supplementary appendix - the lancet appendix. ... bumbacea, roxana silvia; dantes, elena; mihaescu,...

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Kerstjens HAM, Casale TB, Bleecker ER, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med 2015; published online Feb 12. http://dx.doi.org/10.1016/S2213-2600(15)00031-4.

1

Supplementary data

List of trial investigators

Trial 205.418 (trial 1)

Brazil

Adalberto, Rubin; Fritscher, Carlos Cezar; Mattos, Waldo; Oliveira, Julio Cesar Abreu

China

Bai, Chunxue; Chen, Ping; Chen, Ping; Du, Chunhua; Gao, Zhancheng; Kang, Jian; Li, Yali;

Lin, Jiangtao; Liu, Ao; Liu, Chuntao; Liu, Shuang; Tang, Yan; Wang, Changzheng; Wang,

Haoyan; Xiao, Zhenliang

Guatemala

Chur Gonzalez, Victor Hugo; Echeverria, Edgar Contreras; Flores Lopez, Jose Francisco;

Mejia, Jeremias Guerra; Morales, Gerardo Martinez

India

Jain, Manish; Kawedia, Mahendra; Krishnamurthy, Srikanth; Salvi, Sandeep; Santhalingam,

Balamurgan; Satish, KS; Vallandramam Ranganathan, Pattabbhi Raman; Waghray, Pradyut

Japan

Fukue, Masataka; Fukushima, Yasushi; Haida, Michiko; Harada, Hiromasa; Hiramatsu,

Tetsuo; Hori, Noriya; Ide, Yumiko; Kasai, Yoshihiko; Kita, Toshiyuki; Kiyokawa, Hiroshi;

Matsumura, Shinichiro; Murata, Akira; Nakamura, Harumichi; Nakamura, Kiyoshi;

Nakamura, Yoichi; Nakatani, Yuji; Ogawa, Jun-ichi; Oguri, Mitsuru; Ohtsuka, Yoshinori;

Omoto, Akiyoshi; Satoh, Hiroaki; Sekino, Hisakuni; Shibasaki, Atsushi; Takahashi,

Tsuneyuki; Tsukagoshi, Masaaki; Tsutahara, Shin; Ueda, Naohiko; Yamazaki, Hiroomi

Latvia

Babjoniseva, Aurika; Bukovskis, Maris; Iesalniece, Rita; Remberga, Silvija; Reznikova,

Svetlana; Smiltena, Inese

Mexico

Castanon, Jesus Javier; Galindo Galindo, Juan

Peru

Hinojosa, Efrain Ciro Felix; Ore, Danilo Salazar

Poland

Asankowicz-Bargiel, Beata; Cieslak, Malgorzata; Hofman, Teresa; Kuna, Piotr; Pulka,

Grazyna

2

Russia

Alekseeva, Elena; Emelyanov, Alexander; Esip, Valeria; Goryachkina, Ludmila A;

Sidorenko, Irina; Trofimov, Vasilij

USA

Berger, William; Bleecker, Eugene; Casale, Thomas; Covelli, Henry; Finn, Jr, Albert; Ford,

Linda; Gross, Gary; Harris III, James; Kahlstrom, Richard; Kaiser, Harold; Koser, Andras;

Lapidus, Robert; Matz, Jonathan; Mello, Curtis; Meltzer, Eli; Miller, David; Murphy, Kevin;

Nayak, Anjuli; Reyes, Santiago; Tilles, Stephen; Weinstein, Steven

Trial 205.419 (trial 2)

Brazil

Castro, Fabio; Neis, Marcio Abreu; Oliveira, Maria Eunice M; Pizzichini, Emilio

China

Chen, Zhengxian; Cui, Shehuai; Hao, Qinglin; Huang, Yijiang; Jin, Faguang; Liang, Yongjie;

Lin, Yong; Liu, Jinming; Liu, Yuejian; Wan, Huanying; Wu, Changgui; Xie, Canmao;

Zhang, Jin; Zhang, Wei; Zhu, Huili; Zhu, Muyun; Zhu, Shuyang

Colombia

Aguirre, Carlos; Alvarado Castillo, Jaime Andres; Giraldo, Horacio

Germany

Arievich, Helen; Beck, Ekkehard; Beeh, Kai-Michael; Büttner, Claudia; Eich, Andreas;

Franz, Karl-Heinz; Linnhoff, Anneliese; Ludwig-Sengpiel, Andrea; Schenkenberger,

Isabelle; Schmidt, Olaf; Schultz, Thomas; Wagner, Norbert; Zemke, Katrin

India

Bhagat, Raj; Bhide, Mugdha; Gopal, V Nanda; Malpani, Ashish; Pudukudru Anand, Mahesh;

