Studies comparing ICS/LAMA/LABA triple therapy with non-ICS-containing treatment |
Pneumonia capture: investigator reporting confirmed by radiographic imaging and independent adjudication |
Rabe, 2020 [14] | ETHOS (52 weeks) | Post-bronchodilator FEV1 25–50% pred and ≥1 moderate/severe exacerbation or post-bronchodilator FEV1 50–65% pred and ≥2 moderate or ≥1 severe exacerbation in the year prior to screening CAT total score ≥10 | Investigator reported, adjudicated by a clinical end-point independent committee Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required to support the adjudication | BUD/GLY/FOR 320/18/9.6 µg twice daily: 4.2% (90/2144) BUD/GLY/FOR 160/18/9.6 µg twice daily: 3.5% (75/2124) BUD/FOR 320/9.6 µg twice daily: 4.5% (96/2136) | GLY/FOR 18/9.6 µg twice daily: 2.3% (48/2125) | BUD/GLY/FOR 320/18/9.6 µg versus GLY/FOR | 1.9 |
BUD/GLY/FOR 160/18/9.6 µg versus GLY/FOR | 1.6 |
BUD/FOR versus GLY/FOR | 2.0 |
Ferguson, 2018 [26] | KRONOS (24 weeks) | Post-bronchodilator FEV1 ≥25% and <80% pred CAT total score ≥10 | Investigator reported, adjudicated by an independent committee Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required | BUD/GLY/FOR 320/18/9.6 μg twice daily via MDI: 1.9% (12/639) BUD/FOR 320/9.6 μg twice daily via MDI: 1.9% (6/314) BUD/FOR 400/12 µg twice daily via DPI: 1.3% (4/318) | GLY/FOR 18/9.6 μg twice daily via MDI: 1.6% (10/625) | BUD/GLY/FOR versus GLY/FOR | 1.2 |
BUD/FOR 320/9.6 µg via MDI versus GLY/FOR | 1.2 |
BUD/FOR 400/12 µg via DPI versus GLY/FOR | 0.8 |
Pneumonia capture: investigator reporting confirmed by radiographic imaging |
Chapman, 2018
[27] | SUNSET (26 weeks) | Post-bronchodilator FEV1 ≥40% and <80% pred ≤1 moderate/severe exacerbation in the year prior to screening | Investigator reported Radiographic imaging was required to confirm the diagnosis of pneumonia | TIO 18 µg once daily plus SAL/FP 50/500 µg twice daily: 1.7% (9/526) | IND/GLY 110/50 µg once daily: 1.1% (6/527) | TIO+SAL/FP versus IND/GLY | 1.5 |
Lipson, 2018 [13] | IMPACT (52 weeks) | Post-bronchodilator FEV1 <50% pred with ≥1 moderate/severe exacerbation in the year prior to screening, or post-bronchodilator FEV1 50–80% pred and ≥2 moderate or ≥1 severe exacerbation in the year prior to screening CAT total score ≥10 | Investigator reported Radiographic imaging was required to confirm the diagnosis of pneumonia | FF/UMEC/VI 100/62.5/25 µg once daily: 7.6% (317/4151) FF/VI 100/25 µg once daily: 7.1% (292/4134) | UMEC/VI 62.5/25 µg once daily: 4.7% (97/2070) | FF/UMEC/VI versus UMEC/VI | 1.6 |
FF/VI versus UMEC/VI | 1.5 |
Magnussen, 2014 [28] | WISDOM (52 weeks) | Post-bronchodilator FEV1 <50% pred ≥1 exacerbation in the year prior to screening | Investigator reported Radiographic imaging was requested when pneumonia was suspected | FP/SAL/TIO (500 µg twice daily/50 µg twice daily/18 µg once daily): 5.8% (72/1243) | SAL/TIO (50 µg twice daily/18 µg once daily): 5.5% (68/1242) | FP/SAL/TIO versus SAL/TIO | 1.1 |
