. 2022 Mar 28;8(1):00556-2021. doi: 10.1183/23120541.00556-2021

TABLE 2.

Summary of clinical trials for SITT in OAD

Clinical trial	Trial design and end-points – primary/secondary	Patient population	Treatment and duration	Key findings
Global trials
TRILOGY EU [50]	• Phase 3, randomised, double-blind, parallel-group • Pre-dose and 2-hour post-dose morning FEV₁ at week 26 and TDI score at week 26 • COPD exacerbation rate at 52 weeks	• Age ≥40 years • Post-bronchodilator FEV₁ <50% • FEV₁/FVC <70% • ≥1 moderate or severe COPD exacerbation within 1 year of study • Use of ICS/LAMA, LABA/LAMA or LAMA ≥2 months • CAT score ≥ 10 • BDI focal score ≤10	Extrafine BDP/FF/GP pMDI 200/12/25 µg twice daily (n=687) vs Extrafine BDP/FF pMDI 200/12 µg twice daily (n=680) × 52 weeks	• SITT was superior to BDP/FF for pre-dose FEV₁ (MD 81 mL; p<0.001) and 2-hour post-dose FEV₁ (MD 117 mL; p<0.001) • TDI improved in both groups (MD 0.21 Units) • Moderate-to-severe exacerbations occurred in 31% and 35% for adjusted annual rate of 0.41 and 0.53 for SITT versus BDP/FF, respectively (RR 0.77; p=0.005) • Pneumonia rates were similar between the groups
TRINITY EU, South America, Mexico [51]	• Phase 3, randomised, double-blind, parallel-group • COPD exacerbation rate at 52 weeks • Pre-dose morning FEV₁ at week 26	• Current or ex-smokers • Age ≥40 years • Post-bronchodilator FEV₁ <50% • FEV₁/FVC <70% • ≥1 moderate or severe COPD exacerbation within 1 year • Use of ICS/LABA, ICS/LAMA, LABA/LAMA or LAMA ≥2 months • CAT score ≥10	Tiotropium DPI 18 μg QD(n=1076) vs Extrafine BDP/FF pMDI 200/12 μg twice daily plus tiotropium DPI 18 μg once daily (n=537) ×52 weeks	• SITT significantly improved pre-dose FEV₁ versus tiotropium (MD 61 mL; p<0.0001) • Rates of moderate-to-severe COPD exacerbations: SITT was superior to tiotropium (RR 0.80; p=0.0025) and similar to open TT • COPD exacerbation and pneumonia were similar in all treatment groups
TRIBUTE EU [52]	• Phase 3, randomised, double-blind, double-dummy, parallel-group • COPD exacerbation rate at 52 weeks • Pre-dose morning FEV₁	• Current or ex-smokers • Age ≥40 years • Post-bronchodilator FEV₁ <50% • FEV₁/FVC <70% • ≥1 moderate or severe COPD exacerbation within 1 year of study • Use of ICS/LABA, ICS/LAMA, LABA/LAMA or LAMA ≥2 months • CAT score ≥10	Extrafine BDP/FF/GP pMDI 200/12/25 μg twice daily (n=764) vs IND/GP DPI 85/43 μg once daily (n=768) ×52 weeks	• SITT significantly improved mean change from baseline in FEV₁ versus IND/GP at weeks 12 and 40 (MD 32 mL; p<0.01) • Rates of moderate-to-severe COPD exacerbations: SITT was superior to IND/GP (RR 0.85, p= 0.043) • COPD exacerbation and pneumonia were similar across all treatment groups
KRONOS Canada, China, Japan, USA [53]	• Phase 3, randomised, double-blind, parallel-group • COPD exacerbation rate at 24 weeks	• Current or ex-smokers (≥10 pack-years) • Age 40–80 years • Post-bronchodilator FEV₁ ≥25% to 80% • FEV₁/FVC <70% • Use of ≥2 inhaled maintenance therapies for ≥6 weeks • CAT score ≥10	BUD/GP/FF pMDI 320/18/9.6 μg twice daily (n =639) vs GFF pMDI 18/9.6 μg (n= 625) vs BUD/FF pMDI 320/9.6 μg twice daily (n=314) vs OL BUD/FF DPI 400/12 μg twice daily (n=318) ×24 weeks	• SITT significantly improved FEV₁ AUC versus both GFF (LSMD 104 mL; p<0.0001) and BUD/FF (LSMD 91 mL; p<0.0001) • SITT significantly improved pre-dose morning trough FEV₁ versus GFF (22 mL; p=0.139) and BUD/FF pMDI (74 mL; p<0.0001) • TDI focal score was significantly improved with SITT versus OL BUD/FF but not versus GFF • Rates of moderate-to-severe COPD exacerbations: SITT was superior to GFF (p<0.001) • Pneumonia rates were similar between the groups