Sarna, Mukesh Kumar; Swarnakar, Rajesh

Japan

Ando, Koichi; Doi, Masao; Harada, Yasuko; Harita, Shingo; Hashimoto, Shu; Ishigaki,

Masanobu; Karimata, Youichi; Kato, Motokazu; Kim, Hyeteok; Koizumi, Makoto;

Minamoto, Seijiro; Nakamura, Hiroshi; Nishimura, Naoki; Oida, Motoi; Saito, Takefumi;

Sakaguchi, Sachiyo; Senoo, Kanehito; Shimoda, Terufumi; Shimura, Sanae; Shioda,

Masahiko; Sugihara, Naruhiko; Sugino, Yasuteru; Suzuki, Yukio; Tajima, Kahoru;

Taniguchi, Hiroyuki; Tomii, Keisuke; Ueyama, Shigehiro; Watanabe, Kazuyoshi;

Yamaguchi, Munehiro; Yamauchi, Kohei; Yasuda, Kazumasa

3

Mexico

Chavira, Maria del Rosario; Mier, Guillermo

Peru

Antunez, Javier Anselmo Jauregui; Fuchigami, Alberto Matsuno; Guerreros Benavides,

Alfredo Gilberto; Tsukayama Kikumoto, Miguel

Poland

Dobryniewska, Malgorzata; Galaj, Andrzej; Jasieniak-Pinis, Grazyna; Mroz, Robert Marek;

Pisarczyk-Bogacka, Ewa; Waszkuc-Golonko, Joanna

Romania

Agache, Iona Octavia; Alexandrescu, Dana Sorina; Bumbacea, Roxana Silvia; Dantes, Elena;

Mihaescu, Traian; Mocanescu, Daniela; Nicolau, Adriana Veronica; Tanaseanu, Cristina

Mihaiela; Toma, Claudia Lucia; Tudose, Cornelia Elena

USA

Andrews, Charles; Bensch, George; Berman, Gary; Bernstein, Jonathan; Boscia, III, Joseph;

Corren, Jonathan; Dunn, Karen; Fakih, Faisal; Greos, Leon; Korenblat, Phillip; Mansfield,

Lyndon; Moriarity, Timothy; Noonan, Michael; Pearlman, David; Pedinoff, Andrew; Rowe,

Michael; Walker, Robert; Wanderer, Alan

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Supplementary tables

Table S1. Baseline demographics and disease characteristics by trial

Trial 1 Trial 2

Characteristic Total

(N=1070)

Tiotropium

Respimat®

5 µg

(n=264)

Tiotropium

Respimat®

2·5 µg

(n=262)

Placebo

(n=269)

Salmeterol

HFA-MDI

(n=275)

Total

(N=1030)

Tiotropium

Respimat®

5 µg

(n=253)

Tiotropium

Respimat®

2·5 µg

(n=257)

Placebo

(n=254)

Salmeterol

HFA-MDI

(n=266)

Gender, n (%)

Female 635 (59·3) 154 (58·3) 156 (59·5) 166 (61·7) 159 (57·8) 604 (58·6) 146 (57·7) 160 (62·3) 145 (57·1) 153 (57·5)

Age, yearsa 43·3 ± 12·9 44·4 ± 12·6 43·7 ± 13·1 42·5 ± 13·1 42·6 ± 12·6 42·9 ± 12·9 44·3 ± 12·7 43·0 ± 12·6 43·0 ± 13·0 41·5 ± 13·1

Body mass index, kg/m2 a 26·9 ± 6·1 27·1 ± 6·1 26·9 ± 6·3 26·7 ± 6·0 26·8 ± 6·2 26·8 ± 6·3 27·1 ± 6·5 26·3 ± 5·9 27·3 ± 6·6 26·6 ± 6·4

Smoking status, n (%)

Never smoked 923 (86·3) 225 (85·2) 224 (85·5) 241 (89·6) 233 (84·7) 833 (80·9) 195 (77·1) 213 (82·9) 212 (83·5) 213 (80·1)

Ex-smoker 147 (13·7) 39 (14·8) 38 (14·5) 28 (10·4) 42 (15·3) 197 (19·1) 58 (22·9) 44 (17·1) 42 (16·5) 53 (19·9)

Smoking history, pack-yearsa,b 4·28 ± 2·71 4·45 ± 2·59 3·96 ± 2·81 4·59 ± 2·59 4·22 ± 2·86 4·13 ± 2·88 4·53 ± 3·31 4·05 ± 2·98 3·84 ± 2·47 3·98 ± 2·62

