Relationship between exercise endurance and static hyperinflation in a post hoc analysis of two clinical trials in patients with COPD

Figures & data

Table 1 Baseline hyperinflation parameters and exercise tolerance (combined populations)

Parameter	UMEC/VI 62.5/25 μg (N=282)	UMEC 62.5 μg (N=89)	VI 25 μg (N=140)	PBO (N=321)
Age (years), mean (SD)	62.0 (7.9)	61.7 (7.9)	61.5 (8.2)	62.0 (8.2)
Sex (male), n (%)	160 (57)	53 (60)	80 (57)	180 (56)
Pre-bronchodilator FEV1 (L), n	281	88	140	321
Mean (SD)	1.400 (0.450)	1.397 (0.432)	1.395 (0.450)	1.346 (0.433)
Post-salbutamol FEV1 (L), n	282	88	140	319
Mean (SD)	1.547 (0.424)	1.572 (0.408)	1.556 (0.445)	1.511 (0.411)
Post-salbutamol predicted FEV1 (%), n	282	88	140	319
Mean (SD)	51.5 (9.7)	53.2 (9.8)	51.4 (9.6)	50.9 (9.8)
Pre-bronchodilator FVC (L), n	281	88	140	321
Mean (SD)	3.026 (0.871)	3.032 (0.859)	2.937 (0.780)	2.900 (0.846)
Post-salbutamol FVC (L), n	282	88	140	319
Mean (SD)	3.282 (0.912)	3.336 (0.857)	3.193 (0.799)	3.177 (0.871)
IC/TLC (%),^a n	282	88	140	321
Mean (SD)	31.8 (8.1)	31.8 (6.1)	32.6 (7.3)	31.7 (7.3)
ISWT (m), n	282	89	140	320
Mean (SD)	403.2 (149.6)	426.6 (153.3)	415.9 (145.9)	418.9 (152.1)
EET (seconds), n	280	88	137	317
Mean (SD)	307.7 (162.6)	297.1 (159.4)	303.5 (130.4)	328.1 (182.1)

a Note: Data from one patient were excluded from the IC/TLC and IC analyses throughout, due to outlying data (baseline IC 0.12 L, range of other subjects 0.67–4.77 L).

Abbreviations: EET, exercise-endurance time; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IC, inspiratory capacity; ISWT, incremental shuttle-walk test; PBO, placebo; SD, standard deviation; TLC, total lung capacity; UMEC, umeclidinium; VI, vilanterol.

Table 2 LS mean absolute changes from baseline in IC/TLC at day 2 and week 12

LS mean change from baseline	UMEC/VI 62.5/25 μg vs PBO	UMEC 62.5 μg vs PBO	VI 25 μg vs PBO	UMEC/VI 62.5/25 μg vs UMEC 62.5 μg	UMEC/VI 62.5/25 μg vs VI 25 μg
Day 2
n^a	281/317	88/317	139/317	281/88	281/139
IC/TLC (trough), %	3.0	2.2	2.0	0.8	1.0
95% CI	2.4 to 3.6	1.2 to 3.1	1.2 to 2.8	−0.1 to 1.8	0.2 to 1.8
P-value	<0.001	<0.001	<0.001	0.085	0.014
IC/TLC (3 hours postdose), %	4.4^b	3.1	3.6	1.3^b	0.8^b
95% CI	3.8 to 5.0	2.2 to 4.1	2.8 to 4.4	0.3 to 2.2	0.0 to 1.6
P-value	<0.001	<0.001	<0.001	0.010	0.056
Week 12
n^a	248/268	81/268	120/268	248/81	248/120
IC/TLC (trough), %	3.2	1.4	1.3	1.8	1.9
95% CI	2.5 to 3.9	0.3 to 2.4	0.4 to 2.2	0.8 to 2.9	0.9 to 2.8
P-value	<0.001	0.011	0.004	<0.001	<0.001
IC/TLC (3 hours postdose), %	4.3	2.5	2.5	1.8	1.9
95% CI	3.6 to 5.0	1.5 to 3.6	1.5 to 3.4	0.7 to 2.8	1.0 to 2.8
P-value	<0.001	<0.001	<0.001	0.001	<0.001

a Notes: Patients with analyzable data at the given time point (treatment/comparator);

b UMEC/VI, n=280.

Abbreviations: CI, confidence interval; IC, inspiratory capacity; LS, least squares; PBO, placebo; TLC, total lung capacity; UMEC, umeclidinium; VI, vilanterol.

Figure 1 LS mean absolute changes from baseline in trough IC/TLC ratio versus placebo at each clinic visit.

Note: Error bars represent 95% CIs.
Abbreviations: CI, confidence interval; IC, inspiratory capacity; LS, least squares; TLC, total lung capacity; UMEC, umeclidinium; VI, vilanterol.

Figure 2 Effect of UMEC/VI versus comparators on percentage change from baseline in IC/TLC ratio in different subpopulations at week 12.

Notes: Error bars represent 95% CIs. Differences between UMEC/VI and comparators are statistically significant when these lines do not extend below 0.
Abbreviations: CI, confidence interval; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroid; PBO, placebo; TLC, total lung capacity; UMEC, umeclidinium; VI, vilanterol.

Table 3 Percentage changes from baseline EET at day 2 and week 12

Parameter	UMEC/VI 62.5/25 μg (N=282)	UMEC 62.5 μg (N=89)	VI 25 μg (N=140)	PBO (N=321)
Day 2
n^a	280	88	135	315
LS mean percentage change from baseline EET, % (SE)	26.5 (3.3)	15.7 (5.8)	14.9 (4.7)	8.1 (3.1)
Column vs PBO, %	18.4	7.7	6.8	–
95% CI	10.1 to 26.8	−4.7 to 20.1	−3.8 to 17.5
P-value	<0.001	0.226	0.209
UMEC/VI 62.5/25 vs column, %	–	10.8	11.6	–
95% CI		−1.8 to 23.3	0.8 to 22.4
P-value		0.093	0.035
Week 12
n^a	246	80	117	262
LS mean percentage change from baseline EET, % (SE)	27.3 (4.4)	20.4 (7.7)	12.6 (6.3)	10.9 (4.2)
Column vs PBO, %	16.4	9.5	1.7	–
95% CI	4.8 to 27.9	−7.3 to 26.3	−12.9 to 16.3
P-value	0.005	0.269	0.819
UMEC/VI 62.5/25 vs column, %	–	6.9	14.7	–
95% CI		−10.1 to 23.9	−0.1 to 29.4
P-value		0.428	0.051

a Note: Patients with analyzable data at the given time point.

Abbreviations: CI, confidence interval; EET, exercise endurance time (seconds); LS, least squares; PBO, placebo; SE, standard error; UMEC, umeclidinium; VI, vilanterol.

Figure 3 Scatterplots of changes in hyperinflation parameters against changes in exercise endurance (A–C) and lung volume measurements (D–F) at Week 12.

Abbreviations: EET, exercise endurance time; FEV₁, forced expiratory volume in 1 second; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity.

Figure S1 LS mean absolute changes from baseline in lung-volume measurements at day 2 and week 12 using UMEC/VI versus placebo.

Note: Error bars represent 95% CIs.

Abbreviations: CI, confidence interval; FRC, functional residual capacity; FVC, forced vital capacity; IC, inspiratory capacity; LS, least squares; RV, residual volume; UMEC, umeclidinium; VI, vilanterol.

Figure S2 Effect of UMEC/VI versus comparators on percentage change from baseline in RV/TLC ratio in different subpopulations at week 12.

Notes: Error bars represent 95% CIs. Differences between UMEC/VI and comparators are statistically significant when these lines do not extend below 0.

Abbreviations: CI, confidence interval; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; PBO, placebo; RV, residual volume; TLC, total lung capacity; UMEC, umeclidinium; VI, vilanterol.

Figure S3 Effect of UMEC/VI versus comparators on percentage change from baseline in IC volume in different subpopulations at week 12.

Notes: Error bars represent 95% CIs. Differences between UMEC/VI and comparators are statistically significant when these lines do not extend below 0.

Abbreviations: CI, confidence interval; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroid; PBO, placebo; UMEC, umeclidinium; VI, vilanterol.

