Umeclidinium/vilanterol as step-up therapy from tiotropium in patients with moderate COPD: a randomized, parallel-group, 12-week study

Figures & data

Table 1 Demographics and clinical characteristics (ITT population)

Characteristics	UMEC/VI (N=247)	TIO (N=247)
Age (years), mean (SD)	64.5 (8.7)	64.3 (8.7)
Male, n (%)	163 (66)	160 (65)
Ethnicity, Caucasian, n (%)	244 (99)	242 (98)
Current smoker at screening, n (%)a	129 (52)	118 (48)
Smoking pack-years at screening, mean (SD)b	38.6 (20.5)	40.4 (20.2)
Lung function
Post-salbutamol FEV1 at screening, L, mean (SD)	1.79 (0.42)	1.75 (0.38)
Post-salbutamol FEV1/FVC at screening, mean (SD)	53.1 (8.2)	52.9 (8.4)
Post-salbutamol % predicted FEV1, mean (SD)	59.8 (5.5)	59.4 (5.3)
Reversible to salbutamol at screening, n (%)c,d	60 (24)	62 (25)
% reversibility to salbutamol at screening, mean (SD)c,d	8.2 (12.2)	7.7 (10.0)
GOLD grade II at screening, n (%)	247 (100)	247 (100)
Baseline symptomatology/risk, mean (SD)
mMRC dyspnea score at screening	1.9 (0.6)	1.8 (0.6)
mMRC dyspnea score at randomization	1.8 (0.6)	1.8 (0.6)
BDI focal score at Day 1e	6.5 (1.3)	6.5 (1.4)
SGRQ score at baselinef	41.3 (14.4)	42.3 (14.8)
CAT score at baseline	16.7 (6.2)	16.4 (6.5)
% rescue-free days at baselineg	48.8 (40.4)	51.9 (40.6)
Rescue medication use, puffs/d at baselineg	1.1 (1.4)	1.2 (1.8)
Number of moderate-to-severe COPD exacerbationsh 12 months prior to screening, n (%)	86 (35)	81 (33)
GOLD category at screening, n (%)i
A	58 (23)	67 (27)
B	161 (65)	146 (59)
C	1 (<1)	3 (1)
D	27 (11)	31 (13)

Notes:

a Reclassified: patient reclassified as current smoker if they had smoked within 6 months of screening.

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

c Reversibility was defined as an increase in FEV₁ of ≥12% and ≥200 mL following administration of albuterol.

d TIO, n=246.

e UMEC/VI, n=240; TIO, n=245.

f UMEC/VI, n=242; TIO, n=245.

g UMEC/VI, n=246.

h Defined as worsening symptoms of COPD requiring treatment with oral/systemic corticosteroids, antibiotics, or in-patient hospitalization.

i According to mMRC score, lung function impairment, and exacerbation history.

Abbreviations: BDI, baseline dyspnea index; CAT, COPD Assessment Test; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ITT, intent-to-treat; mMRC, modified Medical Research Council; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire; TIO, tiotropium; UMEC, umecli dinium; VI, vilanterol.

Figure 1 Summary of patient disposition.

Notes: *Percentages may not add up due to rounding.
Abbreviations: TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Table 2 Lung function outcomes (ITT population)