Duration of asthma, yearsa 21·7 ± 14·2 22·9 ± 14·7 22·2 ± 14·1 20·2 ± 13·4 21·4 ± 14·5 21·8 ± 14·5 23·1 ± 15·3 21·9 ± 14·5 22·0 ± 13·9 20·4 ± 14·1

Age at onset of asthmaa 21·6 ± 12·9 21·6 ± 12·9 21·5 ± 13·4 22·3 ± 12·9 21·2 ± 12·7 21·1 ± 12·5 21·2 ± 12·7 21·1 ± 12·8 21·0 ± 12·4 21·1 ± 12·2

Total ACQ-7 scorea,c 2·18 ± 0·47 2·23 ± 0·45 2·18 ± 0·51 2·16 ± 0·45 2·15 ± 0·45 2·18 ± 0·51 2·19 ± 0·54 2·16 ± 0·47 2·21 ± 0·55 2·16 ± 0·49

AQLQ scorea,c 4·85 ± 0·92 4·79 ± 0·93 4·87 ± 0·91 4·83 ± 0·92 4·89 ± 0·91 4·80 ± 0·91 4·75 ± 0·97 4·78 ± 0·88 4·87 ± 0·90 4·79 ± 0·88

FEV1, meana

Pre-bronchodilationc 2·2 ± 0·6 2·2 ± 0·6 2·2 ± 0·7 2·3 ± 0·7 2·3 ± 0·6 2·3 ± 0·7 2·3 ± 0·6 2·3 ± 0·7 2·3 ± 0·7 2·4 ± 0·7

% of predicted value before bronchodilation

72·8 ± 8·4 72·2 ± 8·2 73·1 ± 8·6 73·0 ± 8·2 72·8 ± 8·5 72·7 ± 8·2 72·2 ± 8·3 72·5 ± 8·0 73·0 ± 8·4 73·1 ± 8·1

5

% of predicted value after

bronchodilation

89·2 ± 11·3 87·7 ± 11·1 90·2 ± 11·8 89·5 ± 10·4 89·3 ± 11·9 88·5 ± 10·9 87·4 ± 11·4 88·9 ± 10·4 88·7 ± 10·6 88·9 ± 11·1

Reversibility, mL 488 ± 245 459 ± 234 508 ± 254 488 ± 232 498 ± 258 477 ± 234 453 ± 218 495 ± 249 471 ± 215 489 ± 249

% reversibility over pre-

bronchodilator value

22·8 ± 10·7 21·7 ± 9·7 23·7 ± 11·0 22·9 ± 9·8 22·9 ± 12·0 22·0 ± 10·2 21·3 ± 10·5 23·0 ± 10·7 21·7 ± 9·3 21·8 ± 10·2

FVC, bronchodilation, La,c 3·4 ± 0·9 3·4 ± 1·0 3·4 ± 0·9 3·4 ± 0·9 3·5 ± 0·9 3·5 ± 0·9 3·4 ± 1·0 3·5 ± 0·9 3·5 ± 1·0 3·5 ± 0·9

Use of ICSc, n (%) 1069 (99·9) 264 (100) 262 (100) 269 (100) 274 (99·6) 1030 (100) 253 (100) 257 (100) 254 (100) 266 (100)

ICS dose of stable maintenance treatment, μga,c

658·6 ± 203·7

666·4 ± 216·2

649·8 ± 196·2

661·5 ± 209·5

656·7 ± 193·1

660·7 ± 222·0

661·3 ± 216·1

662·1 ± 229·5

675·6 ± 225·4

644·7 ± 217·2

Use of OCSc, n (%) 1 (0·1) 0 0 0 1 (0·4) 2 (0·2) 0 1 (0·4) 0 1 (0·4)

Use of anticholinergicsc, n (%) 4 (0·4) 1 (0·4) 2 (0·8) 0 1 (0·4) 3 (0·3) 1 (0·4) 2 (0·8) 0 0

Use of LABAsc, n (%) 1 (0·1) 1 (0·4) 0 0 0 1 (0·1) 0 0 1 (0·4) 0

Use of leukotriene modifiersc, n (%) 104 (9·7) 28 (10·6) 23 (8·8) 26 (9·7) 27 (9·8) 79 (7·7) 17 (6·7) 25 (9·7) 17 (6·7) 20 (7·5)

All measurements taken at screening visit unless otherwise stated. aValues are mean ± standard deviation; bIn ex-smokers only; bcTaken at randomisation ACQ-7, seven-question Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HFA-MFI, hydrofluoroalkane metered-dose inhaler; ICS, inhaled corticosteroids;

