Table 2 Overview of key clinical trials comparing single or dual bronchodilator therapies with single bronchodilators

GLOW2

Kerwin et al. (2012) [72]

NCT00929110

MC, R, DB, DD, PG, PC, OL

52 weeks

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

GLY 50 μg q.d.

PBO^a

OL TIO 18 μg q.d.

(2:1:1)

529

269

268

N/A

• Time to first moderate or severe exac: comparable risk reduction for GLY and TIO vs PBO^b

 o 34% risk reduction with GLY vs PBO (HR 0.66; 95% CI 0.520, 0.850, p = 0.001)

 o 39% risk reduction with TIO vs PBO (HR 0.61; 95% CI 0.456, 0.821, p = 0.001)

• Rate of moderate or severe exac:

 o 34% with GLY vs PBO (RR 0.66; 95% CI 0.496, 0.869, p = 0.003)

 o P = NS for TIO vs PBO (RR 0.80; 95% CI 0.586, 1.105)

Vogelmeier et al. (2011) [53]

NCT00563381

POET

MC, R, DB, DD, PG, AC

1 year

Moderate-to-very-severe COPD (FEV₁ ≤ 70% predicted and FEV₁/FEV ≤ 0.7) plus a history of exac in the preceding year

TIO 18 μg q.d.

SALM 50 μg b.i.d.

(1:1)

3,707

3,669

Increase in/onset of more than one symptom of COPD (cough, sputum, dyspnea, wheezing, chest tightness) with at least one lasting ≥3 days and requiring treatment with systemic CS, AB or both (criterion for moderate exac) or hospitalization (criterion for severe exac)

• Time to first exac increased by 42 days with TIO vs SALM (145 days vs 187 days; 17% reduced risk; HR 0.83, 95% CI 0.77, 0.90, p < 0.001)

• TIO increased time to first severe exacerbation vs SALM (HR 0.72, 95% CI 0.61, 0.85, p < 0.001)

• TIO significantly reduced risk of moderate and severe exac vs SALM by 14% (HR 0.86, 95% CI 0.79, 0.93, p < 0.001) and 28% (HR 0.72, 95% HR, 0.61, 0.85, p < 0.001), respectively

• TIO vs SALM reduced the annual rate of moderate exac by 7% (0.54 vs 0.59; RR 0.93, 95% CI 0.86, 1.00, p < 0.05) and severe exac by 27% (0.09 vs 0.13; RR 0.73, 95% CI 0.66, 0.82, p < 0.001)

• TIO reduced the risk of exac requiring treatment with CS and or AB (p < 0.001)

Decramer et al. (2013) [80]

NCT00845728 INVIGORATE

MC, R, blinded, DD, PG, AC

52 weeks

Severe COPD (FEV₁ 30% and < 50% predicted and FEV₁/FVC < 0.70 plus and a documented history of ≥ 1 moderate or severe exac in the previous 12 months

IND 150 μg q.d.

TIO 18 μg q.d. (1:1)

1,723

1,721

Worsening for ≥2 consecutive days of ≥2 major symptoms (dyspnea, sputum volume or sputum purulence) or worsening of any one major symptom plus one minor symptom (sore throat, colds, fever without other cause, increased cough or increased wheeze)

• Rate of exac^c: 0.79 with IND and 0.61 with TIO (non-inferiority not met; RR 1.29, p = NS)

• Annual rate of exac higher with IND vs TIO: 0.90 vs 0.73 (RR 1.24; 95% CI 1.12, 1.37, p < 0.0001)^d

• No treatment difference in rates of exac leading to hospitalization in patients receiving ICS

Aaron et al. (2007) [127]

ISRCTN29870041

MC, R, DB, PG, PC

52 weeks

Moderate or severe COPD (FEV₁ < 65% predicted and FEV₁/FVC < 0.7)

TIO 18 μg q.d.

TIO 18 μg q.d. + SALM 50 μg b.i.d.

TIO 18 μg q.d. + SFC 50/500 μg b.i.d.^a

156

148

145

Sustained worsening of patient’s respiratory condition, from stable state and beyond normal day-to-day variations, requiring a change in regular medication^e

• Pts with ≥1 exac: 64.8% TIO + SALM vs 62.8% with TIO (p = NS)

• Exac/pt/yr: 1.75 TIO + SALM vs 1.61 TIO (p = NS)

 o IRR vs TIO: 1.09 (95% CI 0.84, 1.40)

• Time to first exac: 128 days TIO + SALM vs 130 days TIO (p = NS)

• No. of hospitalizations for exac: 38 vs 49 (p = NS)

Wedzicha et al (2013) [24]

NCT01120691 SPARK

MC, R, DB, PG

64 weeks

Severe or very severe COPD (FEV₁ < 50% predicted and FEV₁/FVC < 0.7) plus a documented history of ≥ 1 exac in previous 12 months requiring treatment with systemic CS or AB or both

IND/GLY 110/50 μg q.d.

