Table 1 Key study characteristics for all studies

MOITA, 2008

12 week RCT, PC, DB, MC

Tiotropium; 18 μg; OD

(n = 147) vs. Placebo (n = 164)

31 centres/ Portugal

FEV1 ≤ 70 %; FEV1/FVC ≤ 70 %; excluded if ≥ 3 exacerbations previous year

LABAs, theophylline, mucolytics, ICS, stable doses oral corticosteroids. Temporary increases in theophylline or oral steroids for exacerbations

Theophylline 24 h preparations

VERKINDRE, 2006

12 week RCT, PC, DB, MC

Tiotropium; 18 μg; OD (n = 46) vs. Placebo (n = 54)

10 centres/ France

FEV1 ≤ 50 %; FEV1/SVC ≤ 70 %; residual volume ≥ 125 %; excluded if unstable doses oral corticosteroid 6 wks prior

Stable doses oral corticosteroids, ICS, theophylline preparations, mucolytic agents

Use of SABAs, oral ß2-agonists, or LABAs

COVELLI, 2005

12 week RCT, PC, DB, MC

Tiotropium; 18 μg; OD (n = 100) vs. Placebo (n = 96)

12 centres/ USA

FEV1 ≤ 60 %; FEV1/FVC ≤ 70 %; excluded if exacerbation in prior 6 wks

ICS, LABAs and theophyllines

Cromones, leukotriene antagonists, and inhaled anticholinergics

CASABURI, 2000

13 week RCT, PC, DB, MC

Tiotropium; 18 μg; O (n = 279) vs. Placebo (n = 191)

25 centres/ USA

FEV1 ≤ 65 %; FEV1/FVC ≤ 70 %

Stable doses of theophylline, ICS, oral prednisone

Other inhaled or oral bronchodilators

CASABURI, 2002

Two 56 week RCTs, PC, DB, MC

Tiotropium; 18 μg; OD (n = 550) vs. Placebo (n = 371)

50 centers/ countries NR

FEV1 ≤ 65 %; FEV1/FVC ≤ 70 %;

Stable doses of theophylline, ICS, oral prednisone

NR

NIEWOEHNER, 2005

24 week RCT, PC, DB, MC

Tiotropium; 18 μg; OD (n = 914) vs. Placebo (n = 915)

26 centers/ USA

FEV1 ≤ 60 %; FEV1/FVC ≤ 70 %; excluded if not recovered from exacerbation ≥ 30 days prior

All other respiratory medications (including ICS and LABAs)

Open-label anticholinergic bronchodilator

CHAN, 2007

48 week RCT, PC, DB, MC

Tiotropium; 18 μg, OD (n = 608) vs. Placebo (n = 305)

101 centers/ Canada

FEV1 ≤ 65 %; FEV1/FVC ≤ 70 %; included if ≥ 1 exacerbation previous year but not in 6 weeks prior

Stable dose oral corticosteroids, ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs

NR

TONNEL, 2008

36 week RCT, PC, DB, MC

Tiotropium; 18 μg: OD (n = 266) vs. Placebo (n = 288)

123 centers/ France

FEV1 20-70 %; FEV1/FVC ≤ 70 %;

Stable doses of theophylline preparations (excluding 24-hour preparations), mucolytics, ICS, and oral steroids

NR

HANANIA, 2003

24 week RCT, PC, DB, MC

Salmeterol; 50 μg; BID (n = 177) vs. Placebo (n = 185)

76 centres/ USA

FEV1 >40 % and <65 %; FEV1/FVC < 70 %; symptoms criteria; excluded if oral corticosteroids 6 wks prior

Stable regimen of theophylline

All other corticosteroids and bronchodilators

MAHLER, 2002

24 week RCT, PC, DB, MC, DD

Salmeterol; 50 μg; BID (n = 160) vs. Placebo (n = 181)

65 centers/ countries NR

FEV1 <65 % but >70 L. FEV1/FVC ≤70 %; excluded if moderate or severe exacerbation during run-in

Theophylline

Corticosteroids and other bronchodilators

VAN RUTTEN, 1999

12 week RCT, PC, DB, MC, DD

Salmeterol; 50 μg; BID (n = 47) vs. Placebo (n = 50)

3 centers/ Netherlands

FEV1 ≥40 % and ≤65 %; FEV1/FVC < 60 % (post salbutamol); symptoms criteria;

Stable doses of maintenance drugs

NR

CELLI, 2003

12 week RCT, PC, DB, MC, DD

Salmeterol; 50 μg; BID (n = 554) vs. Placebo (n = 271)

189 centres/ 15 countries

FEV1 20-70 %; FEV1/FVC < 65 %; <15 % reversibility FEV1; symptom criteria; excluded if exacerbation 6 wks prior

Usual medications at stable dose

β2-adrenoceptor agonists, anticholinergics, antibiotics for respiratory tract infection, leukotriene antagonists

GROSS, 2008

12 week RCT, PC, DB, DD, MC

Formoterol; 12 μg; BID (n = 114) vs. Placebo (n = 114)

38 centres/ USA

FEV1 >30 %; FEV1/FVC < 70 %; symptom criteria; excluded if exacerbation in 4 wks prior

Stable doses of inhaled or oral corticosteroids

NR

ROSSI, 2002

12 month RCT, PC,DB,MC

Formoterol; 12 μg; BID (n = 211) vs. Placebo (n = 220)

81 centers worldwide

FEV1 < 70 % of the predicted value and ≥ 0.75 L, FEV1 vital capacity ratio of <88 % of that predicted in men and <89 % in women.