OCS, oral corticosteroids

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Table S2. Medications reported during study treatment phase (temporary or regular use)

Trial 1 Trial 2

Characteristic, n (%) Total

(N=1070)

Tiotropium

Respimat®

5 µg

(n=264)

Tiotropium

Respimat®

2·5 µg

(n=262)

Placebo

(n=269)

Salmeterol

HFA-MDI

(n=275)

Total

(N=1030)

Tiotropium

Respimat®

5 µg

(n=253)

Tiotropium

Respimat®

2·5 µg

(n=257)

Placebo

(n=254)

Salmeterol

HFA-MDI

(n=266)

Glucocorticosteroids 1068 (99·8) 264 (100) 262 (100) 268 (99·6) 274 (99·6) 1030 (100) 253 (100) 257 (100) 254 (100) 266 (100)

Inhaled 1068 (99·8) 264 (100) 262 (100) 268 (99·6) 274 (99·6) 1030 (100) 253 (100) 257 (100) 254 (100) 266 (100)

Oral 64 (6·0) 17 (6·4) 10 (3·8) 19 (7·1) 18 (6·5) 67 (6·5) 14 (5·5) 15 (5·8) 21 (8·3) 17 (6·4)

Intravenous/intramuscular 19 (1·8) 3 (1·1) 3 (1·1) 9 (3·3) 4 (1·5) 29 (2·8) 6 (2·4) 5 (1·9) 8 (3·1) 10 (3·8)

Intranasal 81 (7·6) 17 (6·4) 19 (7·3) 25 (9·3) 20 (7·3) 102 (9·9) 20 (7·9) 28 (10·9) 24 (9·4) 30 (11·3)

Other 17 (1·6) 5 (1·9) 3 (1·1) 3 (1·1) 6 (2·2) 28 (2·7) 6 (2·4) 7 (2·7) 6 (2·4) 9 (3·4)

Use of anticholinergics 12 (1·1) 3 (1·1) 4 (1·5) 3 (1·1) 2 (0·7) 19 (1·8) 3 (1·2) 6 (2·3) 4 (1·6) 6 (2·3)

Use of LABAs 55 (5·1) 15 (5·7) 13 (5·0) 12 (4·5) 15 (5·5) 79 (7·7) 17 (6·7) 18 (7·0) 24 (9·4) 20 (7·5)

Use of leukotriene modifiers 113 (10·6) 31 (11·7) 23 (8·8) 29 (10·8) 30 (10·9) 84 (8·2) 18 (7·1) 25 (9·7) 19 (7·5) 22 (8·3)

Treated set HFA-MFI, hydrofluoroalkane metered-dose inhaler; LABA, long-acting β2-agonist

7

Table S3. Exploratory analyses of adjusted mean difference from salmeterol in lung function responses at Week 24

Total population Trial 1 Trial 2

Active versus salmeterol Active versus salmeterol Active versus salmeterol

End point Treatment N Adjusted mean difference

(95% CI)

N Adjusted mean difference

(95% CI)

N Adjusted mean difference

(95% CI)

FEV1 Peak FEV1(0–3h), mL

Trough FEV1, mL

Tiotropium Respimat® 5 µg

Tiotropium Respimat® 2·5 µg



481

492

481

492

−120 (−50–27)

27 (−11–65)

32 (−9–73)

65 (24–106)

241

247

241

247

−15 (−70–40)

23 (−32–78)

29 (−30–88)

62 (3–121)

240

245

240

245

−8 (−60–45)

35 (−17–87)

27 (−30–83)

70 (14–126)

FVC Peak FVC(0–3h), mL

Trough FVC, mL





481

492

481

492

−26 (−68–16)

20 (−22–62)

12 (−32–57)

39 (−5–84)

241

247

241

247

−20 (−80–39)

51 (−8, 110)

8 (−55–72)

58 (−5–121)

240

245

240

245

−28 (−86–31)

−6 (−64–51)

15 (−47–77)

19 (−43–81)

PEF Morning, L/mina

Evening, L/mina





472

485

472

483

−0·5 (−6·8–5·8)

0·6 (−5·7–6·9)

2·4 (−3·8–8·7)

1·4 (−4·9–7·6)

236

247

236

245

−9·0 (−17·8–−0·2)

−2·0 (−10·8–6·7)

−4·5 (−13·2–4·1)

−0·7 (−9·4–7·9)

236

238

236

238

7·7 (−1·0–16·5)

3·6 (−5·1–12·3)

