Effect of Age on Efficacy and Safety of Fluticasone Furoate/Vilanterol (FF/VI), Umeclidinium (UMEC), and UMEC + FF/VI in Patients with Chronic Obstructive Pulmonary Disease: Analyses of Five Randomized Clinical Trials

Figures & data

Table 1 Study Designs

Study	Duration	Key FEV1 Endpoints and Days of Assessment	Randomization and Stratification	Treatments^a	N
Studies with FF/VI (ICS/LABA)
HZC112206 (NCT01053988)^Citation13	Run-in 2 weeks, single-blind placebo ELLIPTA	Trough FEV1: Days 2, 7, 14, 28, 56, 84, 112, 140, 168, 169 (co-primary endpoint)	1:1:1:1:1 Stratified by smoking status	Placebo	207
				FF 100 µg	206
				VI 25 µg	205
				FF/VI 50/25 µg^b	206
	Treatment period 24 weeks, double-blind	WM FEV1 0─4 hours post-dose: Days 1, 14, 56, 84, 168 (co-primary endpoint)		FF/VI 100/25 µg^b	206
HZC112207 (NCT01054885)^Citation15	Run-in 2 weeks, single-blind placebo ELLIPTA	Trough FEV1: Days 2, 7, 14, 28, 56, 84, 112, 140, 168, 169 (co-primary endpoint)	1:1:1:1:1:1 Stratified by smoking status	Placebo	205
				FF 100 µg	204
				FF 200 µg	203
				VI 25 µg	203
	Treatment period 24 weeks, double-blind	WM FEV1 0─4 hours post-dose: Days 1, 14, 56, 84, 168 (co-primary endpoint)		FF/VI 100/25 µg^b	204
				FF/VI 200/25 µg^b	205
Study with UMEC (LAMA)
DB2113373 (NCT01313650)^Citation17	Run-in 7─14 days, albuterol as needed	Trough FEV1: Days 2, 28, 56, 84, 112, 168, 169 (primary endpoint)	2:3:3:3	Placebo	280
				UMEC 62.5 µg	418
				VI 25 µg	421
	Treatment period 24 weeks, double-blind	WM FEV1 0–6 hours post-dose Days 1, 28, 84, 168 (secondary endpoint)		UMEC/VI 62.5/25 µg	413
Studies with UMEC + FF/VI (LAMA + ICS/LABA)
200109 (NCT01957163)^Citation18	Run-in 4 weeks, open-label FF/VI 100/25 µg	Trough FEV1: Days 2, 28, 56, 84, 85 (primary endpoint)	1:1:1	Placebo + FF/VI 100/25 µg	206
				UMEC 62.5 µg + FF/VI 100/25 µg	206
	Treatment period 12 weeks, double-blind UMEC or placebo, open-label FF/VI	WM FEV1 0–6 hours post-dose Days 1, 28, 84 (secondary endpoint)		UMEC 125 µg^c + FF/VI 100/25 µg	207
200110 (NCT02119286)^Citation18	Run-in 4 weeks, open-label FF/VI 100/25 µg	Trough FEV1: Days 2, 28, 56, 84, 85 (primary endpoint)	1:1:1	Placebo + FF/VI 100/25 µg	206
				UMEC 62.5 µg + FF/VI 100/25 µg	206
	Treatment period 12 weeks, double-blind UMEC or placebo, open-label FF/VI	WM FEV1 0–6 hours post-dose Days 1, 28, 84 (secondary endpoint)
				UMEC 125 µg^c + FF/VI 100/25 µg	207

Notes: ^aTreatments in all studies were administered once daily via the ELLIPTA DPI. ^bFF/VI 100/25 µg is the only licensed dose for COPD. ^cUMEC 62.5 µg is the only licensed dose of UMEC.

Abbreviations: COPD, chronic obstructive pulmonary disease; DPI, dry-powder inhaler; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; UMEC, umeclidinium; VI, vilanterol; WM, weighted mean.