Pneumonia capture: investigator reporting |
Papi, 2018 [12] | TRIBUTE (52 weeks) | Post-bronchodilator FEV1 <50% pred ≥1 moderate/severe exacerbation in the year prior to screening CAT total score ≥10 | Investigator reported | BDP/FOR/GLY 87/5/9 µg twice daily: 3.7% (28/764) | IND/GLY 85/43 µg: 3.6% (27/768) | BDP/FOR/GLY versus IND/GLY | 1.0 |
Vestbo, 2017 [29] | TRINITY (52 weeks) | Post-bronchodilator FEV1 <50% pred ≥1 moderate/severe exacerbation in the year prior to screening CAT total score ≥10 | Investigator reported | BDP/FOR/GLY 100/6/12.5 µg (2 actuations twice daily): 2.6% (28/1077) BDP/FOR 100/6 µg (2 actuations twice daily)+TIO 18 µg (1 actuation once daily): 2.2% (12/537) | TIO 18 µg once daily: 1.8% (19/1076) | BDP/FOR/GLY versus TIO | 1.5 |
BDP/FOR+TIO versus TIO | 1.3 |
Jung, 2012 [30] | (24 weeks) | Post-bronchodilator FEV1 <65% pred | Investigator reported | TIO 18 µg once daily+FP/SAL 250/50 µg twice daily: 0.9% (2/223) | TIO 18 µg once daily: 0.9% (2/232) | TIO+FP/SAL versus TIO | 1.0 |
Studies comparing ICS/LABA dual therapy with non-ICS-containing treatment |
Pneumonia capture: investigator reporting and independent adjudication with/without confirmation by radiographic imaging |
Hanania, 2020 [31] | SOPHOS (52 weeks) | Post-bronchodilator FEV1 ≥25% and <80% pred ≥1 moderate/severe exacerbation in the year prior to screening CAT total score ≥10 | Investigator reported, adjudicated by an independent committee | BUD/FOR 320/10 µg twice daily: 1.6% (10/619) BUD/FOR 160/10 µg twice daily: 2.4% (15/617) | FOR 10 µg twice daily: 2.3% (14/607) | BUD/FOR 320/10 µg versus FOR BUD/FOR 160/10 µg versus FOR | 0.7 1.1 |
Ferguson, 2018 [32] | TELOS (24 weeks) | Post-bronchodilator FEV1 <80% pred CAT total score ≥10 | Investigator reported, adjudicated by an independent committee Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required | BUD/FOR 320/10 μg twice daily via MDI: 0.8% (5/655) BUD/FOR 160/10 μg twice daily via MDI: 1.1% (7/637) BUD 320 µg twice daily via MDI: 0.5% (1/206) BUD/FOR 400/12 µg twice daily via DPI: 1.4% (3/219) | FOR 10 µg twice daily via MDI: 1.4% (9/644) | BUD/FOR 320/10 μg versus FOR | 0.5 |
BUD/FOR 160/10 μg versus FOR | 0.8 |
BUD versus FOR | 0.3 |
BUD/FOR 400/12 µg via DPI versus FOR | 1.0 |
Pneumonia capture: investigator reporting confirmed by radiographic imaging |
Ferguson, 2017 [33] | RISE (26 weeks) | Post-bronchodilator FEV1 ≤70% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2 | Investigator reported Radiographic imaging compatible with the diagnosis of pneumonia and ≥2 of a list of clinical signs, symptoms or laboratory findings were also required | BUD/FOR 320/9 µg twice daily: 0.5% (3/605) | FOR DPI 9 µg twice daily: 1.0% (6/613) | BUD/FOR versus FOR | 0.5 |
