Background
Efficacy Of Bronchodilators In Prevention Of Exacerbations
Non-pharmacological intervention
Pharmacological interventions
Single bronchodilation versus placebo in the prevention of exacerbations
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) |
Comparison of the efficacy of single bronchodilators in the prevention of exacerbations
Study title | Study design | Duration | Patient population | Treatment arms |
N
| Exacerbation definition | Key exacerbation results |
---|---|---|---|---|---|---|---|
Comparison of single BDs
LAMA vs LAMA | |||||||
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. PBOa
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 PBOb
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) |
LAMA vs LABA or LABA vs LAMA | |||||||
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 exacc: 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 |
Comparison of dual vs single BDs
LAMA/LABA vs LAMA or LABA | |||||||
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 medicatione
| • 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 monotherapiesf
• 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) |
Dual bronchodilation versus placebo in the prevention of exacerbations
Dual versus single bronchodilation in the prevention of exacerbations
Single bronchodilation versus ICS/LABA combinations in the prevention of exacerbations
Study title | Study design | Duration | Patient population | Treatment arms |
N
| Exacerbation definition | Key exacerbation results |
---|---|---|---|---|---|---|---|
Single BD vs ICS/LABA
LABA: salmeterol | |||||||
Calverley et al. (2007) [87] NCT00268216 TORCH | MC, R, DB, PG, PC, AC | 3 years | FEV1 < 60% predicted and FEV1/ FVC ≤ 0.7 | SALM 50 μg b.i.d. FP 500 μg b.i.d. SFC 500/50 μg b.i.d. PBOa
| 1,542 1,551 1,546 1,545 | Symptomatic deterioration requiring treatment with AB agents, systemic CS, hospitalization or a combination of these | • Annual rate of moderate or severe exac: 0.97 (SALM), 0.93 (FP), 0.85 (FP/SALM), 1.13 (PBO) • Combination therapy reduced the rate of moderate or severe exac; RR: o FP/SALM vs SALM: 0.88 (95% CI 0.81, 0.95, p = 0.002) o FP/SALM vs FP: 0.91 (95% CI 0.84, 0.99, p = 0.02) • Hospitalization for exac did not differ significantly between FP/SALM and monotherapies |
Ohar et al. (2014) [129] NCT01110200 ADC113874 | MC, R, DB, PG, AC | 26 weeks | FEV1 < 70% predicted and FEV1/ FVC < 0.7 plus recent (≤ 14 days) history of exac requiring hospitalization for ≤ 10 days; ER observation for ≥ 24 h during which OCS/ OCS + AB administered; or physician’s office/ER visit of < 24 h with OCS/OCS + AB and 6-month history of exac-related hospitalization | SALM 50 μg b.i.d. SFC 250/50 μg b.i.d. (1:1) | 325 314 | Worsening for ≥2 documented consecutive days of at least two of: dyspnea, sputum volume, sputum purulence, or at least one of these combined with sore throat, cold symptoms, fever or increased cough or wheeze | • No significant difference between FP/SALM vs SALM in rates of recurrent severe (ratio 0.92; 95% CI 0.58, 1.45) or moderate/severe (ratio 0.82; 95% CI 0.64, 1.06) exac • No difference between FP/SALM vs SALM in time to first moderate/severe exac (HR 0.83; 95% CI 0.63, 1.09) • Annualized exac rates in patient subgroupb lower with FP/SALM (1.54) vs SALM (2.28); ratio 0.68 (95% CI 0.47, 0.97) |
LABA: formoterol | |||||||
Calverley et al. (2010) [130] NCT476099 | MC, R, DB, DD, PG, AC | 48 weeks | Severe stable COPD (FEV1 30–50% predicted and FEV1/FVC ≤ 0.7) plus ≥ 1 exac requiring medical intervention (OCS and/or AB and/or ER visit and/or hospitalization) within 2–12 months before screening and to be clinically stable for 2 months before study entry | FOR 12 μg b.i.d. BDP/FOR 200/12 μg b.i.d. BUD/FOR 400/12 μg b.i.d. (1:1:1) | 239 237 242 | Need for treatment with OCS and/or AB and/or visit/admission to hospital. | • ≥1 exac and mean rate/pt/yr similar between groups; corresponding data were o BDP/FOR: 27.6% and 0.414 o BUD/FOR: 26.9% and 0.423 o FOR: 28.3% and 0.431 • Hospitalizations for exac: 5.6% for BDP/FOR, 2.9% for BUD/FOR and 3.4% for FOR (p < 0.001 and p = 0.008 vs BDP/FOR, respectively) |
