Supplementary materials
METHODS
Study design and treatments
The study was conducted in a total of 163 centres in the United States, Bulgaria, Canada, Chile, Czech Republic, Greece, Japan, Mexico, Poland, Russia, South Africa, Spain, and Thailand.
Ten study outpatient visits were conducted, including screening (Visit 1), a 7–14 day run-in for eligible patients and a 24-week treatment period. The latter consisted of Visits 2–9: Day 1 (randomisation); Day 2; Weeks 4, 8, 12, 16 and 24; and 1 day after the Week 24 visit (Day 169). Lung function and adverse events were also assessed at a follow-up clinic visit (Visit 10) approximately 7 days post-Visit 9 or at the early withdrawal visit.
Statistical analyses
Sample size was calculated to provide sufficient power for the primary and secondary endpoints, including TDI as a symptomatic endpoint, and assumed a two-sided 5% significance level and a residual standard deviation estimate for TDI of 3.24 units.1A study with 273 evaluable patients in each active arm and 182 evaluable patients in the placebo arm was calculated to have 90% power to detect a 1-unit difference between treatments in TDI. The sample size calculated for TDI also gave >99% power to detect a 0.100 L difference between UMEC/VI 62.5/25 mcg and either UMEC 62.5 mcg or VI 25 mcg, or between active treatment and placebo for trough FEV1. Assuming a withdrawal rate of 30%, 399 and 266 patients were needed for each active treatment and placebo, respectively.
REFERENCE
1.Witek TJ Jr, Mahler DA. Minimal important difference of the transition dyspnoea index in a multinational clinical trial.EurRespir J 2003; 21:267-72.
Supplementary Table 1.Summary of lung function measures.
Placebo(N=280) / UMEC 62.5
(N=418) / VI 25
(N=421) / UMEC/VI 62.5/25
(N=413)
Trough FEV1 at Day 169
LS mean change from baseline (SE) / 0.004 (0.0158) / 0.119 (0.0126) / 0.076 (0.0127) / 0.171 (0.0126)
Difference vs placebo
(95% CI) / - / 0.115*
(0.076,0.155) / 0.072*
(0.032,0.112) / 0.167*
(0.128,0.207)
UMEC/VI 62.5/25 vsmonotherapy, (95% CI) / - / 0.052†
(0.017,0.087) / 0.095*
(0.060,0.130) / -
0–6 h WM FEV1 at Day 168
LS mean change from baseline (SE) / 0.001 (0.0158) / 0.151 (0.0128) / 0.123 (0.0128) / 0.243 (0.0127)
Difference vs placebo
(95% CI) / - / 0.150*
(0.110,0.190) / 0.122*
(0.082,0.162) / 0.242*
(0.202,0.282)
UMEC/VI 62.5/25 vs monotherapy (95% CI) / - / 0.092*
(0.056, 0.127) / 0.120*
(0.084, 0.155) / -
Proportion of patients achieving increase in FEV1 of ≥12% and ≥0.2 L above baseline at any time during 0–6 h post-dose on Day 1
Increase, n (%) / 41 (15) / 207 (50) / 196 (47) / 250 (61)
OR vs placebo (95% CI) / - / 5.9*
(4.0,8.6) / 5.1*
(3.5,7.5) / 9.0*
(6.1,13.2)
OR, UMEC/VI 62.5/25 vsmonotherapy (95% CI) / - / 1.5‡
(1.2, 2.0) / 1.7*
(1.3, 2.3) / -
Proportion of patients achieving an increase in trough FEV1 of ≥0.1 L above baseline at Day 169
Increase, n (%) / 53 (19) / 177 (43) / 146 (35) / 201 (49)
OR vs placebo (95% CI) / - / 3.2*
(2.2,4.5) / 2.3*
(1.6,3.3) / 4.1*
(2.9,5.9)
OR, UMEC/VI 62.5/25 vsmonotherapy (95% CI) / - / 1.3
(1.0, 1.7) / 1.8*
(1.4, 2.4) / -
Peak FEV1 at Day 168
LS mean change from baseline (SE) / 0.096 (0.0168) / 0.226 (0.0136) / 0.204 (0.0136) / 0.320 (0.0135)
Difference vs placebo
(95% CI) / - / 0.130*
(0.088,0.172) / 0.108*
(0.066,0.151) / 0.224*
(0.182,0.267)
UMEC/VI 62.5/25 vsmonotherapy (95% CI) / - / 0.094*
(0.057, 0.132) / 0.116*
(0.078, 0.153) / -
Trough FVC at Day 169
LS mean change from baseline (SE) / 0.014 (0.0258) / 0.188 (0.0207) / 0.118 (0.0208) / 0.262 (0.0206)
Difference vs placebo
(95% CI) / - / 0.175*
(0.110,0.239) / 0.105†
(0.040,0.170) / 0.248*
(0.184,0.313)
UMEC/VI 62.5/25 vsmonotherapy (95% CI) / - / 0.074‡
(0.016,0.131) / 0.143*
(0.086,0.201) / -
*p0.001; †p0.01; ‡p0.05
FEV1, forced expiratory volume in one second; FVC, forced vital capacity; LS, least squares; CI, confidence interval; OR, odds ratio; SE, standard error; UMEC/VI, umeclidinium/vilanterol; WM, weighted-mean