Efficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled study

Figures & data

Table 1 Baseline demographics and characteristics

Characteristics	Placebo n=193	UMEC/VI 62.5/25 μg n=194	UMEC/VI 125/25 μg n=193	Total n=580
Age (years), mean (SD)	64.3 (8.78)	64.0 (8.71)	63.7 (8.26)	64.0 (8.57)
Male, n (%)	177 (92)	183 (94)	182 (94)	542 (93)
Ethnicity, n (%)
Asian	193 (100)	194 (100)	193 (100)	580 (100)
East Asian	177 (88)	173 (89)	173 (90)	516 (89)
Southeast Asian	21 (11)	21 (11)	20 (10)	62 (11)
Mixed Asian heritage	2 (1)	0	0	2 (<1)
Body mass index (kg/m^2), mean (SD)	22.44 (3.633)	22.19 (3.611)	22.41 (3.454)	22.35 (3.562)
Smoking status: current smoker, n (%)	65 (34)	56 (29)	48 (25)	169 (29)
Smoking pack-years,a mean (SD)	37.1 (21.83)	37.6 (19.76)	38.9 (22.43)	37.9 (21.34)
Duration of COPD, n (%)
<1 year	40 (21)	45 (23)	47 (24)	132 (23)
≥1 to <5 years	93 (48)	82 (42)	85 (44)	260 (45)
≥5 to <10 years	37 (19)	39 (20)	32 (17)	108 (19)
≥10 to <15 years	14 (7)	20 (10)	22 (11)	56 (10)
≥15 to <20 years	5 (3)	3 (2)	2 (1)	10 (2)
≥20 to <25 years	3 (2)	3 (2)	2 (1)	8 (1)
≥25 years	1 (<1)	2 (1)	3 (2)	6 (1)
GOLD stage, n (%)
Stage II (≥50%–<80% predicted FEV	89 (46)	74 (38)	88 (46)	251 (43)
Stage III (≥30%–<50% predicted FEV1)	79 (41)	84 (44)	84 (44)	247 (43)
Stage IV (<30% predicted FEV1)	25 (13)	35 (18)	21 (11)	81 (14)
Reversible to albuterol and ipratropium,b n (%)	n=191d	n=192d	n=193	n=573d
	95 (50)	85 (44)	91 (47)	271 (47)
Postalbuterol FEV1, L (SD)	n=193 1.168 (0.3708)	n=193d 1.131 (0.3965)	n=193 1.195 (0.3889)	n=579d 1.164 (0.3858)
Postalbuterol FEV1/FVC, mean (SD)	n=193 40.110 (9.5767)	n=193d 38.814 (11.2420)	n=193 40.566 (10.5418)	n=579d 39.830 (10.4840)
ICS use, n (%)	99 (51)	104 (54)	98 (51)	301 (52)
Pretreatment concomitant COPD medications,c n (%)
Any medication	153 (79)	147 (76)	145 (75)	445 (77)
ICS	102 (53)	108 (56)	98 (51)	308 (53)
Long-acting β-agonist	93 (48)	97 (50)	84 (44)	274 (47)
Short-acting β-agonist	42 (22)	45 (23)	44 (23)	131 (23)
Xanthine	51 (26)	40 (21)	36 (19)	127 (22)
Long-acting anticholinergic	34 (18)	31 (16)	36 (19)	101 (17)
Mucolytics	23 (12)	26 (13)	23 (12)	72 (12)
Other COPD medication	21 (11)	13 (7)	21 (11)	55 (9)
Cold, cough, nasal, and/or throat medication	13 (7)	12 (6)	11 (6)	36 (6)
Short-acting anticholinergic	6 (3)	14 (7)	11 (6)	31 (5)

Notes:

a Smoking pack-years = (number of cigarettes smoked per day/20) × number of years smoked;

b reversible was an increase in FEV₁ of ≥12% and ≥0.200 L following administration of both albuterol and ipratropium; nonreversible was an increase in FEV₁ of <0.200 L or a ≥0.200 L increase that was <12% from prealbuterol FEV₁;

c not given for an exacerbation;

d These are the number of patients available to measure these values, which is different from those shown elsewhere in the table.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; SD, standard deviation; UMEC, umeclidinium; VI, vilanterol.

Figure 1 Patient disposition.

Abbreviations: AEs, adverse events; ECG, electrocardiogram; UMEC, umeclidinium; VI, vilanterol.

