure 3.
Difference from placebo in change from baseline in symptom severity over 24 weeks. a Night-time symptoms; b early-morning symptoms; Data are LS means differences from placebo ± 95 % CIs for the pooled ITT population; p < 0.05, p < 0.001 vs placebo; Nocturnal awakenings were the average number of awakenings per night. Other night-time symptoms were measured on a scale from 0 (no symptoms) to 4 (very severe symptoms). Larger negative values indicate greater improvements in symptom severity; CI, confidence interval; FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; LS, least squares
Although improvements in overall night-time symptom severity were observed in all treatment arms, the change from baseline was significantly greater with FDC 400/12 μg compared with the monotherapies (FDC 400/12 μg: −0.25 units [−21.6 %]; aclidinium 400 μg: –0.16 units [−14.5 %]; formoterol 12 μg: −0.19 units [−18.2 %]; p < 0.001 vs aclidinium and p < 0.05 vs formoterol). A similar pattern was observed for improvements from baseline in overall early-morning symptom severity (FDC 400/12 μg: −0.23 units [−17.0 %]; aclidinium 400 μg: −0.14 units [−10.7 %]; formoterol 12 μg: −0.17 units [−13.6 %]; p < 0.001 vs aclidinium and p < 0.01 vs formoterol).
Changes in individual night-time and early-morning symptoms (cough, wheezing, shortness of breath and difficulty bringing up phlegm), limitation of early-morning activities and nocturnal awakenings versus monotherapy are described in an online supplement (Additional file 1 http://www.respiratory-research.com/content/16/1/92/additional).
COPD Exacerbations
The rate of moderate or severe HCRU exacerbations was significantly lower (−29 %) with FDC 400/12 μg compared with placebo. The rate of HCRU exacerbations of any severity was also lower (−24 %) with FDC 400/12 μg compared with placebo; however, the differences did not reach statistical significance (Fig. 4a). Additionally, compared with placebo, FDC 400/12 μg significantly increased the time to first exacerbation for HCRU exacerbations of any severity, and also those that were moderate or severe ( Table 4 ). These results were supported by the EXACT data, where higher rates of exacerbations were observed (1.18–1.51 EXACT exacerbations [any severity] compared with 0.36–0.47 HCRU exacerbations [any severity] per patient per year across treatment groups) and a similar pattern of reduction in exacerbation rate (−22 %) and time to first exacerbation was seen with FDC 400/12 μg versus placebo (Fig. 4b; Table 4 ). Monotherapy data for rate of exacerbation and time to first exacerbation are also shown in Fig. 4 and Table 4 , respectively.
(Enlarge Image)
Figure 4.
Rate of COPD exacerbations based on HCRU (a) and EXACT (b) definitions. Data are LS means and RR (CI) for the pooled ITT-exacerbations population; p < 0.05, p < 0.01 vs placebo, p < 0.05 vs aclidinium; CI, confidence interval; COPD, chronic obstructive pulmonary disease; EXACT; EXAcerbations of Chronic pulmonary disease Tool; FDC, aclidinium/formoterol fixed-dose combination; HCRU, Healthcare Resource Utilisation; ITT, intent-to-treat; LS, least squares; RR, rate ratio
Data for rate of exacerbations stratified by ICS use are presented in Additional file 1 http://www.respiratory-research.com/content/16/1/92/additional. When HCRU or EXACT exacerbations were stratified by concomitant ICS use, patients with concomitant ICS use had higher exacerbation rates compared with those who were not using ICS (Additional file 1: Figure S4 http://www.respiratory-research.com/content/16/1/92/additional). The reduction in rate of moderate to severe HCRU exacerbations and HCRU exacerbations of any severity was significantly greater with FDC 400/12 μg compared with placebo in patients with concomitant ICS use but not those without ICS; the comparisons versus the monotherapies did not reach significance in patients with or without concomitant ICS use (Additional file 1: Figure S4 http://www.respiratory-research.com/content/16/1/92/additional). Similar results were obtained for EXACT exacerbations, although in addition, FDC 400/12 μg significantly reduced the rate of EXACT exacerbations compared with aclidinium 400 μg (Additional file 1: Figure S4 http://www.respiratory-research.com/content/16/1/92/additional).
Data for exacerbation rates stratified by GOLD group are presented in Additional file 1 http://www.respiratory-research.com/content/16/1/92/additional.
Relief-medication Use
Treatment with FDC 400/12 μg reduced overall daily relief-medication use compared with placebo and the monotherapies, although only the comparisons versus placebo and aclidinium reached statistical significance (mean [CI]: FDC 400/12 μg: −1.73 [−1.88, −1.57] puffs/day; aclidinium 400 μg: −1.37 [−1.52, −1.21] puffs/day; formoterol 12 μg: −1.52 [−1.68, −1.37] puffs/day; placebo: −0.82 [−1.00, −0.63] puffs/day; p < 0.001 vs placebo, p < 0.01 vs aclidinium).