Papi, 2017 [24] | EFFECT (52 weeks) | Post-bronchodilator FEV1 ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported Radiologically and/or clinically confirmed per British Thoracic Society criteria | FP/FOR 500/20 μg twice daily: 2.9% (17/587) FP/FOR 250/10 μg twice daily: 3.9% (23/588) | FOR 12 µg twice daily: 1.9% (11/590) | FP/FOR 500/20 μg versus FOR | 1.6 |
FP/FOR 250/10 μg versus FOR | 2.1 |
Wedzicha, 2016 [34] | FLAME (52 weeks) | Post-bronchodilator FEV1 ≥25 to <60% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2 | Investigator reported Radiographic imaging was required | FP/SAL 500/50 µg twice daily: 4.8% (80/1680) | IND/GLY 110/50 µg once daily: 3.2% (53/1678) | FP/SAL versus IND/GLY | 1.5 |
Ohar, 2014 [35] | NCT01110200 (26 weeks) | Post-bronchodilator FEV1 <70% pred Recent exacerbation (≤14 days) | Investigator reported Radiographic imaging was required | FP/SAL 250/50 µg twice daily: 4.1% (13/314) | SAL 50 µg twice daily: 3.1% (10/325) | FP/SAL versus SAL | 1.3 |
Vogelmeier, 2013 [36] | ILLUMINATE (26 weeks) | Post-bronchodilator FEV1 40–80% pred 0 moderate/severe exacerbations in the year prior to screening | Investigator reported Radiographic imaging was required | FP/SAL 500/50 µg twice daily: 1.5% (4/264) | IND/GLY 110/50 µg once daily: 0 (0/258) | | |
Anzueto, 2009 [10] | NCT00115492 (52 weeks) | Post-bronchodilator FEV1 ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported Radiographic imaging was required | FP/SAL 250/50 µg twice daily: 6.6% (26/394) | SAL 50 µg twice daily: 2.5% (10/403) | FP/SAL versus SAL | 2.7 |
Pneumonia capture: investigator reporting |
Suissa, 2018 [37] | Up to 1-year follow-up | Cohort of patients aged ≥55 years with COPD initiating treatment with a LAMA or ICS/LABA during 2002–2015 from the UK's Clinical Practice Research Datalink | Hospital admissions due to severe pneumonia (according to diagnostic codes) | ICS/LABA: 3.1% (380/12 366) | LAMA: 2.3% (279/12 366) of patients | ICS/LABA versus LAMA | 1.4 |
Vestbo, 2016 [38], Crim, 2017 [39] | SUMMIT (event driven, common end date of 3 years) | Post-bronchodilator FEV1 ≥50% and ≤70% pred History or increased risk of cardiovascular disease mMRC dyspnoea score ≥2 | Investigator reported | FF/VI 100/25 µg once daily: 5.7% (237/4140) FF 100 µg once daily: 5.5% (228/4157) | VI 25 µg once daily: 3.9% (163/4140) Placebo: 5.2% (214/4131) | FF/VI versus VI | 1.5 |
FF versus placebo | 1.1 |
Vestbo, 2016 [40] | Salford Lung Study (52 weeks) | ≥1 COPD exacerbations in the previous 3 years | Investigator reported pneumonia SAEs | FF/VI 100/25 µg once daily: 6.7% (94/1396) | Usual care: 5.9% (83/1403) | FF/VI 100/25 µg versus usual care | 1.1 |
Vogelmeier, 2016 [41] | AFFIRM (24 weeks) | Post-bronchodilator FEV1 <80% pred CAT total score ≥10 | Investigator reported | FP/SAL 500/50 µg twice daily: 1.9% (9/466) | ACL/FOR 400/12 µg twice daily: 0.6% (3/467) | FP/SAL versus ACL/FOR | 3.2 |
