Table 1 Overview of key COPD clinical trials comparing single and dual bronchodilator therapies with placebo

Casaburi et al. (2002) [62]

MC, R, DB, PC

1 year

FEV₁ ≤ 65% predicted and ≤ 70% FVC

TIO 18 μg q.d.

PBO (3:2)

550

371

Complex of respiratory events (cough, wheezing, dyspnea or sputum production) lasting >3 days (generally treated with AB ± oral CS)

• ≥1 exac: 36% vs 42% (14% reduction with TIO; p < 0.05)

• Increased time to first exac with TIO vs PBO (p = 0.011)

• Fewer exac events/pt/yr: 0.76 vs 0.95 (20% reduction with TIO; p = 0.045)

• Fewer hospitalizations for exac: 0.086 vs 0.161 events/pt/yr (47% reduction; p = 0.019)

• Fewer patients hospitalized for exac: 5.5% vs 9.4% (41% reduction with TIO; p < 0.05)

Brusasco et al. (2003) [63]

Combined analysis of NCT02172287/NCT02173691

2 x MC, R, DB, DD, PG, PC

6 months

FEV₁ ≤ 65% predicted and ≤ 70% FVC

TIO 18 μg q.d.

PBO

SALM 50 μg b.i.d.^a (1:1:1)

402

400

405

Complex of respiratory symptoms (new onset or increase in one or more of cough, sputum, dyspnea, wheeze, chest discomfort) lasting at least 3 days and usually associated with therapeutic intervention

• Delayed time to first exac with TIO vs PBO (p ≤ 0.01)

• Fewer exac/pt/yr: 1.07 vs 1.49 (28% reduction with TIO vs PBO; p = 0.025)

• Exac days/pt/yr: 17.2 vs 25 (31% reduction with TIO vs PBO; p = 0.025)

• No significant differences between TIO and PBO in hospital admissions, days in hospital or unscheduled physician visits for exac

Niewoehner et al. (2005) [64]

NCT00274547

MC, R, DB, PG, PC

6 months

Moderate-to-severe COPD (FEV₁ ≤ 60% predicted and ≤ 70% FVC)

TIO 18 μg q.d.

PBO (1:1)

914

915

Complex of respiratory symptoms (increase or new-onset) of more than one of cough, sputum, wheezing, dyspnea, or chest tightness with a duration of ≥3 days requiring treatment with AB or systemic CS, hospitalization or both

• ≥1 exac: 27.9% vs 32.3% (OR 0.81; 95% CI 0.66, 0.99; p = 0.037)

• ≥1 hospitalization for exac: 7.0% vs 9.5% (OR 0.72; 95% CI 0.51, 1.01; p = 0.056, NS)

• Extended time to first exac (HR 0.83; 95% CI 0.70, 0.98; p = 0.028)

• Reductions (events/pt/yr) in TIO vs PBO:

 o Frequency of exac: 0.85 vs 1.05 (p = 0.031)

 o Exac days: 12.6 vs 16.0 (p = 0.019)

 o Unscheduled medical visits: 0.39 vs 0.49 (p = 0.019)

 o Hospitalizations for exac: 0.18 vs 0.25 (p = 0.047)

Dusser et al. (2006) [65]

MISTRAL

MC, R, DB, PG, PC

1 year

FEV₁ 30–65% predicted and FEV₁/FVC ≤ 0.7

TIO 18 μg q.d.

PBO (1:1)

500

510

Onset of at least one clinical descriptor (worsening dyspnea, cough or sputum production; appearance of purulent sputum; fever [>38 ºC]; appearance of new chest radiograph abnormality) lasting ≥2 days and requiring dose increase of β₂-agonists, AB, CS or BD

• ≥1 exac: 49.9% vs 60.3% (17% reduction with TIO; p < 0.01)

• Fewer exac/pt/yr: 1.57 vs 2.41 (35% reduction with TIO; p < 0.001)

• TIO reduced exac days by 37% vs PBO (p < 0.001) and delayed time to first exac by ~100 days (p < 0.001)

• ≥1 moderate-to-severe exac: 42.5% vs 53.4% (30% reduction with TIO, p < 0.001)

Powrie et al. (2007) [66]

NCT00405236

SC, R, DB, PC

1 year

FEV₁ < 80% predicted; FEV₁/FVC < 0.7

TIO 18 μg q.d.