Outcome measure	UMEC/VI (N=247)	TIO (N=247)
Change from baseline in trough FEV1, mL
Day 2
na	238	238
LS mean (SE)	91 (12.7)	−9 (12.7)
Difference (95% CI)	101 (65–136)***
Day 28
na	237	230
LS mean (SE)	64 (14.6)	0 (14.7)
Difference (95% CI)	64 (23–105)**
Day 56
na	232	226
LS mean (SE)	63 (14.0)	−9 (14.2)
Difference (95% CI)	72 (33–112)***
Day 84
na	226	229
LS mean (SE)	65 (15.5)	−25 (15.4)
Difference (95% CI)	90 (47–113)***
Day 85
na	224	225
LS mean change (SE)	74 (15.5)	−14 (15.5)
Difference (95% CI)	88 (45–131)***
Change from baseline in FEV1 at 3 h postdose, mL
Day 84
na	225	228
LS mean (SE)	164 (17.8)	91 (17.7)
Difference (95% CI)	73 (24–122)**
Change from baseline in weighted mean FEV1 at 0–3 h postdose, mL
Day 1
na	239	240
LS mean (SE)	141 (9.5)	87 (9.5)
Difference (95% CI)	55 (28–81)***
Day 28
na	221	218
LS mean (SE)	161 (15.2)	81 (15.3)
Difference (95% CI)	80 (37–122)***
Day 56
na	219	218
LS mean (SE)	148 (15.6)	92 (15.7)
Difference (95% CI)	56 (12–100)*
Day 84
na	225	228
LS mean (SE)	151 (16.4)	79 (16.4)
Difference (95% CI)	72 (26–118)**

Notes:

* P<0.05.

** P<0.01.

*** P<0.001.

a Number of subjects with analyzable data at the current time point.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 s; ITT, intent-to-treat; LS, least squares; SE, standard error; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Figure 2 LS mean (SE) change from baseline in trough FEV₁ (ITT population).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 s; ITT, intent-to-treat; LS, least squares; SE, standard error; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Figure 3 Serial LS mean change (95% CI) from baseline in FEV₁ over 0–3 h on Day 1 (A) and Day 84 (B; ITT population).

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

Figure 4 Serial LS mean change (95% CI) from baseline in FEV₁ over 0–24 h on Day 1 (A) and Day 84 (B; 24-h population).

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 s; LS, least squares; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Table 3 Patient-reported outcomes (ITT population)

Outcome measure	UMEC/VI (N=247)	TIO (N=247)
TDI score
Day 28
na	235	238
LS mean (SE)	1.8 (0.16)	1.3 (0.16)
Difference (95% CI)	0.5 (0.0–0.9)*
Day 56
na	232	235
LS mean (SE)	1.9 (0.15)	1.8 (0.15)
Difference (95% CI)	0.1 (−0.3–0.5)
Day 84
na	226	233
LS mean (SE)	2.3 (0.16)	1.9 (0.16)
Difference (95% CI)	0.4 (−0.1–0.8)
SGRQ total score
Day 28
na	232	237
LS mean change (SE)	−3.23 (0.59)	−2.67 (0.59)
Difference (95% CI)	−0.55 (−2.20–1.09)
Day 84
na	225	232
LS mean change (SE)	−4.41 (0.68)	−4.21 (0.67)
Difference (95% CI)	−0.20 (−2.09–1.68)
CAT score
Day 28
na	242	240
LS mean change (SE)	−1.56 (0.31)	−1.17 (0.31)
Difference (95% CI)	−0.39 (−1.25–0.48)
Day 84
na	233	235
LS mean change (SE)	−2.10 (0.36)	−1.84 (0.35)
Difference (95% CI)	−0.26 (−1.25–0.72)

Notes:

* P<0.05.

a Number of subjects with analyzable data at the current time point.

Abbreviations: CAT, COPD Assessment Test; CI, confidence interval; ITT, intent-to-treat; LS, least squares; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Figure 5 Responder analysis of clinically relevant change from baseline in breathlessness assessed by (A) TDI focal score, and health status assessed by either (B) SGRQ total score or (C) CAT score (ITT population).