Table 2 Demographics and Baseline Characteristics

Demographic and Baseline Characteristics	Two 24-Week Studies with FF/VI (HZC112206 and HZC112207 Pooled)		24-Week Study with UMEC (DB2113373)		Two 12-Week Studies with UMEC + FF/VI (200109 and 200110 Pooled)
Age Group	<65 Years	≥65 Years	<65 Years	≥65 Years	<65 years	≥65 Years
N	1339	915	867	665	670	568
Age, years, mean (range)	56.2 (40, 64)	70.8 (65, 85)	56.9 (40, 64)	71.2 (65, 93)	57.6 (42, 64)	70.8 (65, 88)
Male, n (%)	882 (66)	688 (75)	589 (68)	494 (74)	412 (61)	386 (68)
Current smoker, n (%)	882 (66)	340 (37)	551 (64)	208 (31)	418 (62)	195 (34)
Smoking history, pack-years, mean (range)	41.2 (10, 200)	48.5 (10, 196)	43.1 (10, 136)	50.2 (10, 225)	45.1 (10, 166)	51.1 (10, 200)
Post-BD FEV1 at screening, mL, mean (SD)	1555 (504)	1300 (410)	1502 (541)	1232 (390)	1459 (509)	1211 (394)
Percent predicted post-BD FEV1 at screening, mean (range)	48.1 (14, 87)	48.1 (14, 77)	47.4 (13, 74)	47.6 (16, 70)	46.4 (13, 70)	46.0 (17, 76)
Percent FEV1 reversibility, mean (SD)	13.2 (15.3)	14.7 (16.5)	14.7 (15.7)	14.5 (14.6)	13.4 (12.8)	13.1 (12.3)
Post-BD FVC at screening, mL, mean (SD)	3236 (911)	2947 (817)	3133 (884)	2700 (716)	2939 (830)	2588 (700)
Exacerbation history in previous 12 months, n (%)
≥1 moderate^a	318 (24)	229 (25)	256 (30)	166 (25)	84 (13)	95 (17)
≥1 severe^b	126 (9)	67 (7)	114 (13)	60 (9)	22 (3)	12 (2)

Notes: ^aRequiring oral/systemic corticosteroids and/or antibiotics; ^bRequiring hospitalization.

Abbreviations: BD, bronchodilator; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; SD, standard deviation; FF, fluticasone furoate; UMEC, umeclidinium; VI, vilanterol.

Table 3 FEV₁ Endpoints at Study End^a

Studies	FF/VI (HZC112206 and HZC112207 Pooled)				UMEC (DB2113373)				UMEC + FF/VI (200109 and 200110 Pooled)
Age Group	<65 Years		≥65 Years		<65 Years		≥65 Years		<65 Years		≥65 Years
	FF/VI	PBO	FF/VI	PBO	UMEC	PBO	UMEC	PBO	UMEC + FF/VI	PBO + FF/VI	UMEC + FF/VI	PBO + FF/VI
Trough FEV1 at study end^b, mL
n	166	173	117	105	171	125	151	76	213	204	177	165
LS mean (SE)	1457 (17.8)	1314 (17.5)	1400 (21.3)	1289 (22.2)	1455 (18.5)	1346 (21.2)	1222 (16.6)	1099 (23.3)	1423 (10.4)	1287 (10.6)	1387 (11.5)	1282 (11.7)
LS mean change from baseline (SE)	173 (17.8)	30 (17.5)	116 (21.3)	6 (22.2)	112 (18.5)	3 (21.2)	127 (16.6)	4 (23.3)	113 (10.4)	−23 (10.6)	78 (11.5)	−28 (11.7)
Treatment difference vs PBO (95% CI)	143 (95, 192)		111 (51, 170)		110 (55, 165)		123 (67, 179)		136 (107, 165)		105 (73, 137)
p-value	<0.001		<0.001		<0.001		<0.001		<0.001		<0.001
WM FEV1 at study end^c, mL
n	178	178	119	108	169	129	150	77	214	203	176	168
LS mean (SE)	1502 (17.1)	1292 (17.0)	1459 (20.7)	1291 (21.5)	1507 (19.1)	1343 (21.5)	1234 (16.6)	1098 (23.1)	1505 (11.4)	1331 (11.6)	1461 (12.5)	1342 (12.7)
LS mean change from baseline (SE)	220 (17.1)	9 (17.0)	177 (20.7)	8 (21.5)	163 (19.1)	−1 (21.5)	139 (16.6)	3 (23.1)	195 (11.4)	21 (11.6)	150 (12.5)	32 (12.7)
Treatment difference vs PBO (95% CI)	211 (164, 258)		168 (110, 226)		163 (107, 220)		136 (80, 192)		174 (143, 206)		119 (84, 153)
p-value	<0.001		<0.001		<0.001		<0.001		<0.001		<0.001
Ratio of trough FEV1 at study end vs baseline
n	166	173	117	105	171	127	151	76	213	204	177	165
LS mean ratio to baseline (log SE)	1.136 (0.0127)	1.024 (0.0124)	1.106 (0.0152)	0.998 (0.0158)	1.086 (0.0134)	0.993 (0.0153)	1.112 (0.0139)	1.011 (0.0195)	1.090 (0.0083)	0.989 (0.0085)	1.076 (0.0091)	0.973 (0.0093)
Treatment difference vs PBO (95% CI)	1.109 (1.071, 1.148)		1.109 (1.062, 1.157)		1.093 (1.051, 1.138)		1.099 (1.049, 1.152)		1.101 (1.076, 1.127)		1.106 (1.078, 1.134)
p-value	<0.001		<0.001		<0.001		<0.001		<0.001		<0.001