PBO (1:1)

69

73

Presence for ≥2 consecutive days of increase in any two major symptoms (dyspnea, sputum purulence, sputum volume) or increase in one major and one minor symptom (wheeze, sore throat, cough, symptoms of a common cold)

• ≥1 exac: 43% vs 64% (p = 0.01)

• Fewer exac/yr: 1.17 vs 2.46 (52% reduction with TIO; p = 0.001)

• Time to first exac: 236 vs 157 days (p = 0.0092)

• Fewer exac days: 17.3 vs 34.5 (p = 0.002)

• No treatment differences for number of treated exac or hospitalizations for exac

Chan et al. (2007) [125]

SAFE

MC, R, DB, PG, PC

1 year

Moderate-to- severe COPD (FEV₁ ≤ 65% predicted and FEV₁/FVC ≤ 0.7)

TIO 18 μg q.d.

PBO (2:1)

608

305

Complex of respiratory symptoms (new-onset or increase in at least one of cough, sputum, sputum purulence, dyspnea, wheeze, chest discomfort) lasting ≥3 days and requiring treatment with AB ± systemic CS

• No statistically significant differences between TIO and PBO:

 o ≥1 exac: 44.1% vs 41.0%

 o ≥1 hospitalization for exac: 8.4% vs 8.2%

 o Exac/pt/yr: 0.88 vs 0.92

 o Exac days/pt yr: 16.13 vs 16.19

 o Hospitalizations for exac: 0.13 vs 0.15

 o Hospitalization days for exac: 1.14 vs 1.16

Tonnel et al. (2008) [67]

TIPHON

MC, R, DB, PG, PC

9 months

Mild, moderate or severe COPD (FEV₁ 20–70% predicted FEV₁/FVC ≤ 0.7^b)

TIO 18 μg q.d.

PBO (1:1)

266

288

Worsening of COPD (from stable state beyond normal day-to-day variation) that was acute in onset and necessitated a change in regular medication

• ≥1 exac: 38.0% vs 45.1% (p = 0.10; NS)

• Fewer exac/yr: 1.05 vs 1.83 (43% reduction with TIO; p = 0.03)

• Fewer exac days/yr: 10.5 vs 20.6 (49% reduction with TIO; p = 0.02)

• Delayed time to first exac: 201 days vs 181 days (p = 0.0081)

Tashkin et al. (2008) [68]

NCT00144339

UPLIFT

MC, R, DB, PG, PC

4 years

Moderate-to-very severe COPD (FEV₁ ≤ 70% predicted and ≤ 70% FVC)

TIO 18 μg q.d.

PBO (1:1)

2,987

3,006

Increase in/new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheeze, or dyspnea) lasting ≥3 days and requiring treatment with AB or systemic CS

• Exac/pt/yr: 0.73 vs 0.85 (RR 0.86; 95% CI 0.81, 0.91; p < 0.001)

• Exac days/pt/yr: 12.11 vs 13.64 (RR 0.89; 95% CI 0.83, 0.95; p = 0.001)

• Hospitalizations for exac (no./pt/yr): 0.15 vs 0.16 (RR 0.94; 95% CI 0.82, 1.07; p = NS)

• Significantly delayed median time to first exac: 16.7 months (95% CI 14.9, 17.9) vs 12.5 months (95% CI 11.5, 13.8)

• Significantly delayed time to first hospitalization for exac^c

Bateman et al. (2010) [70]

NCT00387088

MC, R, DB, PG, PC

48 weeks

FEV₁ ≤ 60% predicted and FEV₁/FVC ≤ 0.7

TIO 5 μg q.d.^d

PBO (1:1)

1,989

2,002

Complex of respiratory events/symptoms lasting ≥3 days and requiring treatment with AB and/or systemic CS, or prompting a change in regular medication

• ≥1 exac: 35.3% vs 43.1% (HR 0.693; 95% CI 0.625, 0.769; p < 0.0001)

• Fewer exac/pt/yr: 0.69 vs 0.87 (RR 0.79; 95% CI 0.72, 0.87; p < 0.0001)

• Fewer exac requiring hospitalization (pt/yr: 0.12 vs 0.15 (RR 0.81; 95% CI 0.70, 0.93; p < 0.005)

Bateman et al. (2010) [69]

Combined analysis of NCT00168844/NCT00168831

2 x MC, R, DB, PG, PC

1 year

Moderate-to-severe COPD (FEV₁ ≤ 60% predicted and ≤ 70% FVC)

TIO 5 μg q.d.^d

TIO 10 μg q.d.^d

PBO (1:1)

670

667

653

Respiratory adverse events lasting ≥3 days and requiring treatment with AB ± oral CS ± a significant change in prescribed medication including inhaled BD

• ≥1 exac: 37.2% (TIO 5 μg) and 36.9% (TIO 10 μg) vs 44.1% (PBO)