9·6 (0·7–18·4)

4·3 (−4·5–13·1)

Full analysis set aWeekly mean for Week 24

CI, confidence interval; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; peak FEV1(0–3h), peak FEV1 response measured within the first 3 hours after evening dosing; PEF, peak expiratory flow

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Table S4. Exploratory analysis of ACQ-7 responder rate compared with salmeterol at Week 24

End point


(n=513)


(n=515)

HR (95% CI)a HR (95% CI)a

ACQ-7 responder rate 0·91 (0·70–1·18) 0·91 (0·70–1·19)

aActive treatment versus salmeterol

ACQ-7, seven-question Asthma Control Questionnaire; CI, confidence interval; HR, hazard ratio

9

Table S5. Post hoc analyses of Asthma Control Questionnaire responder rate at Week 24

End point Patients Tiotropium Respimat® 5 µg

(n=513)


(n=515)

Salmeterol HFA-MDI

(n=535)

Placebo

(n=518)

ACQ-5 Responder, n (%) 347 (67·6) 341 (66·2) 378 (70·7) 332 (64·1)

No change, n (%) 146 (28·5) 154 (29·9) 133 (24·9) 145 (28·0)

Worsening, n (%) 20 (3·9) 20 (3·9) 24 (4·5) 41 (7·9)

Net response rate, n (%) 327 (63·7) 321 (62·3) 354 (66·2) 291 (56·2)

p valuea 0·12 0·26 0·013

ACQ-6 Responder, n (%) 360 (70·2) 354 (68·7) 391 (73·1) 337 (65·1)

No change, n (%) 129 (25·1) 138 (26·8) 121 (22·6) 137 (26·4)

Worsening, n (%) 24 (4·7) 23 (4·5) 23 (4·3) 44 (8·5)

Net response rate, n (%) 336 (65·5) 331 (64·2) 368 (68·8) 293 (56·6)

p valuea 0·042 0·11 0·0022

Full analysis set. Wilcoxon rank sum test aActive treatment versus placebo ACQ-5, five-question Asthma Control Questionnaire; ACQ-6, six-question Asthma Control Questionnaire; HFA-MDI, hydrofluoroalkane metered-dose inhaler

10

Table S6. Analysis of time to first severe asthma exacerbation and asthma worsening

End point


(n=513)


(n=515)

Salmeterol HFA-MDI

(n=535)

HR (95% CI)a p value HR (95% CI)a p value HR (95% CI)a p value

Time to first severe asthma exacerbation 0·72 (0·45–1·14) 0·16 0·50 (0·30–0·84) 0·0084 0·75 (0·48–1·18) 0·21

Time to first asthma worsening 0·87 (0·69–1·09) 0·22 0·66 (0·52–0·84) 0·0007 0·75 (0·60–0·94) 0·013

aActive treatment versus placebo CI, confidence interval; HFA-MFI, hydrofluoroalkane metered-dose inhaler; HR, hazard ratio

11

Table S7. Exploratory analyses of time to first severe asthma exacerbation and asthma worsening compared with salmeterol over 48 weeks

End point


(n=513)


(n=515)

HR (95% CI)a HR (95% CI)a

Time to first severe asthma exacerbation 0·96 (0·59–1·56) 0·67 (0·39–1·14)

Time to first asthma worsening 1·16 (0·91–1·46) 0·88 (0·69–1·13)

aActive treatment versus salmeterol CI, confidence interval; HR, hazard ratio

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Table S8. Exploratory analysis of adjusted mean difference from salmeterol in Asthma Quality of Life Questionnaire score responses at Week 24

Total population

Active versus salmeterol

End point Treatment N Adjusted mean difference (95% CI)

Asthma Quality of Life Questionnaire Tiotropium Respimat® 5 µg


482

491

−0·109 (−0·204–−0·015)

−0·107 (−0·201–−0·013)

Full analysis set CI, confidence interval

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Table S9A. Adverse events by trial: trial 1

Trial 1

n (%) Total

(N=1070)


(n=264)


(n=262)

Placebo

(n=269)

Salmeterol HFA-MDI

(n=275)

Patients with any adverse event 591 (55·2) 148 (56·1) 139 (53·1) 160 (59·5) 144 (52·4)

Asthma 207 (19·3) 60 (22·7) 36 (13·7) 59 (21·9) 52 (18·9)

Cough 13 (1·2) 4 (1·5) 4 (1·5) 3 (1·1) 2 (0·7)

Rhinitis allergic 12 (1·1) 4 (1·5) 4 (1·5) 2 (0·7) 2 (0·7)