Zheng, 2015 [42] | NCT01376245 (24 weeks) | Asian patients Post-bronchodilator FEV1 ≤70% pred mMRC dyspnoea score ≥2 | Investigator reported | FF/VI 50/25 µg: 1.3% (2/160) FF/VI 100/25 µg: 0.6% (1/161) FF/VI 200/25 µg: 3.1% (5/160) | Placebo: 2.5% (4/162) | FF/VI 50/25 µg versus placebo | 0.5 |
FF/VI 100/25 µg versus placebo | 0.3 |
FF/VI 200/25 µg versus placebo | 1.3 |
Zhong, 2015 [43] | LANTERN (26 weeks) | Post-bronchodilator FEV1 ≥30% and <80% pred ≤1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2 | Investigator reported | FP/SAL 500/50 µg: 2.7% (10/369) | IND/GLY 110/50 µg: 0.8% (3/372) | FP/SAL versus IND/GLY | 3.4 |
Rossi, 2014 [44] | INSTEAD (26 weeks) | GOLD stage II 0 moderate/severe exacerbation in the year prior to screening | Investigator-reported pneumonia SAEs | FP/SAL 500/50 µg twice daily: 0.7% (2/288) | IND 150 µg once daily: 0 (0/293) | FP/SAL versus IND | |
Wedzicha, 2014 [45] | FORWARD (48 weeks) | Post-bronchodilator FEV1 ≥30% and <50% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported | BDP/FOR 200/12 µg twice daily: 3.8% (23/601) | FOR 12 µg twice daily: 1.8% (11/596) | BDP/FOR versus FOR | 2.1 |
Dransfield, 2013 [46], Crim, 2015 [47] | NCT01009463, NCT01017952 (52 weeks) | Post-bronchodilator FEV1 <70% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported | FF/VI 200/25 µg once daily: 6.8% (55/811) FF/VI 100/25 µg once daily: 6.3% (51/806) FF/VI 50/25 µg once daily: 5.9% (48/820) | VI 25 µg once daily: 3.3% (27/818) | FF/VI 50/25 µg versus VI | 1.8 |
FF/VI 100/25 µg versus VI | 1.9 |
FF/VI 200/25 µg versus VI | 2.1 |
Kerwin, 2013 [48] | NCT01053988 (24 weeks) | Post-bronchodilator FEV1 ≤70% pred mMRC dyspnoea score ≥2 | Investigator reported | FF/VI 100/25 µg once daily: 2.4% (5/206) FF/VI 50/25 µg once daily: 1.5% (3/206) FF 100 µg once daily: 1.9% (4/206) | VI 25 µg once daily: 2.4% (5/205) Placebo: 1.4% (3/207) | FF/VI 100/25 µg versus VI | 1.0 |
FF/VI 50/25 µg versus VI | 0.6 |
FF versus placebo | 1.3 |
Martinez, 2013 [49] | NCT01054885 (24 weeks) | Post-bronchodilator FEV1 ≤70% pred mMRC dyspnoea score ≥2 | Investigator reported | FF/VI 200/25 µg once daily: 2.0% (4/205) FF/VI 100/25 µg once daily: 0.5% (1/204) FF 200 µg once daily: 1.5% (3/203) FF 100 µg once daily: 1.0% (2/204) | VI 25 µg once daily: 1.0% (2/203) Placebo: 0 (0/205) | FF/VI 200/25 µg versus VI | 2.0 |
FF/VI 100/25 µg versus VI | 0.5 |
FF 200 µg versus VI | 1.5 |
FF 100 µg versus VI | 1.0 |
Doherty, 2012 [50] | (52 weeks) | Post-bronchodilator FEV1 25–60% pred Symptoms of COPD for ≥24 months prior to enrolment | Investigator reported | MF/FOR 400/10 µg twice daily: 3.1% (7/225) MF/FOR 200/10 µg twice daily: 1.7% (4/239) MF 400 µg twice daily: 2.0% (5/253) | FOR 10 µg twice daily: 1.6% (4/243) Placebo: 0.8% (2/236) | MF/FOR 400/10 µg versus FOR | 1.9 |
MF/FOR 200/10 µg versus FOR | 1.0 |
MF versus placebo | 2.3 |