Table 2 Summary of lung-function, symptomatic, and health-related quality of life measures (ITT population)

Outcomes	Placebo n=193	UMEC/VI 62.5/25 μg n=194	UMEC/VI 125/25 μg n=193
Trough FEV1 on day 169, L	n=162	n=165	n=168
LS mean (SE)	1.040 (0.0147)	1.191 (0.0146)	1.256 (0.0146)
LS mean change (SE)	0.013 (0.0147)	0.164 (0.0146)	0.229 (0.0146)
Column versus placebo difference (95% CI)	–	0.151 (0.110–0.191)***	0.216 (0.175–0.257)***
WM FEV1 0–6 hours postdose on day 1	n=190	n=192	n=192
LS mean (SE)	1.038 (0.0075)	1.197 (0.0075)	1.220 (0.0075)
LS mean change (SE)	0.015 (0.0075)	0.174 (0.0075)	0.197 (0.0075)
Column versus placebo difference (95% CI)	–	0.160 (0.139–0.181)***	0.182 (0.161–0.203)***
Serial FEV1 at 15 minutes postdose at day 1	n=191	n=193	n=191
LS mean (SE)	1.028 (0.0063)	1.133 (0.0063)	1.144 (0.0063)
LS mean change (SE)	0.001 (0.0063)	0.106 (0.0063)	0.117 (0.0063)
Column versus placebo difference (95% CI)	–	0.105 (0.087–0.122)***	0.116 (0.098–0.134)***
Patients achieving an increase in FEV1 of ≥12% and ≥0.200 L above baseline at any time 0–6 hours postdose on day 1
Increase, n (%)	10 (5)	98 (51)	112 (58)
Column versus placebo odds ratio (95% CI)	–	20.5 (10.1–41.6)***	27.8 (13.7–56.6)***
Patients achieving an increase of ≥0.100 L above baseline in trough FEV1 at day 169
Increase, n (%)	42 (22)	112 (58)	118 (61)
Column versus placebo odds ratio (95% CI)	–	5.3 (3.4–8.4)***	6.1 (3.8–9.7)***
Trough FVC at day 169	n=162	n=165	n=168
LS mean (SE)	2.678 (0.0282)	2.938 (0.0280)	3.005 (0.0279)
LS mean change (SE)	0.030 (0.0282)	0.290 (0.0280)	0.358 (0.0279)
Column versus placebo difference (95% CI)		0.260 (0.182, 0.338)***	0.328 (0.250, 0.405)***
Serial trough FVC 15 minutes postdose at day 1	n=191	n=193	n=191
LS mean (SE)	2.662 (0.0172)	2.902 (0.0171)	2.899 (0.0172)
LS mean change (SE)	0.015 (0.0172)	0.255 (0.0171)	0.251 (0.0172)
Column versus placebo difference (95% CI)	–	0.240 (0.192–0.288)***	0.236 (0.188–0.284)***
Time to onset, minutesa	–	28	21
Column versus placebo hazard ratio (95% CI)	–	7.84 (5.69–10.82)***	8.65 (6.27–11.94)***
TDI focal score on day 168	n=162	n=162	n=168
LS mean (SE)	2.0 (0.20)	2.7 (0.20)	2.9 (0.20)
Column versus placebo difference (95% CI)	–	0.7 (0.1–1.2)*	0.9 (0.3–1.4)**
TDI responders at day 168 (≥1-unit change)	n=186	n=184	n=186
Responder, n (%)	105 (56)	118 (64)	128 (69)
Column versus placebo odds ratio (95% CI)	–	1.3 (0.9–2.1)	1.6 (1.1–2.5)*
Rescue-medication use (puffs/day) (weeks 1–24)	n=169	n=172	n=173
LS mean (SE)	1.5 (0.09)	0.8 (0.09)	0.8 (0.09)
LS mean change (SE)	−0.2 (0.09)	−0.8 (0.09)	−0.8 (0.09)
Column versus placebo difference (95% CI)		−0.6 (−0.9 to −0.4)***	−0.7 (−0.9 to −0.4)***
Time to first on-treatment COPD exacerbations
Patients with a COPD exacerbation, n (%)	32 (17)	20 (10)	13 (7)
Probability of having event, % (95% CI)	17.2 (12.4–23.4)	10.9 (7.2–16.4)	7.0 (4.1–11.7)
Column versus placebo hazard ratio (95% CI)	–	0.6 (0.3–1.0)	0.4 (0.2–0.7)**
SGRQ total score at day 168	n=158	n=157	n=163
LS mean (SE)	35.11 (1.035)	33.09 (1.035)	31.35 (1.022)
LS mean change (SE)	−6.30 (1.035)	−8.32 (1.035)	−10.06 (1.022)
Column versus placebo difference (95% CI)		−2.02 (−4.90 to 0.86)	−3.76 (−6.62 to −0.90)**
SGRQ responders (>4-unit decrease from baseline) at day 168
Responders, n (%)	84 (46)	102 (56)	107 (58)
Column versus placebo odds ratio (95% CI)	–	1.5 (1.0–2.4)*	1.8 (1.1–2.7)**
COPD assessment test at day 168	n=164	n=166	n=170
Change from baseline, mean (SD)	−2.26 (6.695)	−3.24 (6.488)	−3.54 (6.386)
Health care-resource utilization, n (%)
Patients requiring unscheduled health care	2 (1)	3 (2)	4 (2)
Patients making an office/practice visit	0	1 (<1)	3 (2)
Patients making urgent care/outpatient visit	0	2 (1)	1 (<1)
Patients making an emergency room visit	2 (1)	1 (<1)	0
Patients spending time in intensive care	0	0	0