ETHOS Australia, Canada, China, EU, South America, USA, UK [54]	• Phase 3, randomised, double-blind, parallel-group • COPD exacerbation rate • Time to death	• Current or ex-smokers • Age ≥40 years • Post-bronchodilator FEV₁ 25–65% • ≥1 moderate or severe COPD exacerbation within 1 year • Use of ICS or SAMA/SABA ≥2 months • CAT score ≥10	BDP/FF/GP MDI 160/9/4.8 µg twice daily (n=2137) vs BDP/FF/GP MDI 160/9/4.8 µg twice daily (n=2121) vs GP/FF MDI 9/4.8 µg twice daily (n=2120) vs BDP/FF MDI 160/4.8 µg twice daily (n=2131) × 52 weeks	• Rates of moderate-to-severe COPD exacerbations: 320-μg SITT was superior to GP/FF (RR 0.76; p<0.001), or BDP/FF 1.24 (RR 0.87; p<0.003); 160-μg SITT was superior to GP/FF (RR 0.75; p<0.001) or BDP/FF 1.24 (RR 0.86; p=0.002) • Low risk of mortality with 320-μg SITT: versus GP/FF (HR 0.54), versus BDP/FF (HR 0.78); low risk with 160-μg SITT versus GP/FF; HR 0.79) but higher versus BDP/FF (HR 1.13) • Pneumonia rates were high with high-dose SITT and BDP/FF
IMPACT Asia-Pacific, Canada, EU, South America, South Africa, USA, UK [55]	• Phase 3, randomised, double-blind, parallel-group • COPD exacerbation rate • Pre-dose morning FEV₁	• Ex-smokers • Age ≥40 years • Post-bronchodilator FEV₁ <50 • ≥1 moderate or severe COPD exacerbation within 1 year • Use of ICS or LAMA or LABA or in combination ≥2 weeks • CAT score ≥10	FF/UMEC/VI DPI 100/62.5/25 µg once daily (n=4151) vs UMEC/VI DPI 62.5/25 µg once daily (n=4134) vs FF/VI DPI 100/25 µg once daily (n=2070) × 52 weeks	• SITT significantly improved pre-dose FEV₁ versus UMEC/VI (MD 97 mL; p<0.001) and versus FF/VI (MD 54 mL; p<0.001) • Rates of moderate-to-severe COPD exacerbations: SITT was superior to UMEC/VI and FF/VI (RR 0.85 and 0.75, respectively; p<0.001 for both) • Significantly low risk of mortality with SITT versus UMEC/VI (HR 0.58, p_unadjusted=0.01) • Risk of clinician-diagnosed pneumonia was significantly higher with SITT versus UMEC/VI (HR 1.53; p<0.001)
TRIGGER EU [38]	• Phase 3, randomised, double-blind, parallel-group • Pre-dose morning FEV₁ • Asthma exacerbation rate	• Age 18–75 years • Uncontrolled asthma (ACQ-7 ≥1.5) • Pre-bronchodilator FEV₁ <80% • At least one exacerbation within 1 year • Use of high-dose ICS/LABA ≥4 weeks	BDP/FF/GP 200/6/10 μg MDI twice daily (n=573) vs BDP/FF 200/6 μg MDI twice daily (n=576) vs OL BDP/FF 200/6 μg MDI twice daily plus tiotropium 2.5 μg once daily (n=288) × 52 weeks	• SITT was superior to BDP/FF for pre-dose FEV₁ (improvement by 73 mL; p=0.0025) at week 26 • Rates of moderate-to-severe asthma exacerbations reduced by 12% for BDP/FF/GP versus BDP/FF, respectively (RR 0.88; p=0.11) • Pneumonia rates were similar between the groups
TRIMARAN EU [38]		• Similar to TRIGGER except use of medium-dose ICS/LABA ≥4 weeks	BDP/FF/GP 100/6/10 μg MDI twice daily (n=579) vs BDP/FF 100/6 μg MDI twice daily (n=576) × 52 weeks	• SITT was superior to BDP/FF for pre-dose FEV₁ (improvement by 57 mL; p=0.0080) at week 26 • Rates of moderate-to-severe asthma exacerbations reduced by 15% for BDP/FF/GP versus BDP/FF, respectively (RR 0.85; p=0.033) • No increased incidence of pneumonia with SITT