LABA: vilanterol | |||||||
Dransfield et al. (2013) [88] Pooled analysis Study 1 NCT01009463 HZC102871 Study 2 NCT01017952 HZC102970 | 2 x MC, R, DB, PG, AC | 1 year | FEV1 ≤ 70% predicted and FEV1/FEV ≤ 0.7 plus a documented history of ≥ 1 exac requiring treatment (systemic/OCS/AB/hospitalization) in the preceding year | VI 25 μg q.d. FF/VI 50/25 μg q.d. FF/VI 100/25 μg q.d. FF/VI 200/25 μg q.d. (1:1:1:1) | 818 820 806 811 | Worsening symptoms of COPD (≥2 consecutive days) necessitating treatment with OCS or AB or both; severe exac were similar events that necessitated hospital admission | • Mean annual rate of moderate and severe exac was significantly lower with FF/VI vs VI alone; yearly ratios vs VI were o 0.8 (p = 0.0398) FF/VI 50/25 μg o 0.8 (p = 0.0244) FF/VI 100/25 μg o 0.7 (p = 0.0004) FF/VI 200/25 μg • Time to first moderate or severe exac longer with FF/VI 100/25 and 200/25 μg vs VI o HR 0.8 (95% CI, 0.7, 1.0, p = 0.0365) and 0.7 (95% CI, 0.5, 0.8, p = 0.0001), respectively • Exac necessitating treatment with CS significantly lower with FF/VI vs VI alone (p < 0.05 for 100/25 μg and p = 0.0009 for 200/25 μg) |
Martinez et al. 2016 [89] NCT01313676 SUMMIT (post hoc analysis) | MC, R, DB, PG, PC | Event-driven, mortalityc
| Moderate COPD (FEV1 ≥ 50– ≤ 70% predicted; FEV1/FEV ≤ 0.7) and a history of/multiple risk factors for CV diseased
| FF/VI 100/25 μg q.d. FF 100 μg q.d. VI 25 μg q.d. PBOa
| 4121 4135 4118 4111 | Moderate exac: treated with AB and/or systemic CS; severe exac: required hospitalization | • % reduction in moderate/severe exacerbations compared with PBO: 12% (95% CI 4, 19) for FF; 10% (95% CI 2, 18) for VI; and 29% (95% CI 22, 35) for FF/VI • % reduction in exacerbations requiring hospital admissions compared with PBO: 18% (95% CI 3, 31) for FF; 20% (95% CI 5, 32) for VI; and 27% (95% CI 13, 39) for FF/VI • FF/VI reduced the rate of moderate/severe exacerbations by 19% vs FF (95% CI 12, 26, p < 0.001) and by 21% vs VI (95% CI 14, 28, p < 0.001) • FF/VI reduced the % of exacerbations requiring hospital admissions by 11% vs FF (95% CI –6, 25, p = 0.204) and by 9% vs VI (95% CI –8, 25, p = 0.282) |
LAMA: tiotropium | |||||||
Wedzicha et al. (2008) [54] NCT00361959 INSPIRE | MC, R, DB, DD, PG | 2 years | Severe and very severe COPD (FEV1 < 50% predicted) and mMRC score ≥ 2 | TIO 18 μg q.d. SFC 500/50 μg b.i.d. | 665 658 | Defined by HCRU: episodes that required treatment with OCS and/or AB or hospitalization | • No difference in overall rate between FP/SALM (1.28/yr) and TIO (1.32/yr) • Exac requiring AB with FP/SALM vs TIO: 0.97 vs 0.82/yr (p = 0.028) • Exac requiring systemic CS with FP/SALM vs TIO: 0.69 vs 0.85/yr (p = 0.039) • Hospitalizations: 16% with FP/SALM vs 13% with TIO (p = NS) |
Study title | Study design | Duration | Patient population | Treatment arms |
N
| Exacerbation definition | Key exacerbation results |
Dual BD vs ICS/LABA
Indacaterol/glycopyrronium | |||||||
NCT01315249 ILLUMINATE (post hoc analysis) | MC, R, DB, DD, PG | 26 weeks | Moderate-to-severe COPD (FEV1 ≥ 40%– < 80% predicted and FEV1/FEV < 0.7) | IND/GLY 110/50 μg q.d. SFC 500/50 μg b.i.d. | 258 264 | Defined by modified Anthonisen criteriae (increased dyspnea, sputum production and sputum purulence) | • No significant difference between treatments; RR (IND/GLY vs FP/SALM) of moderate/severe exac: 0.80 (95% CI 0.41, 1.56) and all exac: 0.69 (95% CI 0.44, 1.07) • IND/GLY reduced risk of time to first exac by 35% vs FP/SALM (HR 0.65; 95% CI 0.44, 0.96, p = 0.03) |