• Exac rate (per pt-yr)

 o TIO 5 μg vs PBO: OR 0.75 (p < 0.01)

 o TIO 10 μg vs PBO: OR 0.74 (p < 0.001)

• Time to first exac (days): 160 and 178 vs 86 (both p < 0.001)

• Hospitalization/pt/yr: 0.12 and 0.16 vs 0.20 (p = NS)

Abrahams et al. (2013) [126]

NCT00528996

MC, R, DB, PG, PC

24 weeks

FEV₁ < 80% predicted and FEV₁/FVC ≤ 0.7

TIO 5 μg q.d.^d

PBO (1:1)

(BEA2810 50, 100 and 200 μg also assessed^a)

427

429

(Total 2,080)

Complex of respiratory events/symptoms (increased/new onset of ≥2 of: shortness of breath, sputum production, [volume], purulent sputum, cough, wheeze, chest tightness) related to COPD, with a duration of ≥3 days requiring a change in treatment

• No significant difference between TIO and PBO in risk of COPD exac

D’Urzo et al. (2011) [71]

NCT01005901 GLOW1

MC, R, DB, PG, PC

26 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30% and < 80% predicted; FEV₁/FVC < 0.7)

GLY 50 μg q.d.

PBO (2:1)

552

270

Increase in ≥2 COPD symptoms or worsening of any one major symptom together with a minor symptom over ≥2 consecutive days. AB ± systemic CS (moderate exac), or hospitalization (severe exac)

• Delayed time to first moderate or severe exac by 31% vs PBO (HR, 0.69; 95% CI 0.500, 0.949; p = 0.023)

• Reduced risk of severe exac leading to hospitalization vs PBO (HR, 0.35; 95% CI 0.141, 0.857; p = 0.022)

• Reduced the proportion of hospitalizations due to exacs vs PBO: 1.7% vs 4.2% (OR, 0.34; 95% CI 0.129, 0.868; p = 0.024)

Kerwin et al. (2012) [72]

NCT00929110 GLOW2

MC, R, DB, PG, PC

52 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30% and < 80% predicted; FEV₁/FVC < 0.7)

GLY 50 μg q.d.

PBO

OL TIO 18 μg q.d.^a (2:1:1)

529

269

268

Increase in ≥2 COPD symptoms or worsening of any one major symptom together with a minor symptom over ≥2 consecutive days. AB ± systemic CS (moderate exac), or hospitalization (severe exac).

• Risk of time to first moderate-to-severe exac reduced by 34% with GLY vs PBO (HR 0.66; 95% CI 0.520, 0.850; p = 0.001)

• Rate of moderate-to-severe exac reduced by 34% with GLY vs PBO (RR 0.66; 95% CI 0.496, 0.869; p = 0.003)

• Exac requiring treatment with systemic CS or AB significantly reduced with GLY vs PBO (OR 0.61 [p = 0.006] and OR 0.69 [p = 0.026], respectively)

Kerwin et al. (2012) [73]

NCT00891462 ACCORD COPD I

MC, R, DB, PG, PC

12 weeks

Moderate-to-severe COPD (FEV₁ ≥ 30% and < 80% predicted; FEV₁/ FVC < 0.7)

ACL 200 μg b.i.d.

ACL 400 μg b.i.d.

PBO (1:1:1)

185

190

186

Increase in COPD symptoms over ≥2 consecutive days resulting in medical intervention

• Rate of any exac significantly reduced with ACL 400 μg vs PBO (RR 0.52; p = 0.0009)

• Trend (not significant) towards reduced rate of moderate-to-severe exac/pt/yr with ACL 200 μg (33%) and ACL 400 μg (34%) vs PBO

Jones et al. (2012) [74]

NCT01001494 ATTAIN

MC, R, DB, PG, PC

24 weeks

Moderate-to-severe COPD (FEV₁ < 80% predicted; FEV₁/ FVC < 0.7)

ACL 200 μg b.i.d.

ACL 400 μg b.i.d.

PBO (1:1:1)

280

272

276

Increase in COPD symptoms over ≥2 consecutive days resulting in increased use of short-acting BD ± ICS (mild exac), AB ± systemic CS (moderate exac), or hospitalization (severe exac)

• Rate of any exac significantly reduced with ACL 200 μg and 400 μg vs PBO (RR: 0.72, 95% CI 0.52, 0.99, p < 0.05 and RR 0.67, 95% CI 0.48, 0.94, p < 0.05, respectively)

• Trend (not significant) towards reduced rate of moderate or severe exac with ACL vs PBO (RR 0.74 for ACL 200 μg [p = 0.08] and 0.72 for ACL 400 μg [p = 0.06])

Donohue et al. (2013) [22]

NCT01313650

DB2113373

MC, R, DB, PG, PC

24 weeks

FEV₁ ≤ 70% predicted and FEV₁/FVC < 0.7

UMEC/VI 62.5/25 μg q.d.^a

UMEC 62.5 μg q.d.