GLY 50 μg q.d.

OL TIO 18 μg q.d.

(1:1:1)

741

741

742

Presence of two major symptoms (dyspnea, sputum volume, sputum purulence) for ≥2 consecutive days or a worsening of one major symptom together with an increase in any one minor symptom (sore throat, cold, fever without other cause, cough, wheeze) for ≥2 consecutive days

• IND/GLY significantly reduced annualized rate of moderate or severe exac by 12% vs GLY (RR 0.88; 95% CI 0.77, 0,99, p = 0.038)

 o 10% reduction vs TIO (RR 0.90; 95% CI 0.79, 1.02, p = NS)

• Rate of all exac reduced with IND/GLY vs GLY (RR 0.85; 95% CI 0.77, 0.94, p = 0.0012) and vs TIO (RR 0.86; 95% CI 0.78, 0.94, p = 0.0017)

Maleki-Yazdi et al. (2014) [128]

NCT01777334

ZEP117115

MC, R, blinded, DD, PG

24 weeks

Moderate-to-very-severe COPD (FEV₁ ≤ 70% predicted and FEV₁/FVC < 0.7) plus mMRC score of ≥ 2

UMEC/VI 62.5/25 μg q.d.

TIO 18 μg q.d.

(1:1)

454

451

Acute worsening of COPD symptoms requiring use of any treatment beyond study drug or rescue albuterol/salbutamol

• Time to first exac reduced with UMEC/VI vs TIO (HR 0.5; 95% CI 0.3, 1.0, p = 0.044)

Decramer et al. (2014) [85]

Study 1 (S1) NCT01316900

DB2113360 Study 2 (S2) NCT01316913

DB2113374

2 x MC, R, blinded, DD, PG, AC

24 weeks

Moderate-to-very-severe COPD (FEV₁ ≤ 70% predicted and FEV₁/FVC < 0.7) plus mMRC score of ≥ 2

UMEC + VI 125 + 25 μg q.d.

UMEC + VI 62.5 + 25 μg q.d.

UMEC 125 μg q.d.

VI 25 μg q.d.

TIO 18 μg q.d.

S1 216

S2 217

S1 212

S2 218

S2 222

S1 209

S1 209

S2 215

Acute worsening of symptoms of COPD requiring the use of any treatment other than study drug or rescue salbutamol

• No significant differences in risk of exac between UMEC + VI vs UMEC, VI or TIO monotherapies. Time to first exac:

 o S1: UMEC 125 μg + VI 25 μg (HR 1.0 vs TIO; 0.6 vs VI)

 o S1: UMEC 62.5 μg + VI 25 μg (HR 1.2 vs TIO; 0.7 vs VI)

 o S2: UMEC 125 μg + VI 25 μg (HR 1.1 vs TIO; 0.6 vs UMEC 125)

 o S2: UMEC 62.5 μg + VI 25 μg (HR 1.9 vs TIO; 0.1.0 vs UMEC 125)

Buhl et al. (2015) [20]

Combined data for NCT01431274

TOnado 1

and NCT01431287

TOnado 2

2 x MC, R, DB, AC, PG

24 weeks

Moderate-to-very-severe COPD (FEV₁ < 80% predicted and FEV₁/FVC < 0.7) plus mMRC score of ≥ 2

TIO + OLO 5/5 μg q.d.

TIO + OLO 2.5/5 μg q.d.

OLO 5 μg q.d.

TIO 5 μg q.d.

TIO 2.5 μg q.d.

1,029

1,030

1,038

1,033

1,032

N/A

• Trend for improvements in moderate/severe exac with TIO + OLO vs monotherapies^f

• Risk ratios for

 o TIO + OLO 5/5 μg vs OLO (0.83; p = 0.033); vs TIO 5 μg (0.92; p = NS)

 o TIO + OLO 2.5/5 μg vs OLO (0.69; p < 0.0001); vs TIO 2.5 μg and 5 μg (both 0.76; p = 0.0021)