Triple therapy with salmeterol/fluticasone propionate 50/250 plus tiotropium bromide improve lung function versus individual treatments in moderate-to-severe Japanese COPD patients: a randomized controlled trial – Evaluation of Airway sGaw after treatment with tripLE

Figures & data

Figure 1 Study design flow diagram.

Abbreviations: SFC, salmeterol/fluticasone propionate; TIO, tiotropium bromide.

Figure 2 CONSORT flow diagram.

Note: ^aModified intent-to-treat (mITT) population comprised patients who received ≥1 dose of study medication and completed ≥2 treatment periods and who had a baseline and at least one on treatment sGaw assessment measure.
Abbreviations: AE, adverse event; SFC, salmeterol/fluticasone propionate; sGaw, specific airway conductance; TIO, tiotropium bromide.

Table 1 Summary of demographics and baseline characteristics (mITT population)

Characteristics	mITT population (N=50)
Number of males/females, n (%)	49 (98)/1 (2)
Mean age (range), years	67.3 (49.0–79.0)
Mean height (range), cm	164.0 (151.0–175.0)
Mean weight (range), kg	60.4 (35.0–85.8)
Smoking history
Current/former, n (%)	18 (36)/32 (64)
Mean number of pack years (range)	46.6 (15.0–114.0)
Mean COPD history (range), years	3.1 (0.0–13.7)
Mean CAT score (range)	11.5 (2.0–28.0)
mMRC dyspnoea score, n (%)
Grade 1	34 (68)
Grade 2	15 (30)
Grade 3	1 (2)
Postdose mean % predicted normal	59.3 (36.7–75.0)
FEV1 (range), %
% reversibility FEV1 (range), %	4.1 (−10.0 to 29.0)
Mean number of exacerbations in last year (range)
Steroid/antibiotic free	0.0 (0.0–0.0)
With steroids/antibiotics	0.1 (0.0–1.0)
Hospitalization	0.0 (0.0–0.0)

Note: N refers to the number of patients in mITT population.

Abbreviations: CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; mITT, modified intent-to-treat; mMRC, modified Medical Research Council.

Table 2 Analysis of sGaw AUC_0–4h on days 1 and 28 (mITT population)

SGaw AUC0–4h	SFC250 + TIO (N=50)	TIO (N=50)	SFC250(N=50)
Day 1
Endpoint adjusted geometric mean (SE log)	0.752 (0.0185)	0.702 (0.0186)	0.704 (0.0185)
Ratio of SFC250 + TIO to individual treatment (SE log)		1.071 (0.0263)	1.068 (0.0261)
97.5% CI		1.009, 1.136	1.007, 1.133
P-value		0.011	0.013
Day 28
Endpoint adjusted geometric mean (SE log)	0.854 (0.0183)	0.737 (0.0183)	0.663 (0.0182)
Ratio of SFC250 + TIO to individual treatment (SE log)		1.158 (0.0260)	1.288 (0.0258)
97.5% CI		1.092, 1.228	1.215, 1.366
P-value		<0.001	<0.001

Abbreviations: AUC, area under the curve; CI, confidence interval; h, hours; mITT, modified intent-to-treat; SE, standard error; SFC, salmeterol/fluticasone propionate; sGaw, specific airway conductance; TIO, tiotropium bromide.

Table 3 Change from baseline in trough pulmonary function tests on day 28 (mITT population)

	SFC250 + TIO vs TIO (n=50)			SFC250 + TIO vs SFC250 (n=50)
	Differencea	97.5% CI	P-value	Differencea	97.5% CI	P-value
Spirometry
FEV1 (L)	0.161	0.075, 0.247	<0.001	0.103	0.017, 0.189	0.008
FVC (L)	0.104	−0.016, 0.225	0.051	0.148	0.028, 0.268	0.006
Plethysmography
sGaw (L/kPa⋅s)	0.116	0.055, 0.177	<0.001	0.147	0.086, 0.208	<0.001
sRaw (kPa/[L/s])	−0.374	−0.600, −0.148	<0.001	−0.413	−0.638, −0.187	<0.001
RV (L)	−0.229	−0.374, −0.085	<0.001	−0.189	−0.332, −0.046	0.003
TGV (L)	−0.092	−0.213, −0.029	0.085	−0.091	−0.211, −0.028	0.083
IC (L)	−0.008	−0.136, 0.121	0.890	−0.008	−0.135, 0.119	0.890
TLC (L)	−0.101	−0.219, 0.017	0.055	−0.105	−0.221, 0.012	0.044

Note:

a Difference between SFC + TIO and individual treatment.

Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IC, inspiratory capacity; mITT, modified intent-to-treat; RV, residual volume; SFC, salmeterol/fluticasone propionate; sGaw, specific airway conductance; sRaw, specific airway resistance; TGV, thoracic gas volume; TIO, tiotropium bromide; TLC, total lung capacity.

Figure 3 (A) sGaw, (B) FEV₁, and (C) RV on days 1 and 28 of treatment.

Abbreviations: mITT, modified intent-to-treat; FEV₁, forced expiratory volume in 1 second; sGaw, specific airways conductance; RV, residual volume; SFC, salmeterol/fluticasone propionate combination; TIO, tiotropium bromide; min, minutes; h, hours.

Table 4 Use of rescue medication presented as the mean number of occasions per 24-hour period

Treatment	SFC250 + TIO	TIO	SFC250
mITT population
N	50	50	50
Mean (SD)	0.2 (0.62)	0.3 (0.82)	0.2 (0.55)
mMRC =1
N	34	34	34
Mean (SD)	0.1 (0.54)	0.2 (0.71)	0.1 (0.40)
mMRC ≥2
N	16	16	16
Mean (SD)	0.4 (0.74)	0.6 (0.95)	0.4 (0.73)

Note: N, number of patients in the mITT population.

Abbreviations: mITT, modified intent-to-treat; mMRC, modified Medical Research Council; SFC, salmeterol/fluticasone propionate; SD, standard deviation; TIO, tiotropium bromide.

Table 5 Adverse events occurring in greater than 3% patients (safety population)\

System order class	Preferred term	SFC250 + TIO (N=52)	TIO (N=51)	SFC250 (N=51)
Any event		17 (33%)	8 (16%)	11 (22%)
Infections and infestations	Nasopharyngitis	3 (6%)	1 (2%)	1 (2%)
Respiratory, thoracic, and mediastinal disorders	Dysphonia	5 (10%)	1 (2%)	3 (6%)
Musculoskeletal and connective tissue disorders	Arthralgia	2 (4%)	0	0

Abbreviations: SFC, salmeterol/fluticasone propionate; TIO, tiotropium bromide.

Table S1 Change from baseline in sGaw and sRaw (mITT population)

Time (minutes)	Day 1					Day 28
	0	30	75	120	240	0	30	75	120	240
sGaw
SFC250 + TIO		0.199 (0.0170)	0.251 (0.0170)	0.287 (0.0170)	0.320 (0.0170)	0.230 (0.0191)	0.326 (0.0171)	0.372 (0.0171)	0.376 (0.0171)	0.368 (0.0171)
TIO		0.158 (0.0171)	0.213 (0.0171)	0.245 (0.0171)	0.252 (0.0171)	0.114 (0.0189)	0.211 (0.0171)	0.250 (0.0171)	0.281 (0.0171)	0.266 (0.0171)
		0.095	0.113	0.083	0.005	,0.001	,0.001	,0.001	,0.001	,0.001
SFC250		0.167 (0.0171)	0.215 (0.0171)	0.242 (0.0172)	0.252 (0.0171)	0.083 (0.0189)	0.151 (0.0171)	0.151 (0.0171)	0.181 (0.0171)	0.196 (0.0171)
		0.190	0.133	0.067	0.005	,0.001	,0.001	,0.001	,0.001	,0.001
sRaw
SFC250 + TIO		−0.765 (0.0425)	−0.875 (0.0425)	−0.954 (0.0425)	−0.990 (0.0425)	−0.752 (0.0707)	−1.028 (0.0536)	−1.089 (0.0536)	−1.119 (0.0536)	−1.041 (0.0536)
TIO		−0.679 (0.0424)	−0.801 (0.0424)	−0.872 (0.0424)	−0.834 (0.0424)	−0.378 (0.0698)	−0.742 (0.0535)	−0.818 (0.0535)	−0.866 (0.0535)	−0.813 (0.0535)
		0.158	0.219	0.171	0.010	,0.001	,0.001	,0.001	,0.001	0.003
SFC250		−0.656 (0.0423)	−0.773 (0.0423)	−0.799 (0.0426)	−0.847 (0.0423)	−0.339 (0.0695)	−0.533 (0.0533)	−0.607 (0.0533)	−0.684 (0.0533)	−0.708 (0.0533)
		0.071	0.091	0.010	0.017	,0.001	,0.001	,0.001	,0.001	,0.001

Notes: Values in the table are given as adjusted mean (standard error). P-values (if present) represent treatment difference.