Notes: TDI responder defined as a ≥1-unit improvement from baseline; SGRQ total score responder defined as a ≥4-unit reduction from baseline; and CAT score defined as a ≥2-unit reduction from baseline.
Abbreviations: CAT, COPD Assessment Test; CI, confidence interval; ITT, intent-to-treat; OR, odds ratio; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Table 4 Summary of AEs and COPD exacerbations (ITT population)

n (%)	UMEC/VI (N=247)	TIO (N=247)
On-treatment AEs	75 (30)	77 (31)
On-treatment drug-related AEs	3 (1)	8 (3)
Any AEs leading to withdrawal/discontinuation of medication	5 (2)	4 (2)
On-treatment nonfatal SAE	6 (2)	6 (2)
On-treatment fatal SAE	1 (<1)	0
AEs reported in ≥3% patients in either treatment arm
Nasopharyngitis	18 (7)	17 (7)
Headache	16 (6)	18 (7)
Patients experiencing a COPD exacerbation	2 (<1)	8 (3)
Cardiovascular events of special interesta	4 (1.6)	3 (1.2)

Notes: AEs with onset during the follow-up period were considered on-treatment and were assigned to the treatment previously received.

a Standardized MedDRA terms included cardiac arrhythmias, cardiac failure, ischemic heart disease, central nervous system hemorrhages, and cerebrovascular conditions.

Abbreviations: AEs, adverse events; ITT, intent-to-treat; MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Figure S1 Serial LS mean change (95% CI) from baseline in FEV₁ over 0–3 h on Day 28 (A) and Day 56 (B; ITT population).

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

Table S1 Additional lung function outcomes (ITT population)

Outcome measure	UMEC/VI (N=247)	TIO (N=247)
Trough FVC (L)
Day 2
na	238	238
LS mean (SE)	131 (18.3)	6 (18.3)
Difference (95% CI)	125 (74–176)***
Day 28
na	237	230
LS mean (SE)	56 (20.5)	−4 (20.7)
Difference (95% CI)	59 (2–116)*
Day 56
na	232	226
LS mean (SE)	36 (20.6)	−23 (20.8)
Difference (95% CI)	59 (2–117)*
Day 84
na	226	229
LS mean (SE)	47 (22.7)	−50 (22.7)
Difference (95% CI)	97 (34–160)**
Day 85
na	224	225
LS mean change (SE)	63 (22.6)	−41 (22.6)
Difference (95% CI)	104 (41–166)**

Notes:

* P<0.05.

** P<0.01.

*** P<0.001.

a Number of subjects with analyzable data at the current time point.

Abbreviations: CI, confidence interval; FVC, forced vital capacity; ITT, intent-to-treat; LS, least squares; SE, standard error; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Table S2 Patient reported outcome responder analyses (ITT population)

Outcome measure	UMEC/VI (N=247)	TIO (N=247)
TDI score responder analysis
Day 28
na	240	245
Responder,b n (%)	139 (58)	112 (46)
Odds ratio (95% CI)	1.67 (1.14–2.45)**
Day 56
na	240	245
Responder,b n (%)	136 (57)	124 (51)
Odds ratio (95% CI)	1.25 (0.85–1.84)
Day 84
na	240	245
Responder,b n (%)	151 (63)	121 (49)
Odds ratio (95% CI)	1.78 (1.21–2.64)**
SGRQ total score responder analysis
Day 28
na	237	244
Responder,c n (%)	99 (42)	100 (41)
Odds ratio (95% CI)	1.05 (0.73–1.53)
Day 84
na	242	245
Responder,c n (%)	104 (43)	117 (48)
Odds ratio (95% CI)	0.83 (0.58–1.19)
CAT score responder analysis
Day 28
na	247	247
Responder,d n (%)	118 (48)	99 (40)
Odds ratio (95% CI)	1.40 (0.96–2.04)
Day 84
na	247	247
Responder,d n (%)	121 (49)	111 (45)
Odds ratio (95% CI)	1.17 (0.81–1.70)

Notes:

** P<0.01.

a Number of subjects with analyzable data at the current time point.

b Defined as a ≥1-unit improvement from baseline.

c Defined as a ≥4-unit improvement from baseline.

d Defined as a ≥2-unit improvement from baseline.

Abbreviations: CAT, COPD Assessment Test; ITT, intent-to-treat; LS, least squares; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.