Notes: ^aTrough FEV₁ at study end was measured as a primary or co-primary endpoint across all studies. WM FEV₁ at study end was measured as a co-primary endpoint in studies HZC112206 and HZC112207 and as a secondary endpoint in studies DB2113373, 200109, and 200110; ^bTrough FEV₁ at study end was measured on day 169 in studies with FF/VI and UMEC and on day 85 in studies with UMEC + FF/VI; ^cWM FEV₁ at study end was measured at 0–4 hours post-dose on day 168 in studies with FF/VI, 0–6 hours post-dose on day 168 in study with UMEC, and 0–6 hours post-dose on day 84 in studies with UMEC + FF/VI.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; LS, least squares; PBO, placebo; SE, standard error; UMEC, umeclidinium; VI, vilanterol; WM, weighted mean.

Figure 1 Change from baseline in trough FEV₁ over the course of the studies comparing FF/VI versus placebo (A and B), UMEC versus placebo (C and D), and UMEC + FF/VI versus placebo + FF/VI (E and F). n=number of patients with data available for at least 1 time point; ***p≤0.001 vs placebo.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; LS, least squares; SE, standard error; UMEC, umeclidinium; VI, vilanterol.

Figure 2 FEV₁ responders (≥100 mL improvement from baseline in trough FEV1) at study end in studies comparing FF/VI versus placebo (A), UMEC versus placebo (B), and UMEC + FF/VI versus placebo + FF/VI (C).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; OR, odds ratio; UMEC, umeclidinium; VI, vilanterol.

Figure 3 Ratio of trough FEV₁/baseline FEV₁ over the course of the studies comparing FF/VI versus placebo (A and B), UMEC versus placebo (C and D), and UMEC + FF/VI versus placebo + FF/VI (E and F). n=number of patients with data available for at least 1 time point; ***p≤0.001 vs placebo.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; LS, least squares; SE, standard error; UMEC, umeclidinium; VI, vilanterol.

Table 4 Trough FVC at Study End

Studies	FF/VI (HZC112206 and HZC112207 Pooled)							UMEC (DB2113373)							UMEC + FF/VI (200109 and 200110 Pooled)
Age Group	<65 Years				≥65 Years			<65 Years			≥65 Years				<65 Years			≥65 Years
	FF/VI		PBO		FF/VI		PBO	UMEC	PBO		UMEC		PBO		UMEC + FF/VI		PBO + FF/VI	UMEC + FF/VI	PBO + FF/VI
Trough FVC at study end^a, mL
n	239	249		167		158		216		173		200		105	222	224		189	186
LS mean (SE)	3120 (31.9)	3014 (31.4)		2761 (32.3)		2716 (33.7)		3020 (29.5)		2820 (33.8)		2618 (28.5)		2478 (39.9)	2784 (17.5)	2560 (17.8)		2719 (19.1)	2565 (19.5)
LS mean change from baseline (SE)	152 (31.9)	45 (31.4)		133 (32.3)		88 (33.7)		180 (29.5)		−20 (33.8)		203 (28.5)		64 (39.9)	157 (17.5)	−68 (17.8)		92 (19.1)	−62 (19.5)
Treatment difference vs PBO (95% CI)	107 (19, 194)			45 (−47, 137)				200 (112, 288)				140 (44, 236)			225 (176, 273)			154 (101, 208)
p-value	0.017			0.334				<0.001				0.004			<0.001			<0.001

Notes: ^aTrough FVC at study end was measured on day 169 in studies with FF/VI and UMEC and on day 85 in studies with UMEC + FF/VI.