VI 25 μg q.d.^a

PBO (3:3:3:2)

413

418

421

280

Acute worsening of symptoms of COPD requiring emergency treatment, hospitalization or use of additional therapy beyond study drug/rescue salbutamol (e.g. oral CS and AB)

• Reduced risk of exac with UMEC vs PBO (HR 0.6; 95% CI 0.4, 1.0, p < 0.05)

Celli et al. (2014) [75]

NCT01313637

MC, R, DB, PG, PC

24 weeks

FEV₁ ≤ 70% predicted and FEV₁/FVC < 0.7

UMEC/VI 125/25 μg q.d.^a

UMEC 125 μg q.d.

VI 25 μg q.d.^a

PBO (3:3:3:2)

403

407

404

275

Acute worsening of symptoms of COPD requiring emergency treatment, hospitalization or use of any therapy beyond study drug/rescue albuterol

• Reduced risk of COPD exac with UMEC vs PBO (HR 0.5; 95% CI 0.3, 0.8, p ≤ 0.006)

Stockley et al. (2006) [76]

MC, R, DB, PC

1 year

FEV₁ < 70% predicted and established history of exacerbations (≥2 in previous year needing treatment with AB and/or oral CS)

SALM 50 μg b.i.d.

PBO (1:1)

316

318

Exacerbations were identified using an event-based definition in which a worsening of symptoms required a change in medication. Exacerbations classed as moderate if required treatment with AB +/- oral CS/increase in ICS dose; severe if required hospital admission

• Mean number of moderate/severe exac/year in ITT population was lower with SALM (0.93) vs PBO (1.18); p = NS

• Mean number of moderate/severe exac/year in PP population was significantly lower with SALM (0.58) vs PBO (0.83); p = 0.007

Dahl et al. (2010) [77]

NCT00393458 INVOLVE

MC, R, DB, DD, PG, PC

1 year

Moderate-to-severe COPD (FEV₁ < 80% and ≥ 30% predicted and FEV₁/FVC < 0.7)

IND 300 μg q.d.

IND 600 μg q.d.

PBO

FOR 12 μg b.i.d.^a

(1:1:1:1)

437

428

432

435

Onset/worsening of more than one respiratory symptom (dyspnea, cough, sputum purulence/volume or wheeze) for >3 consecutive days plus documented proof of intensified treatment (e.g. systemic CS, AB or oxygen) ± hospitalization/ER visit

• Exac: 32.8% (IND 300 μg) and 29.3% (IND 600 μg) vs 36.3% (PBO)

• Time to first exac improved with IND 300 μg and 600 μg vs PBO: HR 0.77 (95% CI 0.606, 0.975, p < 0.05) and 0.69 (95% CI 0.538, 0.882, p < 0.05)

• RR vs PBO were 0.82 for IND 300 μg (p = NS) and 0.74 (0.74, 95% CI 0.56, 0.97, p < 0.05) for IND 600 μg

Donohue et al. (2010) [79]

NCT00463567 INHANCE

MC, R, DB, PC

26 weeks

Moderate-to-severe COPD

IND 150 μg q.d.

IND 300 μg q.d.

PBO

OL TIO 18 μg q.d.^a

416

416

418

415

Onset/worsening of one or more respiratory symptoms (dyspnea, cough, sputum purulence/volume, or wheeze) for ≥3 consecutive days, plus intensified treatment (e.g., systemic CS, AB, oxygen) ± hospitalization/ER visit

• Risk of time to first exac reduced vs PBO for IND 150 μg (HR 0.69; 95% CI 0.51, 0.94; p = 0.019); numerically reduced risk for IND 300 μg (HR 0.74; 95% CI 0.55, 1.01, p = 0.054)

• RR of exac vs PBO: 0.67 IND 150 μg (95% CI 0.46, 0.99; p = 0.044); for IND 300 μg (0.75, 95% CI 0.51, 1.08, p = NS)

• Rate of exac/yr: 0.50 and 0.53 vs 0.72 for IND 150 μg, 300 μg vs PBO, respectively

Chapman et al. (2011) [78]

NCT00677807 INDORSE

MC, R, DB, PC

26-week extension (52 weeks including core study; see above)

Moderate-to-severe COPD (FEV₁ < 80% and ≥ 30% predicted; and FEV₁/FVC < 0.7)

IND 150 μg q.d.

IND 300 μg q.d.

