Table 1.
Overview of key COPD clinical trials comparing single and dual bronchodilator therapies with placebo
| Study title | Study design | Duration | Patient population | Treatment arms | N | Exacerbation definition | Key exacerbation results (Comparator vs placebo) |
|---|---|---|---|---|---|---|---|
|
Single BD (LAMA) vs PBO
Tiotropium | |||||||
| 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 ≤ 0.7b) | 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 exacc |
| 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 assesseda) |
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 |
| Glycopyrronium | |||||||
| 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) |
| Aclidinium | |||||||
| 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]) |
| Umeclidinium | |||||||
| 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) |
|
Single BD (LABA) vs PBO
Salmeterol | |||||||
| 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 |
| Indacaterol | |||||||
| 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 μge |
|
Dual bronchodilation (LAMA/LABA) vs PBO
Aclidinium/formoterol | |||||||
| 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) |
| Umeclidinium/vilanterol | |||||||
| 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) |
aData not included; bAccording to 1995 American Thoracic Society criteria; cHospitalizations occurred in <50% of patients and therefore a median time to first event could not be calculated; dSoft mist formulation delivered via the Respimat® device; eStudy was not powered to make comparison; fData for aclidinium/formoterol 400/6 μg b.i.d. not reported in publication. AB antibiotics, AC active controlled, ACCORD COPD I AClidinium in Chronic Obstructive Respiratory Disease COPD I, ACL aclidinium; A/F aclidinium/formoterol, AUGMENT Aclidinium/formoterol FUmarate Combination for InvestiGative use in the TreatMENT of Moderate-to-Severe COPD, ATTAIN Aclidinium To Treat Airway obstruction In COPD patieNts, BD bronchodilators, b.i.d. twice daily, CI confidence interval, CS corticosteroids, DB double blind, DD double dummy, ER emergency room, exac exacerbation, EXACT EXAcerbations of Chronic pulmonary disease Tool, FEV 1 forced expiratory volume in 1 s, FVC forced vital capacity, FOR formoterol, GLOW2 GLycopyrronium bromide in COPD airWays clinical Study 2, GLY glycopyrronium, HCRU Healthcare Resource Utilization, HR hazard ratio, ICS inhaled corticosteroids, IND indacaterol, INHANCE INdacaterol [versus tiotropium] to Help Achieve New COPD treatment Excellence, INVOLVE: Indacaterol: Value in COPD: Longer Term Validation of Efficacy and Safety, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, MC multicenter, MISTRAL Mesure de l’Influence de Spiriva® sur les Troubles Respiratoires Aigus à Long terme, NS not statistically significant, OL open label, OR odds ratio, PBO placebo, PC placebo controlled, PG parallel group, PP per protocol; pt patient, q.d. once daily, R randomized, RR relative risk, SALM salmeterol, SC single center, SVC slow vital capacity, TIO tiotropium, UMEC umeclidinium, VI vilanterol, UPLIFT: Understanding Potential Long-Term Impacts on Function with Tiotropium, yr year