CAPTAIN Australia, Canada, EU, Japan, South Korea, South America, South Africa, USA, UK [39]	• Phase 3, randomised, double-blind, parallel-group • Pre-dose morning FEV₁ • Asthma exacerbation rates	• Age 18–75 years • Uncontrolled asthma (ACQ-7 ≥1.5) • Pre-bronchodilator FEV₁ 30–85% • Post-bronchodilator FEV₁ ≥12% and ≥200 mL in 20–60 min • Use of ICS/LABA ≥3 months	FF/UMEC/VI DPI 100/31.25/25 μg (n=405) once daily versus FF/UMEC/VI DPI 100/62.5/25 μg (n=406) once daily versus FF/UMEC/VI DPI 200/31.25/25 μg (n=404) once daily versus FF/UMEC/VI DPI 200/62.5/25 μg (n=408) once daily versus FF/VI 100/25 μg DPI (n=40) once daily versus FF/VI 200/25 μg DPI (n=406) once daily × 52 weeks	• High-dose LAMA SITT was superior to FF/VI 100/25 μg for pre-dose FEV₁ (LSMD, 110 mL; p<0.001); High-dose ICS SITT was superior to FF/VI 200/25 μg (92 mL; p<0.0001) • Adding UMEC 31.25 μg to FF/VI had similar outcomes; supported by FEV₁ at 3 hours post-dose • Rates of moderate-to-severe asthma exacerbation reductions were non-significant for FF/UMEC 62.5 μg/VI versus FF/VI (pooled analysis) • Pneumonia rates were similar between the groups
IRIDIUM Asia-Pacific, EU South America, UK [49]	• Phase 3, randomised, double-blind, double-dummy, parallel-group • Pre-dose morning FEV₁ • Asthma exacerbation rate	• Age 18–75 years • Uncontrolled asthma (ACQ-7 ≥1.5) • Pre-bronchodilator FEV₁ <80% • Post-bronchidilator increase in FEV₁ of ≥12% and ≥200 mL • Use of ICS/ LABA ≥3 months	MF/IND/GLY DPI 80/150/50 μg once daily (n=620) vs MF/IND/GLY DPI 160/150/50 μg once daily (n=619) vs MF/IND DPI 160/150 μg once daily (n=617) vs MF/IND DPI 320/150 μg once daily (n=618) vs FLU/SAL DPI 500/50 μg twice daily (n=618) × 52 weeks	• Medium and high-dose SITT was superior to corresponding doses of MF/IND for pre-dose FEV₁ (MD 76 mL; p<0.001 and MD 65 mL, respectively; p<0.001 for both) • Improvements in pre-dose FEV₁ were greater for both medium-dose SITT (99 mL; p<0.001) and high-dose triple therapy (119 mL; p<0.001) versus FLU/SAL at week 26 • Rates of moderate-to-severe asthma exacerbations reduced by 13% (medium dose) and 15% (high-dose) for SITT versus corresponding dose of MF/IND versus FLU/SAL • Pneumonia rates were similar between the groups
Indian trial
Salvi et al.; Indian double-blind RCT [42]	• Phase 3, randomised, double-blind, active-control, parallel-group, noninferiority study • COPD patients • Change from baseline in trough FEV₁ at the end of 12 weeks	• COPD patients • Age ≥40 to ≤75 years, with FEV₁/FVC <0.70 • Using mono/dual therapy with ICSs, LAMAs, or LABAs for ≥1 month	GB/FF/FP 12.5/12/250 μg twice daily (n=198) or GB/FF/FP 50/12/250 μg twice daily (n=198) for 12 weeks	• LSMD in pre-dose FEV₁ from baseline at 12 weeks was noninferior between the groups (p<0.05) • LSMD change from baseline in post-dose FEV₁ was comparable (p=0.38) • Comparable efficacy in terms of change in trough FEV₁

ACQ: Asthma Control Questionnaire; AE: adverse events; BDI: baseline dyspnoea index; BDP/FF/GP: beclomethasone/formoterol/glycopyrronium; BUD/GP/FF: budesonide/ glycopyrronium/formoterol fumarate; DPI: dry powder inhaler; CAT: COPD assessment test; FF/UMEC/VI: fluticasone furoate/umeclidinium/vilanterol; FEV₁: forced expiratory volume in 1 s; FEV₁ AUC: FEV₁ area under the curve; FVC: forced vital capacity; FLU/SAL: fluticasone propionate/salmeterol; GFF: glycopyrronium and formoterol fumarate; ICS: inhaled corticosteroid; LABA: long-acting β-agonist; LAMA: long-acting muscarinic antagonist; LSMD: least squares mean difference; MD: mean difference; MF/IND/GLY: mometasone/indacaterol/glycopyrronium; OAD: obstructive airway disease; OL: open label; pMDI: pressurised metered-dose inhalers; RR: rate ratio; SABA: short-acting β-agonists; SAMA: short-acting muscarinic antagonists; SGRQ: St. George's Respiratory Questionnaire; SITT: single-inhaler triple therapy; TDI: transition dyspnoea Index; TT: triple therapy.