Notes:

* P≤0.05;

** P≤0.01;

*** P<0.001;

a the first time during the 0- to 6-hour postdose period at which a scheduled postdose FEV₁ was ≥0.100 L above baseline.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ITT, intent-to-treat; LS, least squares; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; UMEC, umeclidinium; VI, vilanterol; WM, weighted mean.

Figure 2 LS mean change from baseline in trough FEV₁ up to day 169 (ITT population).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ITT, intent-to-treat; LS, least squares; UMEC, umeclidinium; VI, vilanterol.

Figure 3 LS mean change from baseline in serial FEV₁ on day 1 (ITT population).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ITT, intent-to-treat; LS, least squares; UMEC, umeclidinium; VI, vilanterol.

Figure 4 LS mean TDI focal score (ITT population).

Abbreviations: CI, confidence interval; ITT, intent-to-treat; LS, least squares; TDI, Transition Dyspnea Index; UMEC, umeclidinium; VI, vilanterol.

Table 3 Overall summary of AEs (ITT population)

	Placebo n=193	UMEC/VI 62.5/25 μg n=194	UMEC/VI 125/25 μg n=193
All AEs, n (%)
Any on-treatment AE	76 (39)	65 (34)	66 (34)
Any posttreatment AE	2 (1)	1 (<1)	4 (2)
Any on-treatment drug-related AE	10 (5)	7 (4)	9 (5)
Any AE leading to permanent discontinuation of study drug or withdrawal from studya	17 (9)	16 (8)	7 (4)
Any on-treatment nonfatal SAE	17 (9)	14 (7)	5 (3)
Any posttreatment nonfatal SAE	1 (<1)	0	0
Any on-treatment drug-related nonfatal SAE	1 (<1)	1 (<1)	0
Any drug-related fatal SAE	0	0	1 (<1)
Any fatal SAE	0	1 (<1)	1 (<1)
AE reported by ≥3% of patients in any treatment group, n (%)
Nasopharyngitis	18 (9)	17 (9)	18 (9)
Upper respiratory tract infection	11 (6)	19 (10)	13 (7)
Chronic obstructive pulmonary disease	9 (5)	9 (5)	3 (2)
Cough	4 (2)	6 (3)	4 (2)
On-treatment AEs of special interest,b n (%)
Any cardiovascular event	6 (3)	3 (2)	11 (6)
Anticholinergic events, n (%)
Dry mouth	3 (2)	1 (<1)	4 (2)
Urinary retention	0	0	1 (<1)

Notes:

a Includes both on-treatment and posttreatment AEs;

b incidence of AEs of special interest comprised of events in selected Standardised MedDRA Queries (SMQs) and/or individual preferred terms (PTs). Cardiovascular AEs of special interest comprised SMQs for cardiac arrhythmias, cardiac failure, cardiac ischemia (myocardial infarction, other ischemic heart disease), and stroke (central nervous system hemorrhages and cerebrovascular conditions). Anticholinergic AEs of special interest comprised terms in the anticholinergic syndrome SMQs. Urinary retention comprised PTs of urinary retention, urinary hesitation, decreased micturition frequency, decreased urine flow, and Fowler’s syndrome.