Tashkin, 2012 [51] | NCT00383435 (52 weeks) | Post-bronchodilator FEV1 ≥25% and ≤60% pred Symptoms of COPD for ≥24 months | Investigator reported | MF/FOR 400/10 µg twice daily: 1.8% (4/217) MF/FOR 200/10 µg twice daily: 0.5% (1/207) MF 400 µg twice daily: 1.0% (2/210) | FOR 10 µg twice daily: 1.9% (4/209) | MF/FOR 400/10 µg versus FOR | 1.0 |
MF/FOR 200/10 µg versus FOR | 0.3 |
MF versus FOR | 0.5 |
Sharafkhaneh, 2012 [52] | NCT00419744 (52 weeks) | Pre-bronchodilator FEV1 ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported | BUD/FOR 320/9 µg twice daily: 6.4% (26/407) BUD/FOR 160/9 µg: 4.7% (19/408) | FOR 9 µg twice daily: 2.7% (11/403) | BUD/FOR 320/9 µg versus FOR | 2.3 |
BUD/FOR 160/9 µg versus FOR | 1.7 |
Calverley, 2010 [53] | NCT00476099 (48 weeks) | Post-bronchodilator FEV1 30–50% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported | BDP/FOR 200/12 µg twice daily: 2.2% (5/232) BUD/FOR 400/12 µg twice daily: 2.9% (7/238) | FOR 12 µg twice daily: 0.4% (1/233) | BDP/FOR versus FOR | 5.0 |
BUD/FOR versus FOR | 6.9 |
Rennard, 2009 [54] | NCT00206167 (52 weeks) | Post-bronchodilator FEV1 ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2 | Investigator reported | BUD/FOR 320/9 µg twice daily: 4.0% (20/494) BUD/FOR 160/9 µg twice daily: 3.4% (17/494) | FOR 9 µg twice daily: 3.4% (17/495) Placebo: 5.0% (24/481) | BUD/FOR 320/9 µg versus FOR | 1.2 |
BUD/FOR 160/9 µg versus FOR | 1.0 |
Ferguson, 2008 [11] | NCT00144911 (52 weeks) | Post-bronchodilator FEV1 ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening | Investigator reported | FP/SAL 250/50 µg twice daily: 7.4% (29/394) | SAL 50 µg twice daily: 3.9% (15/388) | FP/SAL versus SAL | 1.9 |
Tashkin, 2008 [55] | NCT00206154 (26 weeks) | Pre-bronchodilator FEV1 ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2 | Investigator reported | BUD/FOR 320/9 µg twice daily: 0.4% (1/277) BUD/FOR 160/9 µg twice daily: 0.7% (2/281) BUD 320 µg twice daily+FOR 9 µg twice daily: 0.7% (2/287) BUD 320 µg twice daily: 1.1% (3/275) | FOR 9 µg twice daily: 0.4% (1/284) Placebo: 0.3% (1/300) | BUD/FOR 320/9 µg versus FOR | 1.0 |
BUD/FOR 160/9 µg versus FOR | 2.0 |
BUD 320 µg+FOR 9 µg versus FOR | 2.0 |
BUD versus placebo | 3.3 |
Wedzicha, 2008 [56], Calverley, 2011 [57] | INSPIRE (2 years) | Post-bronchodilator FEV1 <50% pred, mMRC dyspnoea score ≥2, clinical history of exacerbations | Investigator reported | FP/SAL 500/50 µg twice daily: 7.6% (50/658) | TIO 18 µg once daily: 3.6% (24/665) | FP/SAL versus TIO | 2.1 |
Calverley, 2007 [58], Crim, 2009 [59] | TORCH (3 years) (pneumonia incidences from a post hoc analysis focusing on pneumonia are reported here) | Pre-bronchodilator FEV1 <60% pred | Investigator reported | FP 500 µg twice daily: 14.4% (224/1552) FP/SAL 500/50 µg twice daily: 16.0% (248/1546) | SAL 50 µg twice daily: 10.5% (162/1542) Placebo: 9.0% (139/1544) | FP/SAL versus SAL | 1.5 |
FP versus placebo | 1.6 |