Abbreviations: CI, confidence interval; FF, fluticasone furoate; FVC, forced vital capacity; LS, least squares; PBO, placebo; SE, standard error; UMEC, umeclidinium; VI, vilanterol.

Table 5 Adverse Events

Studies	FF/VI (HZC112206 and HZC112207 Pooled)					UMEC (DB2113373)				UMEC + FF/VI (200109 and 200110 Pooled)
	<65 Years		≥65 Years			<65 Years		≥65 Years		<65 Years		≥65 Years
Patients with AEs, n (%)	FF/VI	PBO	FF/VI		PBO	UMEC	PBO	UMEC	PBO	UMEC + FF/VI	PBO + FF/VI	UMEC + FF/VI	PBO + FF/VI
n	242	252	168		160	217	174	201	106	223	224	189	186
Any AE	122 (50)	116 (46)	81 (48)		80 (50)	110 (51)	87 (50)	106 (53)	43 (41)	82 (37)	87 (39)	60 (32)	66 (35)
Any serious AE	12 (5)	10 (4)	11 (7)		11 (7)	15 (7)	6 (3)	12 (6)	3 (3)	5 (2)	8 (4)	5 (3)	9 (5)
Common AEs^a
Nasopharyngitis	19 (8)	17 (7)		16 (10)	14 (9)	13 (6)	11 (6)	16 (8)	5 (5)	11 (5)	20 (9)	7 (4)	9 (5)
Headache	18 (7)	12 (5)		11 (7)	8 (5)	18 (8)	21 (12)	14 (7)	5 (5)	12 (5)	9 (4)	5 (3)	2 (1)
Upper respiratory tract infection	21 (9)	7 (3)		8 (5)	6 (4)	10 (5)	6 (3)	11 (5)	8 (8)	4 (2)	3 (1)	6 (3)	6 (3)
Other AEs of interest
Oral candidiasis	8 (3)	1 (<1)		4 (2)	2 (1)	1 (<1)	0	1 (<1)	1 (<1)	0	2 (<1)	0	1 (<1)
Oropharyngeal candidiasis	4 (2)	4 (2)		5 (3)	1 (<1)	–	–	–	–	–	–	–	–
Pneumonia	0 (0)	1 (<1)		4 (2)	2 (1)	0	0	0	0	2 (<1)	3 (1)	0	1 (<1)
Lower respiratory tract infection	1 (<1)	6 (2)		1 (<1)	5 (3)	–	–	1 (<1)	0	–	–	0	0
Cardiac disorders, any event	15 (6)	14 (6)		8 (5)	17 (11)	11 (5)	5 (3)	11 (5)	3 (3)	3 (1)	6 (3)	1 (<1)	3 (2)
Vascular disorders, any event	1 (<1)	5 (2)		2 (1)	5 (3)	7 (3)	6 (3)	4 (2)	2 (2)	1 (<1)	5 (2)	1 (<1)	3 (2)
Renal and urinary disorders, any event	2 (<1)	3 (1)		1 (<1)	1 (<1)	4 (2)	1 (<1)	4 (2)	1 (<1)	0	3 (1)	3 (2)	1 (<1)
Eye disorders, any event	2 (<1)	1 (<1)		3 (2)	3 (2)	1 (<1)	3 (2)	5 (2)	2 (2)	2 (<1)	2 (<1)	–	–

Notes: ^aAEs reported with an incidence of ≥5% in active or placebo treatment arms across any of the studies.

Abbreviations: AE, adverse event; FF, fluticasone furoate; PBO, placebo; UMEC, umeclidinium; VI, vilanterol.

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