Abbreviations: SFC, salmeterol/fluticasone propionate; sGaw, specific airway conductance; sRaw, specific airway resistance; TIO, tiotropium; mITT, modified intent-to-treat.

Table S2 Postdose raw mean (standard deviation log) values of sGaw and sRaw (mITT population)

Time (minutes)	Day 1					Day 28
	0	30	75	120	240	0	30	75	120	240
sGaw
SFC250 + TIO	0.511 (0.4773)	0.706 (0.4037)	0.758 (0.3972)	0.795 (0.3866)	0.820 (0.4023)	0.727 (0.4671)	0.829 (0.3964)	0.868 (0.4073)	0.880 (0.3867)	0.851 (0.4477)
TIO	0.476 (0.5474)	0.655 (0.4356)	0.709 (0.4262)	0.741 (0.4174)	0.735 (0.4565)	0.598 (0.5364)	0.708 (0.4584)	0.746 (0.4516)	0.774 (0.4581)	0.753 (0.4794)
SFC250 + TIO	0.501 (0.5680)	0.667 (0.4703)	0.715 (0.4567)	0.728 (0.4758)	0.749 (0.4542)	0.573 (0.5124)	0.638 (0.5034)	0.650 (0.4572)	0.679 (0.4519)	0.689 (0.4605)
sRaw
SFC250 + TIO	1.954 (0.4788)	1.414 (0.4025)	1.320 (0.3977)	1.257 (0.3866)	1.218 (0.4028)	1.378 (0.4676)	1.207 (0.3975)	1.152 (0.4074)	1.136 (0.3879)	1.176 (0.4473)
TIO	2.104 (0.5488)	1.527 (0.4352)	1.411 (0.4273)	1.349 (0.4163)	1.359 (0.4564)	1.672 (0.5355)	1.413 (0.4583)	1.341 (0.4518)	1.292 (0.4579)	1.329 (0.4785)
SFC250 + TIO	1.996 (0.5686)	1.499 (0.4684)	1.400 (0.4572)	1.375 (0.4771)	1.336 (0.4557)	1.742 (0.5108)	1.570 (0.5049)	1.539 (0.4572)	1.472 (0.4504)	1.449 (0.4605)

Abbreviations: SFC, salmeterol/fluticasone propionate; sGaw, specific airway conductance; sRaw, specific airway resistance; TIO, tiotropium; mITT, modified intent-to-treat.

Table S3 Change from baseline pulmonary function tests (mITT population)

Time (minutes)	Day 1			Day 28
	0	120	240	0	120	240
FEV1
SFC250 + TIO		0.203 (0.0147)	0.216 (0.0147)	0.237 (0.0269)	0.328 (0.0176)	0.326 (0.0176)
TIO		0.170 (0.0147)	0.192 (0.0147)	0.076 (0.0269)	0.174 (0.0176)	0.170 (0.0176)
		0.085	0.222	<0.001	<0.001	<0.001
SFC250		0.194 (0.0147)	0.209 (0.0147)	0.134 (0.0269)	0.195 (0.0176)	0.189 (0.0177)
		0.645	0.728	0.008	<0.001	<0.001
FVC
SFC250 + TIO		0.269 (0.0290)	0.281 (0.0290)	0.265 (0.0403)	0.345 (0.0258)	0.319 (0.0258)
TIO		0.255 (0.0290)	0.233 (0.0290)	0.161 (0.0403)	0.253 (0.0258)	0.256 (0.0258)
		0.727	0.224	0.051	0.012	0.082
SFC250		0.291 (0.0290)	0.276 (0.0290)	0.117 (0.0403)	0.227 (0.0258)	0.153 (0.0261)
		0.578	0.902	0.006	0.001	<0.001
FEV1/FVC ratio
SFC250 + TIO		0.025 (0.0033)	0.026 (0.0033)	0.030 (0.0052)	0.049 (0.0039)	0.050 (0.0039)
TIO		0.016 (0.0033)	0.024 (0.0033)	0.003 (0.0052)	0.020 (0.0039)	0.016 (0.0039)
		0.036	0.674	<0.001	<0.001	<0.001
SFC250		0.021 (0.0033)	0.027 (0.0033)	0.022 (0.0052)	0.027 (0.0039)	0.032 (0.0039)
		0.327	0.870	0.223	<0.001	0.001
RV
SFC250 + TIO		−0.368 (0.0300)	−0.407 (0.0306)	−0.382 (0.0543)	−0.428 (0.0360)	−0.443 (0.0360)
TIO		−0.348 (0.0312)	−0.346 (0.0315)	−0.153 (0.0542)	−0.360 (0.0366)	−0.370 (0.0366)
		0.634	0.155	<0.001	0.183	0.158
SFC250		−0.373 (0.0303)	−0.466 (0.0299)	−0.193 (0.0533)	−0.326 (0.0355)	−0.355 (0.0355)
		0.906	0.158	0.003	0.045	0.082
TGV
SFC250 + TIO		−0.274 (0.0259)	−0.333 (0.0265)	−0.210 (0.0414)	−0.317 (0.0262)	−0.396 (0.0262)
TIO		−0.307 (0.0270)	−0.291 (0.0273)	−0.118 (0.0414)	−0.274 (0.0267)	−0.319 (0.0267)
		0.384	0.268	0.085	0.249	0.039
SFC250		−0.296 (0.0262)	−0.424 (0.0259)	−0.119 (0.0405)	−0.242 (0.0259)	−0.314 (0.0259)
		0.559	0.014	0.083	0.043	0.026
IC
SFC250 + TIO		0.142 (0.0239)	0.189 (0.0244)	0.043 (0.0415)	0.176 (0.0257)	0.241 (0.0257)
TIO		0.180 (0.0250)	0.176 (0.0253)	0.051 (0.0414)	0.120 (0.0262)	0.158 (0.0262)
		0.269	0.714	0.890	0.133	0.025
SFC250		0.174 (0.0242)	0.229 (0.0239)	0.051 (0.0405)	0.118 (0.0254)	0.144 (0.0254)
		0.347	0.249	0.890	0.112	0.008
TLC
SFC250 + TIO		−0.140 (0.0226)	−0.149 (0.0230)	−0.168 (0.0395)	−0.142 (0.0250)	−0.156 (0.0250)
TIO		−0.125 (0.0235)	−0.113 (0.0238)	−0.068 (0.0394)	−0.152 (0.0255)	−0.160 (0.0255)
		0.637	0.275	0.055	0.763	0.919
SFC250		−0.115 (0.0228)	−0.191 (0.0225)	−0.064 (0.0386)	−0.121 (0.0247)	−0.170 (0.0247)
		0.426	0.195	0.044	0.554	0.706
IC/TLC ratio
SFC250 + TIO		0.028 (0.0032)	0.036 (0.0033)	0.015 (0.0052)	0.033 (0.0033)	0.044 (0.0033)
TIO		0.033 (0.0033)	0.032 (0.0034)	0.010 (0.0052)	0.027 (0.0034)	0.033 (0.0034)
		0.248	0.357	0.475	0.213	0.017
SFC250		0.032 (0.0032)	0.045 (0.0032)	0.010 (0.0051)	0.024 (0.0033)	0.031 (0.0033)
		0.370	0.040	0.462	0.063	0.005

Notes: Values in the table are given as adjusted mean (standard error). P-values (if present) represent treatment difference.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IC, inspiratory capacity; RV, residual volume; TGV, thoracic gas volume; TIO, tiotropium; TLC, total lung capacity; mITT, modified intent-to-treat.

Table S4 Postdose raw mean (standard deviation) pulmonary function test values (mITT population)

Time (minutes)	Day 1			Day 28
	0	120	240	0	120	240
FEV1
SFC250 + TIO	1.522 (0.4462)	1.728 (0.4553)	1.741 (0.4582)	1.760 (0.5244)	1.856 (0.5040)	1.854 (0.5286)
TIO	1.523 (0.4750)	1.696 (0.4912)	1.718 (0.5029)	1.599 (0.4709)	1.703 (0.4614)	1.698 (0.4888)
SFC250	1.542 (0.4989)	1.731 (0.4859)	1.746 (0.4820)	1.676 (0.5301)	1.723 (0.5198)	1.712 (0.5248)
FVC
SFC250 + TIO	3.253 (0.6491)	3.532 (0.7369)	3.544 (0.7266)	3.520 (0.7388)	3.613 (0.7303)	3.588 (0.7214)
TIO	3.271 (0.6856)	3.526 (0.7176)	3.503 (0.7085)	3.431 (0.7062)	3.521 (0.6966)	3.524 (0.6929)
SFC250	3.284 (0.7293)	3.566 (0.7420)	3.550 (0.7273)	3.400 (0.7011)	3.496 (0.7395)	3.428 (0.7010)
FEV1/FVC ratio
SFC250 + TIO	0.471 (0.1139)	0.496 (0.1139)	0.497 (0.1134)	0.501 (0.1148)	0.519 (0.1154)	0.519 (0.1129)
TIO	0.467 (0.1174)	0.485 (0.1151)	0.493 (0.1162)	0.470 (0.1178)	0.489 (0.1168)	0.485 (0.1183)
SFC250	0.470 (0.1137)	0.491 (0.1165)	0.497 (0.1165)	0.492 (0.1159)	0.497 (0.1208)	0.499 (0.1122)
RV
SFC250 + TIO	3.477 (0.6932)	3.088 (0.5778)	3.035 (0.5362)	3.095 (0.6857)	2.989 (0.5587)	2.988 (0.5713)
TIO	3.421 (0.7140)	3.069 (0.5537)	3.032 (0.6173)	3.268 (0.6212)	3.051 (0.6197)	3.041 (0.6020)
SFC250	3.366 (0.7503)	3.021 (0.6078)	2.930 (0.5694)	3.200 (0.6806)	3.096 (0.6485)	3.068 (0.6568)
TGV
SFC250 + TIO	4.373 (0.7405)	4.084 (0.6667)	4.029 (0.7164)	4.141 (0.7349)	4.021 (0.7128)	3.954 (0.6936)
TIO	4.354 (0.8071)	4.033 (0.7088)	4.053 (0.7017)	4.239 (0.7256)	4.069 (0.7296)	4.024 (0.6820)
SFC250	4.336 (0.8103)	4.031 (0.6854)	3.918 (0.6980)	4.236 (0.7495)	4.111 (0.7311)	4.039 (0.7502)
IC
SFC250 + TIO	2.301 (0.5075)	2.441 (0.5534)	2.489 (0.5678)	2.378 (0.5455)	2.479 (0.6204)	2.532 (0.5926)
TIO	2.300 (0.5304)	2.459 (0.5717)	2.453 (0.6691)	2.341 (0.5843)	2.411 (0.5163)	2.461 (0.5153)
SFC250	2.274 (0.5455)	2.455 (0.5519)	2.510 (0.5604)	2.333 (0.5376)	2.414 (0.5339)	2.440 (0.5609)
TLC
SFC250 + TIO	6.673 (0.8505)	6.524 (0.8505)	6.517 (0.9140)	6.519 (0.9129)	6.500 (0.9169)	6.486 (0.9131)
TIO	6.653 (0.9622)	6.491 (0.9433)	6.505 (0.9839)	6.580 (0.9397)	6.479 (0.8901)	6.484 (0.8858)
SFC250	6.608 (0.9389)	6.486 (0.9174)	6.427 (0.8924)	6.569 (0.9356)	6.526 (0.9358)	6.477 (0.9443)
IC/TLC ratio
SFC250 + TIO	0.345 (0.0675)	0.374 (0.0675)	0.382 (0.0696)	0.365 (0.0672)	0.380 (0.0744)	0.390 (0.0699)
TIO	0.346 (0.0694)	0.378 (0.0671)	0.374 (0.0826)	0.355 (0.0686)	0.373 (0.0652)	0.380 (0.0609)
SFC250	0.345 (0.0716)	0.378 (0.0649)	0.390 (0.0681)	0.355 (0.0667)	0.370 (0.0643)	0.377 (0.0685)

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IC, inspiratory capacity; RV, residual volume; TGV, thoracic gas volume; SFC, salmeterol/fluticasone propionate; TIO, tiotropium; TLC, total lung capacity; mITT, modified intent-to-treat.