Table S1 LS mean absolute changes from baseline in IC at day 2 and week 12

LS mean change from baseline	UMEC/VI 62.5/25 μg vs PBO	UMEC 62.5 μg vs PBO	VI 25 μg vs PBO	UMEC/VI 62.5/25 μg vs UMEC 62.5 μg	UMEC/VI 62.5/25 μg vs VI 25 μg
Day 2
n^a	281/316	88/316	139/316	281/88	281/139
IC (trough), L	0.198	0.137	0.131	0.061	0.067
95% CI	0.154 to 0.242	0.072 to 0.202	0.076 to 0.186	−0.005 to 0.127	0.011 to 0.123
P-value	<0.001	<0.001	<0.001	0.069	0.019
IC (3 hours postdose), L	0.270^b	0.174^b	0.228^b	0.096	0.042
95% CI	0.223 to 0.316	0.105 to 0.243	0.169 to 0.287	0.026 to 0.166	−0.018 to 0.102
P-value	<0.001	<0.001	<0.001	0.007	0.169
Week 12
n^a	248/268	81/268	120/268	248/81	248/120
IC (trough), L	0.216	0.065	0.083	0.150	0.132
95% CI	0.167 to 0.264	−0.005 to 0.136	0.022 to 0.144	0.079 to 0.221	0.070 to 0.194
P-value	<0.001	0.068	0.008	<0.001	<0.001
IC (3 hours postdose), L	0.276	0.142	0.152	0.134	0.125
95% CI	0.229 to 0.324	0.073 to 0.212	0.091 to 0.212	0.064 to 0.204	0.064 to 0.186
P-value	<0.001	<0.001	<0.001	<0.001	<0.001

Note:

a Patients with analyzable data at the given time point (treatment/comparator);

b PBO, n=317.

Abbreviations: CI, confidence interval; IC, inspiratory capacity; LS, least squares; PBO, placebo; UMEC, umeclidinium; VI, vilanterol.

Table S2 LS mean percentage changes from baseline in RV/TLC at day 2 and week 12

LS mean percentage change from baseline	UMEC/VI 62.5/25 μg vs PBO	UMEC 62.5 μg vs PBO	VI 25 μg vs PBO	UMEC/VI 62.5/25 μg vs UMEC 62.5 μg	UMEC/VI 62.5/25 μg vs VI 25 μg
Day 2
n^a	281/317	88/317	139/317	281/88	281/139
RV/TLC (trough)	−7.3	−5.8	−4.9	−1.5	−2.5
95% CI	−8.7 to −6.0	−7.8 to −3.8	−6.6 to −3.2	−3.6 to 0.5	−4.2 to −0.7
P-value	<0.001	<0.001	<0.001	0.137	0.006
RV/TLC (3 hours postdose)	−10.0^b,c	−8.0^c	−7.4^c	−2.0^b	−2.7^b
95% CI	−11.4 to −8.6	−10.1 to −5.9	−9.2 to −5.6	−4.1 to 0.1	−4.5 to −0.9
P-value	<0.001	<0.001	<0.001	0.058	0.004
Week 12
n^a	248/268	81/268	120/268	248/81	248/120
RV/TLC (trough)	−7.7	−5.3	−4.5	−2.4	−3.1
95% CI	−9.4 to −6.0	−7.8 to −2.8	−6.7 to −2.4	−4.9 to 0.1	−5.3 to −0.9
P-value	<0.001	<0.001	<0.001	0.064	0.005
RV/TLC (3 hours postdose)	−9.8	−7.1	−6.1	−2.7	−3.8
95% CI	−11.6 to −8.0	−9.7 to −4.5	−8.3 to −3.8	−5.4 to −0.1	−6.1 to −1.5
P-value	<0.001	<0.001	<0.001	0.042	0.001

Notes:

a Patients with analyzable data at the given time point (treatment/comparator);

b UMEC/VI, n=280;

c PBO, n=316.

Abbreviations: CI, confidence interval; LS, least squares; PBO, placebo; RV, residual volume; TLC, total lung capacity; UMEC, umeclidinium; VI, vilanterol.