PBO

420

418

425

Onset/worsening of more than one respiratory symptom (dyspnea, cough, sputum purulence/volume, or wheeze) for >3 consecutive days, plus intensified treatment (e.g., systemic CS, AB, oxygen) ± hospitalization/ER visit

• Exac/yr: 0.39 (IND 150 μg; p < 0.05) and 0.38 (IND 300 μg; p = NS) vs 0.54 (PBO)

• RR of exac vs PBO: 0.64 IND 150 μg (95% CI 0.43, 0.96, p = 0.029); 0.62 IND 300 μg (95% CI 0.42, 0.92, p = 0.018)

• Time to first exac: HR (vs PBO): 0.82 (95% CI 0.51, 1.34) IND 150 μg; 0.86 (95% CI 0.53, 1.39) IND 300 μg^e

Singh et al. (2014) [23]

NCT01462942 ACLIFORM-COPD

MC, R, DB, PG, PC/AC

24 weeks

Moderate-to-severe COPD (FEV₁ < 80% and ≥ 30% predicted and FEV₁/FVC < 0.7)

A/F 400/12 μg b.i.d.

A/F 400/6 μg b.i.d.

ACL 400 μg b.i.d.^a

FOR 12 μg b.i.d.^a PBO (2:2:2:2:1)

385

381

385

384

194

HCRU: increase of COPD symptoms during ≥2 consecutive days that require a change in COPD treatment; and EXACT: persistent increase from baseline in total EXACT score of ≥9 points for ≥3 days or ≥12 points for ≥2 days

• HCRU rate: 27% lower with A/F 400/12 μg vs PBO (did not reach significance); RR were 0.73 A/F 400/12 μg and 0.80 A/F 400/6 μg

• EXACT rate: significantly lower with A/F 400/12 μg vs PBO (0.71; 95% CI 0.5, 0.9, p < 0.05)

• No. pts hospitalized for exac was low and similar between treatments

Bateman et al. (2015) [84]

Pooled analysis of ACLIFORM-COPD and AUGMENT NCT01462942/NCT01437397

2 x MC, R, DB, PG, PC/AC

24 weeks

Moderate-to-severe COPD (FEV₁ < 80% and ≥ 30% predicted and FEV₁/FVC < 0.7)

A/F 400/12 μg b.i.d.

A/F 400/6 μg b.i.d.^f

ACL 400 μg b.i.d.^a

FOR 12 μg b.i.d.^a PBO

723

719

725

723

531

HCRU: increase in COPD symptoms during ≥2 consecutive days that required a change in COPD treatment; and EXACT: persistent increase from baseline in total EXACT score of ≥9 points for ≥3 days or ≥12 points for ≥2 days

• HCRU rate: 24% (RR 0.76; p = NS) and 29% (RR 0.71; p < 0.05) reductions in any and in moderate or severe exac, respectively

• Increased time to first exac vs PBO:

 o Any severity (HR 0.72; 95% CI 0.53, 0.97, p < 0.05)

 o Moderate or severe (HR 0.70; 95% CI 0.51, 0.96, p < 0.05)

• Results supported by EXACT data:

 o RR 0.78 (95% CI 0.65, 0.94, p < 0.001)

 o Time to first EXACT exac of any severity (HR 0.79; 95% CI 0.65, 0.95, p < 0.05)

Donohue et al. (2013) [22]

NCT01313650

DB2113373

MC, R, DB, PG, PC/AC

24 weeks

FEV₁ ≤ 70% predicted and FEV₁/FVC < 0.7

UMEC/VI 62.5/25 μg q.d.

UMEC 62.5 μg q.d.^a

VI 25 μg q.d.^a

PBO (3:3:3:2)

413

418

421

280

Acute worsening of symptoms of COPD requiring emergency treatment, hospitalization or use of additional therapy beyond study drug/rescue salbutamol (e.g. oral CS and AB)

• Reduced risk of exac with UMEC/VI vs PBO (HR 0.5; 95% CI 0.3, 0.8, p ≤ 0.01)

Celli et al. (2014) [75]

NCT01313637

MC, R, DB, PG, PC/AC

24 weeks

FEV₁ ≤ 70% predicted and FEV₁/FVC < 0.7

UMEC/VI 125/25 μg q.d.

UMEC 125 μg q.d.^a

VI 25 μg q.d.^a

PBO (3:3:3:2)

403

407

404

275

Acute worsening of symptoms of COPD requiring emergency treatment, hospitalization or use of any therapy beyond study drug/rescue albuterol

• Reduced risk of COPD exac with UMEC/VI vs PBO (HR 0.4; 95% CI 0.2, 0.6, p ≤ 0.006)