Inhaled salbutamol (100 microgram per puff) or equivalent doses of albuterol in US centers as needed

NR

DAHL, 2001

12 week RCT, PC, DB, DD, MC

Formoterol 12 μg; BID (n = 194) vs. Placebo (n = 200)

57 centres/ Europe, Russia, Canada, USA

FEV1 <70 %; FEV1/FVC < 88 % for men and <89 % for women; symptom criteria; excluded if used oral corticosteroids 4 wks prior

Stable ICS, short courses of antibiotics, oral corticosteroids, and/or oxygen in case of exacerbation or respiratory infection

NR

BRIGGS, 2005

12 week RCT, DB, MC

Tiotropium 18 μg; OD (n = 328) vs. Salmeterol; 50 μg; BID (n = 325)

50 centres/ Europe, UK and USA

FEV1 ≤ 60 %; FEV1/FVC ≤ 70 %; excluded if exacerbation 4 wks prior

All usual medications

LABAs different from study medication

B2334, 2008/ DAHL, 2010

52 week RCT, PC, DB, MC, DD

Indacaterol; 300 μg; OD (n = 437) vs. Formoterol; 12 μg; BID (n = 435) vs. Placebo (n = 432)

# centres NR/ 25 countries in S. America, Europe, Russia, Africa, and Asia

FEV1 ≥ 30 % and <80 %; FEV1/FVC < 70 %; reversible and non-reversible patients included; excluded if hospitalisation 6 wks prior to trial or during run-in period

ICS monotherapy

Tiotropium, short acting anti-cholinergics, fixed combinations of β2-agonists and ICS or β 2-agonists and inhaled anticholinergics, LABAs, and other SABAs, theophylline, other xanthines, parenteral or oral corticosteroids

B2335S, 2008/ DONOHUE, 2010

26 week RCT, PC, DB (except for tiotropium arm), MC, DD; Adaptive seamless

Indacaterol; 150 μg; OD (n = 420) vs. Indacaterol; 300 μg; OD (n = 418) vs. Tiotropium; 18 μg; OD (n = 410) vs. Placebo (n = 425)

# centres NR/ Argentina, Canada, Europe, India, Italy, Korea, Taiwan, USA

FEV1 ≥ 30 % and <80 %; FEV1/FVC < 70 %; reversible and non-reversible patients included; excluded if hospitalisation 6 wks prior

ICS monotherapy

Tiotropium, short acting anti-cholinergics, fixed combinations of β2-agonists and ICS or β 2-agonists and inhaled anticholinergics, LABAs, and other SABAs, theophylline, other xanthines, parenteral or oral corticosteroids

B2336, 2009/ KORNMANN, 2010

26 week RCT, PC, DB, MC, DD

Indacaterol; 150 μg; OD (n = 333) vs. Salmeterol; 50 μg; BID (n = 334) vs. Placebo (n = 335)

# centres NR/ Canada, Colombia, Europe and Russia, Slovakia, India, Peru, Taiwan

FEV1 ≥ 30 % and <80 %; FEV1/FVC < 70 %; reversible and non-reversible patients included; excluded if hospitalisation 6 wks prior

ICS monotherapy

Tiotropium, short acting anti-cholinergics, fixed combinations of β2-agonists + ICS or β 2- agonists + inhaled anticholinergics, LABAs, theophylline, other xanthines, parenteral or oral corticosteroids

B2346, 2008/ FELDMAN, 2010

12 week RCT, PC, DB, MC, DD

Indacaterol; 150 μg; OD (n = 211) vs. Placebo (n = 205)

# centres NR/ USA, Australia/ New Zealand, Belgium

FEV1 ≥ 30 % and <80 %; FEV1/FVC < 70 %; reversible and non-reversible patients included; excluded if hospitalisation 6 wks prior

ICS monotherapy

Tiotropium, short acting anti-cholinergics, fixed combinations of β2-agonists and ICS or β 2-agonists and inhaled anticholinergics, LABAs, and other SABAs, theophylline, other xanthines, parenteral or oral corticosteroids

B2354, 2010

12 week RCT, PC, DB, MC

Indacaterol; 75 μg; OD (n = 163) vs. Placebo (n = 160)

# centres NR/ USA

FEV1 ≥ 30 % and <80 %; FEV1/FVC < 70 %; Excluded if exacerbation in 6 wks prior

Antibiotics or oral corticosteroids for exacerbation; ICS monotherapy

LABAs; anticholinergic

B2355, 2010

12 week RCT, PC, DB, MC

Indacaterol; 75 μg; OD (n = 159) vs. Placebo (n = 159)

# centres NR/ USA

FEV1 ≥ 30 % and <80 %; FEV1/FVC < 70 %; Excluded if exacerbation in 6 wks prior

Antibiotics or oral corticosteroids for exacerbation; ICS monotherapy

LABAs; anticholinergic