. 2020 Nov 27;15:3105–3122. doi: 10.2147/COPD.S273497

Table 5.

Efficacy of Formoterol in Triple Therapy Combinations

Clinical Trial	Patient Population	Treatments and Duration^a	Key Findings
TRILOGY⁴⁰ EU	Age ≥40 years Postbronchodilator FEV₁ <50% FEV₁/FVC <70% ≥1 moderate or severe COPD exacerbation within 1 year of study Use of ICS/LABA, ICS/LAMA, LAMA/LABA, or LAMA monotherapy ≥2 months CAT score ≥10 BDI focal score ≤10	Extrafine BDP/FF/GP pMDI 200/12/25 μg BID (n=687) vs Extrafine BDP/FF pMDI 200/12 μg BID (n=680) × 52 weeks	Triple therapy was superior to BDP/FF for predose FEV₁ (mean difference, 81 mL; p<0.001) and 2-hour postdose FEV₁ (mean difference, 117 mL; p<0.001) at week 26 TDI improved in both groups (mean difference, 0.21 units) Moderate to severe exacerbations occurred in 31% and 35% for adjusted annual rates of 0.41 and 0.53 for BDP/FF/GP vs BDP/FF, respectively (RR, 0.77; p=0.005) In patients with history of >1 exacerbation, BDP/FF/GP reduced rate of moderate to severe exacerbations by 33% (p=0.019) Treatment-emergent AEs were similar between groups
TRINITY⁴¹ EU, South America, Mexico	Current or ex-smokers Age ≥40 years Postbronchodilator FEV₁ <50% FEV₁/FVC <70% ≥1 moderate or severe COPD exacerbation within 1 year of study Use of ICS/LABA, ICS/LAMA, LAMA/LABA, or LAMA monotherapy ≥2 months CAT score ≥10	Extrafine BDP/FF/GP pMDI 200/12/25 μg BID (n=1077) vs Tiotropium DPI 18 μg QD (n=1076) vs Extrafine BDP/FF pMDI 200/12 μg BID plus tiotropium DPI 18 μg QD (n=537) × 52 weeks	Rates (per-patient per-year) of moderate to severe COPD exacerbations were 0.46 for BDP/FF/GP, 0.57 for tiotropium, and 0.45 for BDP/FF + tiotropium Fixed triple therapy was superior to tiotropium (p=0.0025) Fixed and open triple therapy were similar Reductions in exacerbations were greater for patients with eosinophil count ≥2% BDP/FF/GP also significantly improved predose FEV₁ vs tiotropium (mean difference, 61 mL; p<0.0001) Most common AE was COPD exacerbation and pneumonia was reported in all treatment groups (BDP/FF/GP, 3%; tiotropium, 2%, BDP/FF + tiotropium, 2%)
TRIBUTE⁴² EU	Current or ex-smokers Age ≥40 years Postbronchodilator FEV₁ <50% FEV₁/FVC <70% ≥1 moderate or severe COPD exacerbation within 1 year of study Use of ICS/LABA, ICS/LAMA, LAMA/LABA, or LAMA monotherapy ≥2 months CAT score ≥10	Extrafine BDP/FF/GP pMDI 200/12/20 μg BID (n=764) vs IND/GP DPI 85/43 μg QD (n=768) × 52 weeks	Rates (per-patient per-year) of moderate to severe COPD exacerbations were 0.50 for BDP/FF/GP and 0.59 for IND/GP (RR, 0.85; p=0.043) Reductions in exacerbations were greater for patients with eosinophil count ≥2% BDP/FF/GP also significantly improved mean change from baseline in FEV₁ vs IND/GP at weeks 12 and 40 (mean difference, 32 mL; p<0.01) Most common AE was COPD exacerbation; pneumonia was reported in 4% of patients in each treatment group
KRONOS⁵¹ Canada, China, Japan, US	Current or ex-smokers (≥10 pack-years) Age 40–80 years Postbronchodilator 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 BID (n=639) vs GFF pMDI 18/9.6 μg BID (n=625) vs BUD/FF pMDI 320/9.6 μg BID (n=314) vs OL BUD/FF DPI 400/12 μg BID (n=318) × 24 weeks	Triple therapy significantly improved FEV₁ AUC_0–4h vs both BUD/FF arms (LSM difference, 104 mL and 91 mL; both p<0.0001) BUD/GP/FF also significantly improved predose morning trough FEV₁ vs GFF (22 mL; p=0.139) and BUD/FF pMDI (74 mL; p<0.0001) Annual rates of moderate to severe COPD exacerbations were 0.46 for BUD/FF/GP vs 0.95 for GFF (p<0.0001), 0.56 for BUD/FF pMDI, and 0.55 for BUD/FF DPI TDI focal score was significantly improved with triple therapy vs BUD/FF DPI but not vs GFF or BUD/FF pMDI Most common AEs were nasopharyngitis and upper respiratory tract infection; pneumonia occurred in 2% of all groups except OL BUD/FF DPI, where it occurred in 1%
ETHOS⁴⁴^,⁴⁵ EU, China, US	Current or ex-smokers (≥10 pack-years) Age 40–80 years Postbronchodilator FEV₁ <65% FEV₁/FVC <70% Moderate or severe exacerbation history within 1 year of study: ≥1, if postbronchodilator FEV₁ <50% ≥2 moderate or ≥1 severe, if postbronchodilator FEV₁ ≥50% Use of ≥2 inhaled maintenance therapies for ≥6 weeks CAT score ≥10	BUD/GP/FF pMDI 320/18/9.6 μg BID vs BUD/GP/FF pMDI 160/18/9.6 μg BID vs BUD/FF pMDI 320/9.6 μg BID vs GFF pMDI 18/9.6 μg BID All products formulated using co-suspension technology × 52 weeks	Both doses of BUD/GP/FF significantly reduced moderate or severe exacerbations vs dual therapies, GFF, and BUD/FF

Abbreviations: AE, adverse event; AUC_0–4h, area under the curve from 0 to 4 hours; BDI, baseline dyspnea index; BDP, beclomethasone dipropionate; BID, twice daily; BUD, budesonide; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; EU, European Union; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; FVC, forced vital capacity; GFF, glycopyrronium/formoterol fumarate; GP, glycopyrronium bromide; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; LSM, least squares mean; OL, open-label; pMDI, pressurized metered-dose inhaler; QD, once daily; RR, rate ratio; TDI, Transition Dyspnea Index; US, United States.

Note: ^aBold font indicates trial duration.