Zhong et al. (2015) [28] NCT01709903 LANTERN | MC, R, DB, DD, PG | 26 weeks | Moderate-to-severe COPD (FEV1 ≥ 30– < 80% predicted and FEV1/FEV < 0.7), mMRC score ≥ 2 and history of ≤ 1 exac in the previous year | IND/GLY 110/50 μg q.d. SFC 500/50 μg b.i.d. | 372 372 | Worsening of symptoms captured via eDiary; defined by Anthonisen criteriae. Moderate exac: requiring treatment with systemic CS and/or AB; severe exac: requiring hospitalization/ER visit > 24 hours | • Annualized rate of moderate or severe exac significantly lower with IND/GLY vs FP/SALM (31% reduction; p = 0.048) • IND/GLY prolonged time to first moderate or severe exac by 35% (p = 0.028) • In patients with a history of moderate or severe exac, annualized rate |
Wedzicha et al. (2016) [29] NCT01782326 FLAME | MC, R, DB, DD, PG, NI | 52 weeks | Moderate-to-very severe COPD (FEV1 ≥ 25– < 60% predicted and FEV1/FEV < 0.7), mMRC score ≥ 2 and documented history of ≥ 1 exac treated with systemic CS and/or AB in previous year | IND/GLY 110/50 μg q.d. SFC 500/50 μg b.i.d. | 1,680 1,682 | Defined according to Anthonisen criteriae. Categorized as mild (worsening of symptoms for >2 consecutive days but not requiring treatment), moderate (treated with systemic CS and/or AB) or severe (requiring hospital \admission/ER visit of >24 h plus systemic CS and/or AB) | • Annual rate of all exac: IND/GLY (3.59) was non-inferior to FP/SALM (4.03): representing an 11% lower rate (RR, 0.89, 95% CI 0.83, 0.96, p = 0.003) • IND/GLY showed superiority to FP/SALM as the upper limits of the 95% CIs for the primary endpoint RRs were less than 1 • IND/GLY had a longer time to first exac than the FP/SALM group (median, 71 days [95% CI 60, 82] vs. 51 days [95% CI 46, 57]: HR 0.84 (95% CI 0.78, 0.91, representing a 16% lower risk; p < 0.001) |
Aclidinium/formoterol | |||||||
Vogelmeier et al. (2015) [132] NCT01908140 AFFIRM | MC, R, DB, DD, AC | 24 weeks | Symptomatic pts with FEV1 < 80%, FEV1/FVC < 0.7 and CAT ≥ 10 | A/F 400/12 μg b.i.d. SFC 500/50 μg b.i.d. | 468 463 | Defined by HCRU or identified using EXACT | • ≥1 exac: comparable between treatment groups: o HCRU: 15.8% (A/F) vs 16.6% (FP/SALM); OR 0.95 o EXACT: 37.8% (A/F) vs 39.5% (FP/SALM); OR 0.94 |
Umeclidinium/vilanterol | |||||||
Donohue et al. (2015) [26] Study 1 NCT01817764 DB2114930 Study 2 NCT01879410 DB2114951 | MC, R, DB, DD, PG | 12 weeks | Moderate-to-severe COPD (FEV1 ≥ 30– ≤ 70% predicted), mMRC score ≥ 2, no exacerbations in the previous year | UMEC/VI 62.5/25 μg q.d. SFC 250/50 μg b.i.d. | 353 and 349 353 and 348 | Captured only as a safety event. Defined as an acute worsening of COPD symptoms requiring use of AB, systemic CS, and/or emergency treatment or hospitalization | NCT01817764 • Exac rate was the same in each treatment group: o 3% (UMEC/VI) vs 3% (FP/SALM) NCT01879410 • Exac rate was the same in each treatment group: o 3% (UMEC/VI) vs 3% (FP/SALM) |
Singh et al. (2015) [92] NCT01822899 | MC, R, DB, DD, PG | 12 weeks | Moderate-to-severe COPD (FEV1 ≥ 30– ≤ 70% predicted and FEV1/FVC < 0.7), mMRC score ≥ 2, no exacerbations in the previous year | UMEC/VI 62.5/25 μg q.d. SFC 500/50 μg b.i.d. | 358 358 | Captured only as a safety event. Not defined | • Exac rate was similar between treatment groups: o 2% (UMEC/VI) vs <1% (FP/SALM) |
Tiotropium/olodaterol | |||||||
Beeh et al. (2016) [133] NCT01969721 ENERGITO | MC, R, DB, DD, PG | 12 weeks | Moderate-to-severe COPD (FEV1 ≥ 30– < 80% predicted and FEV1/FEV < 0.7), no exacerbations in the previous 3 months | TIO/OLO 5/5 μg q.d. TIO/OLO 5/2.5 μg q.d. SFC 500/50 μg b.i.d. SFC 250/50 μg b.i.d. | 221 215 219 212 | Captured only as a safety event as ‘COPD worsening’ | • Exac rate was similar among each of the high- and low-dose groups: o 9.0% (TIO/OLO 5/5 μg) and 8.7% (FP/SALM 500/50 μg) o 5.6% (TIO/OLO 5/2.5 μg) and 4.2% (FP/SALM 250/50 μg) |