Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity

Figures & data

Figure 1 Patient disposition.

Abbreviation: AE, adverse event.

Table 1 Patient characteristics and demographics

Characteristic	Total (n=184)
Sex, n (%)
Male	165 (89.7)
Female	19 (10.3)
Age, years, mean (SD)	72.8 (7.1)
Weight, kg, mean (SD)	58.7 (12.1)
Height, cm, mean (SD)	162.5 (7.1)
Body mass index, kg/m^2, mean (SD)	22.2 (4.0)
Smoking status, n (%)
Ex-smoker	152 (82.6)
Current smoker	32 (17.4)
Smoking history, pack-years, mean (SD)	61.0 (28.5)
Pulmonary function data, mean (SD)
FEV1 post-bronchodilator, L	1.228 (0.407)
FEV1 change from pre-bronchodilator, L	0.097 (0.103)
FEV1 % change from pre-bronchodilator	10.619 (11.215)
% Predicted normal FEV1a	52.629 (15.207)
FVC, L	2.952 (0.656)
FEV1/FVC, %	41.803 (10.685)
IC, L	1.822 (0.488)
SVC, L	2.879 (0.652)
FEV1 category, n (%)
GOLD 2 (≥50–<80%)	100 (54.3)
GOLD 3 (≥30–<50%)	68 (37.0)
GOLD 4 (<30%)	16 (8.7)
6MWT
Distance traveled, m	293.8 (93.3)
Patient discontinued, n (%)	20 (10.9)
SpO2 decrease <83%,b n (%)	56 (30.4)
6MWT stopped prematurely, n (%)	52 (28.3)
SpO2 (before exercise)	94.0 (2.32)
SpO2 (end of exercise)	88.4 (5.11)
SpO2 at 5 min after	94.8 (2.33)
Pulse rate, bpm (before exercise)	75.4 (11.9)
Pulse rate, bpm (end of exercise)	97.2 (14.7)
Pulse rate at 5 min after, bpm	77.1 (13.0)
Average daily duration of METs, mean (SD)
≥2 METs, min	181.4 (82.0)
≥3 METs, min	47.4 (30.2)
≥4 METs, min	10.7 (10.8)
Average daily active strength of ≥3 METs (min METs), mean (SD)	157.0 (101.1)
mMRC dyspnea score, mean (SD)	1.9 (0.7)
CAT total score, mean (SD)	16.6 (7.5)
Concomitant therapy at baseline, n (%)
LAMA	119 (64.7)
LABA	11 (6.0)
ICS/LABA	8 (4.3)
ICS/LAMA	38 (20.7)
LAMA/LABA	0 (0.0)
LAMA/LABA/ICS	0 (0.0)

Notes:

a Based on predicted values defined by the European Community for Steel and Coal.

b Including two missing data.

Abbreviations: 6MWT, 6-min walk test; bpm, beats per minute; CAT, COPD assessment test; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroid; LABA, long-acting beta-2-agonist; LAMA, long-acting muscarinic antagonist; METs, metabolic equivalents; mMRC, modified Medical Research Council; SpO₂, oxygen saturation by pulse oximetry; SVC, slow vital capacity.

Figure 2 IC and lung function parameters after 6 weeks of treatment with T or T/O.

Notes: (A) IC 60 min post-dose. (B) FVC 30 min post-dose. (C) FEV₁ in 1 s 30 min post-dose. (D) SVC 60 min post-dose.
Abbreviations: FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; IC, inspiratory capacity; SVC, slow vital capacity; T, tiotropium; T/O, tiotropium/olodaterol.

Figure 3 6MWD after 6 weeks of treatment with T or T/O.

Notes: (A) Overall population. (B) GOLD III/IV patients. (C) Six-minute walk test completers.
Abbreviations: 6MWD, 6-min walk distance; GOLD, Global Initiative for Chronic Obstructive Lung Disease; T, tiotropium; T/O, tiotropium/olodaterol.

Figure 4 Physical activity after 6 weeks of treatment with T or T/O, excluding individuals with <8 hours wearing time or less than 2 valid days.

Notes: (A) Average daily duration of activity ≥2 METs. (B) Average number of steps per day.
Abbreviations: METs, metabolic equivalents; T, tiotropium; T/O, tiotropium/olodaterol.

Table 2 Adverse events

Adverse event	T 5 μg, (n=182)	T/O 5/5 μg, (n=180)
AEs, n (%)
Any AE	63 (34.6)	68 (37.8)
Severe AEs	3 (1.6)	4 (2.2)
Drug-related AEa	8 (4.4)	6 (3.3)
AEs leading to discontinuation	3 (1.6)	1 (0.6)
AEs with an incidence ≥2%
Viral upper respiratory tract infection	11 (6.0)	18 (10.0)
Worsening COPD	9 (4.9)	9 (5.0)
Worsening bronchitis	3 (1.6)	3 (1.7)
Fall	1 (0.5)	5 (2.8)
Pneumonia	3 (1.6)	1 (0.6)
Hyperuricemia	1 (0.5)	3 (1.7)
Thirst	1 (0.5)	3 (1.7)

Note:

a Investigator determined.

Abbreviations: AE, adverse event; T, tiotropium; T/O, tiotropium/olodaterol.

Table S1 Investigator, site, and IRB list

Investigator name	Site name (location)	IRB (location)	Approval number (date)
Hataji, Osamu	Matsusaka City Hospital (Matsusaka, Mie, Japan)	Same as on the left	(22 Dec 2015)a
Higashimoto, Yuji	Kindai University Hospital (Osakasayama, Osaka, Japan)	Same as on the left	1724 (22 Dec 2015)a
Kondoh, Yasuhiro	Tosei General Hospital (Seto, Aichi, Japan)	Same as on the left	H271104Ba679+BI1744 (24 Nov 2015)a
Suzuki, Masaru	Hokkaido University Hospital (Sapporo, Hokkaido, Japan)	Same as on the left	15066 (15 Dec 2015)
Ohbayashi, Hiroyuki	Tohno Chuo Clinic (Mizunami, Gifu, Japan)	Shinagawa East One Medical Clinic (Minato-ku, Tokyo, Japan)	(14 Dec 2015)a
Saito, Takefumi	NHO Ibarakihigashi National Hospital (Naka-gun, Ibaraki, Japan)	Same as on the left	(18 Dec 2015)a
Asai, Kazuhisa	Osaka City University Hospital (Osaka, Osaka, Japan)	Same as on the left	(17 Dec 2015)a
Miura, Motohiko	Japan Organization of Occupational Health and Safety Tohoku Rosai Hospital (Sendai, Miyagi, Japan)	Same as on the left	15A012a (17 Dec 2015)
Miyao, Naoki	Medical Corporation Kokankai Kokan Clinic (Kawasaki, Kanagawa, Japan)	Nihon Kokan Hospital (Kawasaki, Kanagawa, Japan)	(03 Dec 2015)a
Nagashima, Hirotaka	Shinjuku Research Park Clinic (Shinjuku-ku, Tokyo, Japan)	Tokyo-Eki Center-building Clinic (Chuo-ku, Tokyo, Japan)	427200-20151211 (11 Dec 2015)
Sugiura, Hisatoshi	Tohoku University Hospital (Sendai, Miyagi, Japan)	Same as on the left	151031 (21 Dec 2015)
Harada, Toshiyuki	Japan Community Health Care Organization Hokkaido Hospital (Sapporo, Hokkaido, Japan)	Same as on the left	(10 Dec 2015)a
Hiramatsu, Tetsuo	Hiramatsu Internal and Respiratory Medicine Clinic (Komaki, Aichi, Japan)	Shinagawa East One Medical Clinic (Minato-ku, Tokyo, Japan)	(14 Dec 2015)a
Tsuchiya, Michiko	Rakuwakai Otowa Hospital (Kyoto, Kyoto, Japan)	Same as on the left	1509 (11 Dec 2015)
Kinoshita, Takashi	Kurume University Hospital (Kurume, Fukuoka, Japan)	Same as on the left	215039 (18 Feb 2016)
Tsuda, Tohru	Kirigaoka Tsuda Hospital (Kitakyushu, Fukuoka, Japan)	Same as on the left	(15 Dec 2015)a
Muro, Shigeo	Kyoto University Hospital (Kyoto, Kyoto, Japan)	Same as on the left	1749 (13 Jan 2016)
Utsumi, Yu	Iwate Medical University Hospital (Morioka, Iwate, Japan)	Same as on the left	215041 (16 Dec 2015)
Ichiwata, Toshio	Tokyo Medical University Hachioji Medical Center (Hachioji, Tokyo, Japan)	Same as on the left	(29 Jan 2016)a
Kaneko, Masahiro	Kobe City Hospital Organization Kobe City Medical Center West Hospital (Kobe, Hyogo, Japan)	Same as on the left	(14 Dec 2015)a
Samukawa, Takuya	Kagoshima University Hospital and Dental Hospital (Kagoshima, Kagoshima, Japan)	Same as on the left	15012 (16 Dec 2015)
Motegi, Takashi	Respiratory Care Clinic, Nippon Medical School (Chiyoda-ku, Tokyo, Japan)	Nihon Medical School (Bunkyo-ku, Tokyo, Japan)	127024 (08 Jan 2016)
Minakata, Yoshiaki	NHO Wakayama Hospital (Hidaka-gun, Wakayama, Japan)	Same as on the left	201502 (11 Dec 2015)
Fuke, Satoshi	KKR Sapporo Medical Center (Sapporo, Hokkaido, Japan)	Same as on the left	(04 Jan 2016)a
Kato, Motokazu	Kishiwada City Hospital (Kishiwada, Osaka, Japan)	Same as on the left	(19 Jan 2016)a
Gon, Yasuhiro	Nihon University Itabashi Hospital (Itabashi-ku, Tokyo, Japan)	Same as on the left	2712-1448 (18 Dec 2015)
Nagai, Atsushi	Shin-yurigaoka General Hospital (Kawasaki, Kanagawa, Japan)	Koyasu Neurosurgical Clinic (Yokohama, Kanagawa, Japan)	(25 Jan 2016)a
Harada, Hiromasa	Yao Tokushukai General Hospital (Yao, Osaka, Japan)	Tokushukai Group IRB (Chiyoda-ku, Tokyo, Japan)	004-15-02 (18 Dec 2015)
Tomii, Keisuke	Kobe City Medical Center General Hospital (Kobe, Hyogo, Japan)	Same as on the left	15–25 (15 Dec 2015)
Harada, Yasuko	Nishi Fukuoka Hospital (Fukuoka, Fukuoka, Japan)	Same as on the left	(17 Dec 2015)a
Saito, Masahiko	Uji Tokushukai Medical Center (Uji, Ktoto, Japan)	Tokushukai Group IRB (Chiyoda-ku, Tokyo, Japan)	007-15-12 (18 Dec 2015)
Sato, Tadashi	Juntendo University Hospital (Bunkyo-ku, Tokyo, Japan)	Same as on the left	2015-022 (25 Dec 2015)
Sagara, Hironori	Showa University Hospital (Shinagawa-ku, Tokyo, Japan)	Same as on the left	1511022 (201501) (08 Jan 2016)
Nakamura, Hiroyuki	Sakaide City Hospital (Sakaide, Kagawa, Japan)	Same as on the left	(22 Jan 2016)a
Shikama, Yusuke	Showa University Fujigaoka Hospital (Yokohama, Kanagawa, Japan)	Same as on the left	2015100 (08 Jan 2016)
Osaki, Shinichi	Osaki Internal and Respiratory Clinic (Kitakyushu, Fukuoka, Japan)	Hoshikuma Hihuka Allergy Clinic (Fukuoka, Fukuoka, Japan)	(22 Dec 2015)a
Nishimura, Koichi	National Center for Geriatrics and Gerontology (Obu, Aichi, Japan)	Same as on the left	15108 (01 Feb 2016)
Koba, Hiroyuki	Teine Keijinkai Clinic (Sapporo, Hokkaodo, Japan)	Same as on the left	TKC2016-01 (12 Feb 2016)
Miki, Keisuke	NHO Toneyama National Hospital (Toyonaka, Osaka, Japan)	Same as on the left	27–52 (29 Feb 2016)
Mizobe, Yuriko	Nihonbashi Sakura Clinic (Chuo-ku, Tokyo, Japan)	Same as on the left	(29 Jan 2016)a
Onari, Yojiro	Mazda Hospital (Aki-gun, Hiroshima, Japan)	Koyasu Neurosurgical Clinic (Yokohama, Kanagawa, Japan)	(29 Aug 2016)a
Hayakawa, Hiroshi	NHO Tenryu Hospital (Hamamatsu, Shizuoka, Japan)	Same as on the left	(14 Sept 2016)a
Kawamura, Tetsuji	NHO Himeji Medical Center (Himeji, Hyogo, Japan)	Same as on the left	321 (07 Oct 2016)
Isobe, Takeshi	Shimane University Hospital (Izumo, Shimane, Japan)	Same as on the left	28-8 (15 Sept 2016)

Note:

a No reference number on the approval letter from IRB.

Abbreviation: IRB, institutional review board.

Table S2 Treatment difference between tiotropium/olodaterol and tiotropium by GOLD stage subgroup

	Treatment	n	Adjusted mean (SE) 6MWDa	Adjusted mean change from baseline (SE) in 6MWDa	Comparison vs T 5 μg
					Adjusted mean of difference (SE)a	95% CI	p-value
GOLD II	T 5 μg	97	326.4 (6.7)	11.7 (6.7)	−5.4 (6.9)	(−19.0, 8.2)	0.4349
	T/O 5/5 μg	96	321.0 (6.7)	6.3 (6.7)
GOLD III	T 5 μg	65	294.4 (9.3)	15.7 (9.3)	16.9 (9.2)	(−1.5, 35.3)	0.0714
	T/O 5/5 μg	66	311.3 (9.3)	32.6 (9.3)
GOLD IV	T 5 μg	16	239.4 (16.0)	3.8 (16.0)	21.2 (15.9)	(−13.0, 55.4)	0.2048
	T/O 5/5 μg	16	260.6 (16.0)	24.9 (16.0)

Notes:

a The adjusted mean values (SE) are obtained from fitting an MMRM model including treatment and period as categorical fixed effects, study baseline as a covariate, and patient as a random effect.

Abbreviations: 6MWD, 6-min walk distance; GOLD, Global Initiative for Chronic Obstructive Lung Disease; MMRM, mixed-effects model repeated measures; O, olodaterol; SE, standard error; T, tiotropium; T/O, tiotropium/olodaterol.