Oropharyngeal pain 8 (0·7) 4 (1·5) 3 (1·1) 0 1 (0·4)

Nasopharyngitis 78 (7·3) 22 (8·3) 18 (6·9) 22 (8·2) 16 (5·8)

Upper respiratory tract infection 67 (6·3) 7 (2·7) 16 (6·1) 19 (7·1) 25 (9·1)

Sinusitis 23 (2·1) 5 (1·9) 7 (2·7) 4 (1·5) 7 (2·5)

Bronchitis 19 (1·8) 7 (2·7) 4 (1·5) 3 (1·1) 5 (1·8)

Respiratory tract infection 13 (1·2) 4 (1·5) 1 (0·4) 4 (1·5) 4 (1·5)

Pharyngitis 10 (0·9) 1 (0·4) 4 (1·5) 3 (1·1) 2 (0·7)

Urinary tract infection 10 (0·9) 4 (1·5) 2 (0·8) 2 (0·7) 2 (0·7)

Decreased peak expiratory flow rate 142 (13·3) 34 (12·9) 28 (10·7) 51 (19·0) 29 (10·5)

Headache 15 (1·4) 3 (1·1) 7 (2·7) 5 (1·9) 0

Hypertension 13 (1·2) 2 (0·8) 6 (2·3) 3 (1·1) 2 (0·7)

Adverse events in the treated set (described by preferred term) that were reported for ≥1·5% of patients in any treatment group HFA-MFI, hydrofluoroalkane metered-dose inhaler

14

Table S9B. Adverse events by trial: trial 2

Trial 2

n (%) Total

(N=1030)


(n=253)


(n=257)

Placebo

(n=254)

Salmeterol HFA-MDI

(n=266)

Patients with any adverse event 610 (59·2) 148 (58·5) 163 (63·4) 149 (58·7) 150 (56·4)

Nasopharyngitis 101 (9·8) 19 (7·5) 31 (12·1) 26 (10·2) 25 (9·4)

Upper respiratory tract infection 61 (5·9) 12 (4·7) 11 (4·3) 22 (8·7) 16 (6·0)

Pharyngitis 21 (2·0) 8 (3·2) 6 (2·3) 2 (0·8) 5 (1·9)

Sinusitis 16 (1·6) 3 (1·2) 6 (2·3) 2 (0·8) 5 (1·9)

Bronchitis 15 (1·5) 4 (1·6) 5 (1·9) 2 (0·8) 4 (1·5)

Urinary tract infection 11 (1·1) 4 (1·6) 2 (0·8) 3 (1·2) 2 (0·8)

Respiratory tract infection 11 (1·1) 4 (1·6) 3 (1·2) 3 (1·2) 1 (0·4)

Influenza 7 (0·7) 2 (0·8) 1 (0·4) 4 (1·6) 0

Acute sinusitis 8 (0·8) 2 (0·8) 0 2 (0·8) 4 (1·5)

Gastroenteritis viral 4 (0·4) 4 (1·6) 0 0 0

Asthma 206 (20·0) 51 (20·2) 46 (17·9) 56 (22·0) 53 (19·9)

Oropharyngeal pain 16 (1·6) 6 (2·4) 5 (1·9) 4 (1·6) 1 (0·4)

Cough 15 (1·5) 6 (2·4) 4 (1·6) 2 (0·8) 3 (1·1)

Rhinitis allergic 13 (1·3) 1 (0·4) 5 (1·9) 2 (0·8) 5 (1·9)

Dysphonia 9 (0·9) 6 (2·4) 0 2 (0·8) 1 (0·4)

Decreased peak expiratory flow rate 92 (8·9) 25 (9·9) 21 (8·2) 28 (11·0) 18 (6·8)

15

Increased gamma-glutamyl transferase 8 (0·8) 4 (1·6) 2 (0·8) 0 2 (0·8)

Increased alanine aminotransferase 6 (0·6) 4 (1·6) 1 (0·4) 1 (0·4) 0

Headache 31 (3·0) 5 (2·0) 11 (4·3) 9 (3·5) 6 (2·3)

Thirst 14 (1·4) 6 (2·4) 2 (0·8) 2 (0·8) 4 (1·5)

Pyrexia 6 (0·6) 2 (0·8) 4 (1·6) 0 0

Ligament strain 5 (0·5) 4 (1·5) 0 0 0

Muscle spasms 8 (0·8) 4 (1·6) 2 (0·8) 1 (0·4) 1 (0·4)

Hypertension 12 (1·2) 2 (0·8) 4 (1·6) 1 (0·4) 5 (1·9)