Abbreviations: AE, adverse event; ITT, intent-to-treat; SAE, serious AE; UMEC, umeclidinium; VI, vilanterol.

Table S1 Medications prior to screening: use of the medications according to the defined time intervals prior to visit 1

Medication	Time interval prior to visit 1
Depot corticosteroids	12 weeks
Systemic, oral, parenteral (intra-articular) corticosteroids	4 weeks
Antibiotics (for lower respiratory tract infection)	4 weeks
ICS/LABA combination products if ICS/LABA therapy is discontinued completely	30 days
Use of ICS at a dose >1,000 mcg/day of fluticasone propionate or equivalenta	30 days
Initiation or discontinuation of ICS usea	30 days
PDE4 inhibitors (roflumilast)	14 days
Long-acting anticholinergics (eg, tiotropium)	7 days
Theophyllinesb	12 hours (stable dose of theophylline alone allowed during the study but must be withheld 12 hours prior to each study visit)
Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton)	48 hours
Oral beta2 -agonists
Long-acting	48 hours
Short-acting	12 hours
Inhaled long-acting beta2-agonists (LABA, eg, salmeterol, formoterol, indacaterol)	48 hours
LABA/ICS combination products only if discontinuing LABA therapy an switching to ICS monotherapyc	48 hours for LABA component
Inhaled sodium cromoglycate or nedocromil sodium	24 hours
Inhaled short-acting beta2-agonistsd	4 hours
Inhaled short-acting anticholinergicsb (eg, ipratropium bromide)	4 hours (stable dose of ipratropium alone allowed during the study, provided that the subject is on a stable dose regimen from screening [Visit 1 and remains so throughout the study] but must be withheld 4 hours prior to each study visit)
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products	4 hours
Any other investigational drug	30 days or 5 half-lives, whichever is longer

Notes:

a Use of a consistent dose of ICS was permitted provided the dose did not exceed 1,000 mcg of fluticasone propionate or equivalent; ICS use was not to be initiated or discontinued within 30 days prior to Visit 1.

b Ipratropium bromide or theophylline was permitted, provided that the subject was on a stable dose from Screening (Visit 1) and remained on the stable dose throughout the study; however, ipratropium bromide must have been withheld for 4 hours; theophylline must have been withheld for 12 hours prior to and during each clinic visit.

c Dose of ICS must have been consistent with that contained in the ICS/LABA combination product.

d Use of study provided salbutamol was permitted during the study, except during the 4-hour period prior to spirometry testing.

Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist.

Table S2 Analysis of SGRQ total score (ITT population)

	Placebo N=193	UMEC/VI 62.5/25 μg N=194	UMEC/VI 125/25 μg N=193
Day 28
N (1)*	182	182	183
N (2)**	182	175	177
LS mean (SE)	38.19 (0.875)	35.83 (0.884)	34.18 (0.881)
LS mean change (SE)	−3.22 (0.875)	−5.59 (0.884)	−7.23 (0.881)
Column vs placebo difference (95% CI)		−2.36 (−4.81, 0.08)	−4.01 (−6.45, −1.57)
P-value		0.058	0.001
Day 84
N (1)	182	182	183
N (2)	166	171	173
LS mean (SE)	36.62 (0.972)	33.30 (0.961)	31.72 (0.957)
LS mean change (SE)	−4.80 (0.972)	−8.11 (0.961)	−9.69 (0.957)
Column vs placebo difference (95% CI)		−3.32 (−6.00, −0.63)	−4.89 (−7.58, −2.21)
P-value		0.016	<0.001
Day 168
N (1)	182	182	183
N (2)	158	157	163
LS mean (SE)	35.11 (1.035)	33.09 (1.035)	31.35 (1.022)
LS mean change (SE)	−6.30 (1.035)	−8.32 (1.035)	−10.06 (1.022)
Column vs placebo difference (95% CI)		−2.02 (−4.90, 0.86)	−3.76 (−6.62, −0.90)
P-value		0.168	0.010

Notes: Analysis performed using a repeated measures model with covariates of treatment, baseline (score prior to dosing on day 1), smoking status, country/region, day, day by baseline, and day by treatment interactions.

* N (1) represents number of subjects with analyzable data for one or more time points.

** N (2) represents number of subjects with analyzable data at the current time point.

Abbreviations: CI, confidence interval; ITT, intent-to-treat; LS, least squares; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol.