Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, ­Double-Blind Studies

Figures & data

Figure 1.  Summary of patient disposition in Study 1 (A) and Study 2 (B). 
AE, adverse event; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; PBO, placebo; PP, per protocol; UMEC, umeclidinium.
*The run-in population included screening failures, run-in failures, and those in the ITT population (i.e., any patient who took at least one dose of open-label FP/SAL during the run-in period). Study 1: Reasons for withdrawal: PBO + FP/SAL: AE (n = 6), withdrew consent (n = 3), lost to follow-up (n = 2), protocol deviation (n = 4), lack of efficacy (n = 11), subject reached protocol-stopping criteria (n = 1); UMEC 62.5 + FP/SAL: PBO + FP/SAL: AE (n = 5), withdrew consent (n = 1), protocol deviation (n = 3), lack of efficacy (n = 5); UMEC 125 + FP/SAL: AE (n = 10), withdrew consent (n = 5), protocol deviation (n = 3), lack of efficacy (n = 3). Study 2: Reasons for withdrawal: PBO + FP/SAL: AE (n = 13), withdrew consent (n = 7), lost to follow-up (n = 1), protocol deviation (n = 2), lack of efficacy (n = 8); UMEC 62.5 + FP/SAL: AE (n = 10), withdrew consent (n = 8), protocol deviation (n = 1), lack of efficacy (n = 6); UMEC 125 + FP/SAL: AE (n = 6), withdrew consent (n = 4), lost to follow-up (n = 1), protocol deviation (n = 1), lack of efficacy (n = 6).

Table 1.  Patient demographics and characteristics (ITT population) at screening and baseline

	Study 1			Study 2
PBO + FP/SAL 250/50	UMEC 62.5 + FP/SAL 250/50	UMEC 125 + FP/SAL 250/50	PBO + FP/SAL 250/50	UMEC 62.5 + FP/SAL 250/50	UMEC 125 + FP/SAL 250/50
(n = 205)	(n = 204)	(n = 205)	(n = 201)	(n = 203)	(n = 202)	Age, years
Age, years	63.4 (8.27)	62.7 (7.84)	63.2 (8.95)	65.7 (7.92)	64.5 (8.31)	65.5 (7.89)
Male, n (%)	132 (64)	133 (65)	142 (69)	123 (61)	140 (69)	120 (59)
Current smoker at screening^a, n (%)	116 (57)	102 (50)	115 (56)	77 (38)	73 (36)	78 (39)
Smoking pack-years	48.4 (25.86)	49.8 (24.53)	50.4 (27.88)	45.1 (25.73)	44.3 (27.76)	42.8 (21.76)
Post-albuterol % predicted FEV1	47.4 (13.34)	46.8 (12.35)	46.7 (13.12)	44.8 (13.32)	43.9 (11.53)	47.6 (12.77)
Post-albuterol FEV1/FVC	47.39 (10.818)	46.72 (9.758)	46.63 (10.972)	44.58 (11.117)	45.02 (10.622)	47.06 (11.076)
Baseline FEV1, L	1.310 (0.4602)	1.312 (0.4745)	1.354 (0.5405)	1.137 (0.4507)^b	1.155 (0.4419)	1.207 (0.4789)
Baseline FVC, L	2.758 (0.8382)	2.785 (0.8120)	2.854 (0.9147)	2.508 (0.7880)^b	2.599 (0.7970)	2.592 (0.8482)
Percent reversibility to albuterol	14.5 (13.48)	16.2 (14.37)	16.2 (14.25)	13.4 (12.54)	16.1 (13.22)^c	16.6 (14.43)
Rescue-free days at baseline, %^d	45.4 (41.61)	46.8 (41.45)	44.4 (41.88)	39.1 (42.20)	40.9 (41.37)	37.8 (40.63)
Number of puffs of rescue medication (albuterol)/day^d	1.9 (2.40)	1.9 (2.27)	2.1 (2.64)	2.2 (2.37)	2.4 (2.90)	2.2 (2.41)
CAT score at baseline	18.16 (7.021)	17.79 (7.404)	18.71 (6.921)	18.08 (7.425)	18.12 (7.347)	17.02 (7.075)
SGRQ score at baseline^e	43.97 (17.558)	43.38 (17.572)	45.39 (16.145)	47.80 (17.678)	46.40 (16.713)	44.94 (15.689)
GOLD stage, n (%)
II	100 (49)	89 (44)	91 (44)	78 (39)	71 (35)	95 (47)
III	84 (41)	100 (49)	85 (41)	92 (46)	108 (53)	88 (44)
IV	21 (10)	15 (7)	29 (14)	31 (15)	24 (12)	19 (9)
Reversible^f to albuterol, n (%)	69 (34)	80 (39)	77 (38)	55 (27)	62 (31)^c	66 (33)
Reversible^f to albuterol and ipratropium^g, n (%)	106 (52)	118 (58)	121 (59)	104 (53)	103 (52)	115 (58)
Any pre-treatment concomitant medication, n (%)	196 (96)	187 (92)	186 (91)	189 (94)	196 (97)	195 (97)
Long-acting β2-agonist, n (%)	114 (56)	118 (58)	113 (55)	128 (64)	132 (65)	132 (65)
Inhaled corticosteroids, n (%)	98 (48)	112 (55)	106 (52)	121 (60)	119 (59)	122 (60)
Long-acting muscarinic antagonist, n (%)	92 (45)	82 (40)	94 (46)	60 (30)	65 (32)	57 (28)

CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; FVC, forced vital capacity; GOLD, Global initiative for Obstructive Lung Disease; ITT, intent-to-treat; PBO, placebo; SD, standard deviation; SGRQ, St. George's Respiratory Questionnaire; UMEC, umeclidinium.

Values are reported as mean (SD) unless otherwise stated.

aReclassified: Patient reclassified as current smoker if smoked within 6 months; ^bn = 200; ^cn = 202; ^dStudy 1: PBO + FP/SAL 250/50, n = 203; UMEC 62.5 + FP/SAL 250/50, n = 202; UMEC 125 + FP/SAL 250/50, n = 200; Study 2: PBO + FP/SAL 250/50, n = 196, UMEC 62.5 + FP/SAL 250/50, n = 202; UMEC 125 + FP/SAL 250/50, n = 195; ^eStudy 1: PBO + FP/SAL 250/50, n = 203; UMEC 62.5 + FP/SAL 250/50, n = 200; UMEC 125 + FP/SAL 250/50, n = 204; Study 2: PBO + FP/SAL 250/50, n = 201, UMEC 62.5 + FP/SAL 250/50, n = 202; UMEC 125 + FP/SAL 250/50, n = 198; ^freversible to albuterol (and to albuterol and ipratropium) was defined as an increase in FEV₁ of ≥ 12% and ≥ 200 mL following administration of the drug(s); ^gin Study 1, 
n = 203 for PBO + FP/SAL 250/50, n = 204 for UMEC 62.5 + FP/SAL 250/50, n = 204 for UMEC 125 + FP/SAL 250/50; in Study 2, n = 198 for PBO + FP/SAL 250/50, n = 199 for UMEC 62.5 + FP/SAL 250/50, n = 200 for UMEC 125 + FP/SAL 250/50.

Table 2.  Lung function, rescue use and HRQoL endpoints for both studies (ITT population)

	Study 1			Study 2
	PBO + FP/SAL 250/50 (n = 205)	UMEC 62.5 + FP/SAL 250/50(n = 204)	UMEC 125 + FP/SAL 250/50(n = 205)	PBO + FP/SAL 250/50(n = 201)	UMEC 62.5 + FP/SAL 250/50(n = 203)	UMEC 125 + FP/SAL 250/50(n = 202)
Trough FEV1 at Day 85, La	n = 177	n = 190	n = 184	n = 169	n = 178	n = 183
LS mean Difference vs PBO + FP/SAL 250/50 (95% CI)	—	0.147*(0.107, 0.187)	0.138*(0.097, 0.178)	—	0.127*(0.089, 0.164)	0.148*(0.111, 0.185)
0–6 h post-dose WM FEV1 at Day 84, L	n = 176	n = 186	n = 183	n = 171	n = 178	n = 184
LS mean difference vs PBO + FP/SAL 250/50 (95% CI)	—	0.164*(0.126, 0.203)	0.160*(0.122, 0.199)	—	0.144*(0.107, 0.182)	0.165*(0.128, 0.203)
Proportion of patients with trough FEV1 ≥ 0.100 L at Day 85	n = 204	n = 204	n = 203	n = 200	n = 203	n = 202
Odds ratio vs PBO + FP/SAL 250/50 (95% CI)	—	5.6*(3.5, 8.9)	4.5*(2.8, 7.2)	—	4.1*(2.6, 6.5)	5.7*(3.6, 9.1)
Proportion of patients with FEV1 increase ≥ 12% and ≥ 0.200 L at Day 1	n = 205	n = 204	n = 205	n = 200	n = 203	n = 202
Odds ratio vs PBO + FP/SAL 250/50 (95% CI)	—	5.5*(3.5, 8.6)	5.2*(3.4, 8.2)	—	5.3*(3.4, 8.4)	5.6*(3.6, 8.9)
Peak FEV1 at Day 84, L	n = 179	n = 190	n = 185	n = 171	n = 178	n = 184
LS mean difference vs PBO + FP/SAL 250/50 (95% CI)	—	0.186*(0.145, 0.226)	0.168*(0.127, 0.208)	—	0.147*(0.107, 0.186)	0.167*(0.128, 0.206)
Trough FVC at Day 85, L	n = 177	n = 190	n = 184	n = 169	n = 178	n = 183
LS mean difference vs PBO + FP/SAL 250/50 (95% CI)	—	0.243*(0.178, 0.308)	0.244*(0.179, 0.309)	—	0.162*(0.095, 0.230)	0.165*(0.098, 0.232)
Rescue albuterol use, Weeks 1–12
Percentage of rescue-free days, mean (SD)	n = 184	n = 192	n = 185	n = 177	n = 192	n = 193
	49.7 (38.99)	59.4 (40.85)	56.1 (41.24)	40.7 (41.57)	49.9 (41.62)	53.8 (40.43)
Change from baseline in percentage of rescue-free days, mean (SD)	n = 184	n = 191	n = 183	n = 174	n = 191	n = 187
	4.9 (25.66)	13.3 (28.66)	11.1 (25.70)	1.9 (27.38)	8.4 (30.23)	15.2 (28.25)
LS mean difference vs PBO + FP/SAL 250/50 (95% CI), mean puffs/day	n = 184	n = 191	n = 183	n = 174	n = 191	n = 187
	—	-0.3†(-0.5, -0.1)	-0.3†(-0.5, -0.1)	—	-0.2(-0.5, 0.0)	-0.5*(-0.8, -0.3)
CAT score, Day 84
Mean change from baseline (SD)	n = 179	n = 190	n = 185	n = 172	n = 180	n = 184
	-0.77 (5.697)	-0.81 (5.543)	-0.92 (5.112)	0.41 (5.445)	-1.31 (7.182)	-1.42 (5.880)
SGRQ score, Day 84	n = 177	n = 186	n = 183	n = 172	n = 176	n = 177
LS mean change from baseline (SE)	-2.26 (0.710)	-3.57 (0.696)	-2.77 (0.697)	-1.50 (0.778)	-3.50 (0.769)	-4.54 (0.768)
LS mean difference vs PBO + FP/SAL 250/50 (95% CI)	—	-1.32(-3.27, 0.64)	-0.51(-2.47, 1.44)	—	-1.99(-4.14, 0.16)	-3.04†(-5.19, -0.89)

CAT, COPD assessment test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FP/SAL, fluticasone propionate/salmeterol combination; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HRQoL, health-related quality of life; ITT, intent-to-treat; LS, least squares; PBO, placebo; SD, standard deviation; SE, standard error; SGRQ, St. George's Respiratory Questionnaire; UMEC, umeclidinium; WM, weighted mean.

*p < 0.001; †p < 0.050.

aAnalyses of trough FEV₁ at Day 85 (primary endpoint) performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 minutes’ and 5 minutes’ pre-dose on Day 1), smoking status, Day, Day by baseline, and Day by treatment interactions.

Figure 2.  LS mean (95% CI) change from baseline in trough FEV₁ (L) in Study 1 (A) and Study 2 (B) (ITT). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; LS, least squares; PBO, placebo; UMEC, umeclidinium. Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, Day, Day by baseline and Day by treatment interactions.

Figure 3.  LS mean (95% CI) change from baseline in 0–6 hours WM FEV₁ (L) in Study 1 (A) and Study 2 (B) (ITT). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; LS, least squares; PBO, placebo; UMEC, umeclidinium; WM, weighted mean. Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, Day, Day by baseline and Day by treatment interactions.

Figure 4.  Serial (24 hours) FEV₁ LS mean (95% CI) change from baseline on Day 1 and Day 84 (ITT population) in Study 1 (A) and Study 2 (B). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FP/SAL, fluticasone propionate/salmeterol combination; ITT, intent-to-treat; LS, least squares; PBO, placebo; UMEC, umeclidinium. Analyses performed using a separate repeated measures model for each Day with covariates of treatment, baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, time, time by baseline and time by treatment interactions.

Table 3. Summary of on-treatment AEs reported by ≥ 3% of patients in any treatment group

	Study 1			Study 2
	PBO + FP/SAL 250/50	UMEC 62.5 + FP/SAL 250/50	UMEC 125 + FP/SAL 250/50	PBO + FP/SAL 250/50	UMEC 62.5 + FP/SAL 250/50	UMEC 125 + FP/SAL 250/50
	(n = 205)	(n = 204)	(n = 205)	(n = 201)	(n = 203)	(n = 202)
Any on-treatment AEs, n (%)	85 (41)	78 (38)	76 (37)	74 (37)	78 (38)	73 (36)
Most common on-treatment AEs, n (%)^a
Headache	10 (5)	9 (4)	14 (7)	9 (4)	9 (4)	6 (3)
Nasopharyngitis	10 (5)	5 (2)	5 (2)	9 (4)	6 (3)	10 (5)
Cough	3 (1)	7 (3)	5 (2)	1 (< 1)	3 (1)	1 (< 1)
Upper respiratory tract infection	6 (3)	1 (< 1)	3 (1)	4 (2)	6 (3)	5 (2)
Back pain	5 (2)	2 (< 1)	4 (2)	5 (2)	5 (2)	6 (3)
Pneumonia	0	1 (< 1)	2 (< 1)	6 (3)	3 (1)	5 (2)
COPD	3 (1)	2 (< 1)	1 (< 1)	8 (4)	3 (1)	1 (< 1)
Any on-treatment SAEs, n (%)	8 (4)	4 (2)	6 (3)	15 (7)	6 (3)	6 (3)
Any AEs leading to permanent discontinuation of medication/withdrawal, n (%)	6 (3)	4 (2)	10 (5)	12 (6)	9 (4)	6 (3)
Fatal AEs, n (%)	0	0	1 (< 1)	1 (< 1)	1 (< 1)	0
Number of patients with a COPD exacerbation, n (%)^b	13 (6)	9 (4)	7 (3)	20 (10)	10 (5)	8 (4)
Number of COPD exacerbations
0	192 (94)	195 (96)	198 (97)	181 (90)	193 (95)	194 (96)
1	13 (6)	9 (4)	7 (3)	20 (10)	10 (5)	8 (4)
≥ 2	0	0	0	0	0	0

AE, adverse event; COPD, chronic obstructive pulmonary disease; FP/SAL, fluticasone propionate/salmeterol combination; PBO, placebo; SAE, serious adverse event; UMEC, umeclidinium.

aReported by ≥ 3% of patients on any treatment in either study; ^bpercentages calculated using n as the denominator.