Adverse events in the treated set (described by preferred term) that were reported for ≥1·5% of patients in any treatment group

HFA-MFI, hydrofluoroalkane metered-dose inhaler

16

Table S10A. Serious adverse events: trial 1

Trial 1

System organ class/

preferred term, n (%)

Screening

(n=1070)

Tiotropium

Respimat®

5 µg

(n=264)

Tiotropium

Respimat®

2·5 µg

(n=262)

Placebo

(n=269)

Salmeterol

HFA-MDI

(n=275)

Total

(treatment)

(n=1070)

Total

(post-treatment)

(n=1070)

Total

(study)

(N=1070)

Total with serious adverse events 2 (0·2) 4 (1·5) 5 (1·9) 10 (3·7) 7 (2·5) 26 (2·4) 0 28 (2·6)

Appendicitis 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Chikungunya virus infection 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Gastroenteritis 0 0 1 (0·4) 0 1 (0·4) 2 (0·2) 0 2 (0·2)

Peritonsillar abscess 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Pneumonia 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Pyelonephritis 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Urinary tract infection 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Acute myocardial infarction 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Atrial fibrillation 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Coronary artery disease 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Myocardial infarction 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Cerebrovascular accident 0 0 0 2 (0·7) 1 (0·4) 3 (0·3) 0 3 (0·3)

Intracranial haematoma 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Asthma 2 (0·2) 0 0 1 (0·4) 1 (0·4) 2 (0·2) 0 4 (0·4)

Haemoptysis 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

17

Pulmonary embolism 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Vitreous haemorrhage 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Duodenal obstruction 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Cholelithiasis 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Post-procedural bile leak 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Dehydration 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Osteoarthritis 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Benign salivary gland neoplasm 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Gastrointestinal tract adenoma 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Uterine leiomyoma 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Abortion spontaneous 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Abortion spontaneous complete 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Cervical dysplasia 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Abortion induced 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Deep vein thrombosis 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Hypertension 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Percentages are calculated using total number of patients per treatment as the denominator. Medical Dictionary for Regulatory Activities version used for reporting: 15.1 HFA-MFI, hydrofluoroalkane metered-dose inhaler

18

Table S10B. Serious adverse events: trial 2

Trial 2

System organ class/

preferred term, n (%)

Screening

(n=1030)

Tiotropium

Respimat®

5 µg

(n=253)

Tiotropium

Respimat®

2·5 µg

(n=257)

Placebo

(n=254)

Salmeterol

HFA-MDI

(n=266)

Total

(treatment)

(n=1030)

Total

(post-treatment)

(n=1030)

Total

(study)

(N=1030)

Total with serious adverse events 8 (0·8) 7 (2·8) 7 (2·7) 4 (1·6) 4 (1·5) 22 (2·1) 1 (0·1) 31 (3·0)

Asthma 1 (0·1) 1 (0·4) 2 (0·8) 2 (0·8) 1 (0·4) 6 (0·6) 0 7 (0·7)

Eosinophilic pneumonia 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Nasal polyps 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Sleep apnoea syndrome 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Asthmatic crisis 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Anal fistula 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Colitis 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Ileus paralytic 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Anal polyp 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Haemorrhoids 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Suprapubic pain 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Anaphylactic reaction 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Pneumonia 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Pyelonephritis 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Chemical poisoning 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

19

Intestinal anastomosis complication 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Humerus fracture 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Osteoarthritis 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Rhabdomyolysis 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Spinal osteoarthritis 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Ovarian adenoma 0 1 (0·4) 0 0) 0 1 (0·1) 0 1 (0·1)

Cerebral haemorrhage 0 0 0 1 (0·4) 0 1 (0·1) 0 1 (0·1)

Cervicobrachial syndrome 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Diabetic neuropathy 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Ectopic pregnancy 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Abortion spontaneous 0 0 0 0 0 0 1 (0·1) 1 (0·1)

Benign prostatic hyperplasia 0 0 0 0 1 (0·4) 1 (0·1) 0 1 (0·1)

Parovarian cyst 0 1 (0·4) 0 0 0 1 (0·1) 0 1 (0·1)

Hypertension 0 0 1 (0·4) 0 0 1 (0·1) 0 1 (0·1)

Hypertensive crisis 1 (0·1) 1 (0·4) 0 0 0 1 (0·1) 0 2 (0·2)

Diabetic retinopathy 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Diabetes mellitus 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Depression 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Diabetic nephropathy 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Microalbuminuria 1 (0·1) 0 0 0 0 0 0 1 (0·1)

Percentages are calculated using total number of patients per treatment as the denominator. Medical Dictionary for Regulatory Activities version used for reporting: 15.1


20

Supplementary figures

Figure S1. FEV1 responses at Week 24 by trial

21

Adjusted mean FEV1(0–3h) response taken at each time point at the Week 24 visit: (A) Trial 1; (B) Trial 2. Response defined as difference from baseline value at

randomisation. 0 hours denotes the trough FEV1 value taken 10 minutes prior to inhalation of study medication, between 18:00 and 20:00. Error bars are ± standard error.

Mean FEV1 ± standard deviation at baseline for trial 1: tiotropium Respimat® 5 µg, 2154 ± 610 mL; tiotropium Respimat

® 2·5 µg, 2247 ± 651 mL; salmeterol, 2305 ± 648

mL; placebo, 2251 ± 650 mL; trial 2: tiotropium Respimat® 5 µg, 2257 ± 647 mL; tiotropium Respimat

® 2·5 µg, 2284 ± 651 mL; salmeterol, 2367 ± 665 mL; placebo, 2268

± 693 mL. Population: full analysis set

FEV1, forced expiratory volume in 1 second; HFA-MFI, hydrofluoroalkane metered-dose inhaler

22

Figure S2. FEV1 responses over 24 weeks by trial

25

Adjusted mean FEV1 responses over the 24-week treatment period. (A) Trial 1 peak FEV1(0–3h) response; (B) Trial 2 peak FEV1(0–3h) response; (C) Trial 1 trough FEV1

response; (D) Trial 2 trough FEV1 response. Error bars are ± standard error. Mean FEV1 ± standard deviation at baseline for trial 1: tiotropium Respimat® 5 µg, 2154 ± 610

mL; tiotropium Respimat® 2·5 µg, 2247 ± 651 mL; salmeterol, 2305 ± 648 mL; placebo, 2251 ± 650 mL; trial 2: tiotropium Respimat

® 5 µg, 2257 ± 647 mL; tiotropium

Respimat® 2·5 µg, 2284 ± 651 mL; salmeterol, 2367 ± 665 mL; placebo, 2268 ± 693 mL. Population: full analysis set

FEV1, forced expiratory volume in 1 second; HFA-MFI, hydrofluoroalkane metered-dose inhaler; peak FEV1(0–3h), peak FEV1 response measured within the first 3 hours after

evening dosing

26

Figure S3. Morning and evening mean weekly PEF responses by trial

29

(A) Trial 1 adjusted mean morning PEF response; (B) Trial 2 adjusted mean morning PEF response; (C) Trial 1 adjusted mean evening PEF response; (D) Trial 2 adjusted

mean evening PEF response. Error bars are ± standard error. Mean PEF ± standard deviation at baseline for trial 1: tiotropium Respimat® 5 µg, 350·4 ± 97·1 L/min;

tiotropium Respimat® 2·5 µg, 361·1 ± 101·2 L/min; salmeterol, 370·2 ± 111·6 L/min; placebo, 360·1 ± 104·9 L/min; trial 2: tiotropium Respimat

® 5 µg, 360·1 ± 98·8

L/min; tiotropium Respimat® 2·5 µg, 361·3 ± 110·2 L/min; salmeterol, 379·0 ± 104·2 L/min; placebo, 357·2 ± 107·1 L/min. Population: full analysis set

HFA-MFI, hydrofluoroalkane metered-dose inhaler; PEF, peak expiratory flow

30

Figure S4. Cumulative severe exacerbations and asthma worsening

31

(A) Cumulative proportion of patients having a severe exacerbation; (B) Cumulative proportion of patients having asthma worsening. Population: pooled trial 1 and trial 2,

full analysis set


32

Figure S5. FEV1 responses over 24 hours

Adjusted mean FEV1 responses over 24 hours, assessed at Week 24. Lung function tests were conducted 10 minutes before dosing of trial medication, 30 minutes, 1 hour,

2 hours, 3 hours, 4 hours, 11 hours 50 minutes, 12 hours 30 minutes, 13 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, 22 hours, 23 hours, and 23 hours 50 minutes

after inhalation of trial medication. Tiotropium Respimat® 5 µg, n=140; tiotropium Respimat

® 2·5 µg, n=144; placebo, n=146; salmeterol, n=150. Data are from a subgroup

of centres where 24-hour measurements were performed. Error bars are ± standard error

FEV1, forced expiratory volume in 1 second; HFA-MFI, hydrofluoroalkane metered-dose inhaler

supplementary appendix - the lancet appendix. ... bumbacea, roxana silvia; dantes, elena; mihaescu,...

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