Formoterol for the Treatment of Chronic Obstructive Pulmonary Disease

Figures & data

Table 1 Comparative Pharmacology and Pharmacokinetic Characteristics of LABAs

Characteristic	Formoterol	Indacaterol	Olodaterol	Vilanterol	Salmeterol
B2 agonism	Full agonist	Partial agonist	Nearly full agonist	Partial agonist	Partial agonist
Selectivity	β2 > β3 > β1	β2 > β3 > β1	β2 >> β1 > β3	β2 >> β3 > β1	β2 >> β1 > β3
Potency	++	+	++	++	+
Lipophilicity	++	+++	++	+++	+++
Elimination half-life	~10 hours	40–56 hours	7.5 hours	21 hours	5.5 hours
Onset of action in COPD	Within 5 minutes	Within 5 minutes	Within 5 minutes	Within 5 minutes	~10 minutes
Duration of action	12 hours	24 hours	≥24 hours	22 hours	12 hours

Note: Data from these studies.^{1,3–7,53–59}

Abbreviations: COPD, chronic obstructive pulmonary disease; LABA, long-acting β₂-agonist.

Figure 1 The bronchodilator effect of formoterol occurs rapidly. A single inhalation of medication was administered to 24 patients with stable COPD in a randomized, three-way, crossover study. Reprinted from Respiratory Medicine, Vol 95 (10), Benhamou et al, Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradil Aerolizer) with salbutamol (Ventodisk), pages 817–821, Copyright 2001, with permission from Elsevier.⁸

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second.

Table 2 Available Formoterol Products

Formoterol Products	Brand Name	Delivery Method	Approvals	Dosage
Monotherapy products
Formoterol	Atimos Modulite^®	pMDI	EU	12 μg BID; up to 4 inhalations daily for severe COPD
Formoterol inhalation powder^a	Foradil Aerolizer^®	Capsule used with Aerolizer inhaler	US 2001 EU	12 μg every 12 hours
Formoterol inhalation solution	Perforomist^®	Nebulizer	US 2001	One 20 μg/2 mL vial every 12 hours
Combination with corticosteroid
Mometasone-formoterol	Dulera^®	pMDI	US 2010 (asthma only)	No COPD indication
Beclomethasone-formoterol	Fostair^® (EU) Fostex^® (Poland)	pMDI and DPI	EU	100/6 μg per inhalation; 2 inhalations BID 100/6 μg per inhalation (dosing frequency not specified)
Budesonide-formoterol	Symbicort^® Symbicort Turbohaler^® Fobumix Easyhaler^®	pMDI DPI DPI	US 2006 EU 2014 EU 2016	160/4.5 μg per inhalation; 2 inhalations BID 200/6 μg per inhalation; 2 inhalations BID 160/4.5 μg per inhalation; 2 inhalations BID
Combination with LAMA
Glycopyrrolate-formoterol	Bevespi AEROSPHERE^®	pMDI (co-suspension technology)	US 2016 EU 2018	9/4.8 μg per inhalation; 2 inhalations BID
Aclidinium-formoterol	Duaklir Pressair^® Duaklir Genuair^®	DPI DPI	US 2019 EU 2014	400/12 μg per inhalation; 1 inhalation BID 340/12 μg per inhalation; 1 inhalation BID
Triple therapy (LABA, LAMA, ICS)
Budesonide-glycopyrrolate- formoterol	Breztri AEROSPHERE^®	pMDI	US 2020	160/9/4.8 µg per inhalation; 2 inhalations BID
Beclomethasone-formoterol-glycopyrronium	Trimbow^®	pMDI	EU 2017	100/6/10 μg per inhalation; 2 inhalations BID

Note: ^aNo longer available.

Abbreviations: BID, twice daily; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; EU, European Union; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; pMDI, pressurized metered-dose inhaler; US, United States.

Table 3 Efficacy of Formoterol in Combination with ICS

Clinical Trial	Patient Population	Treatments and Duration^a	Key Findings
SHINE^Citation19 US, EU, South Africa	Current or ex-smokers (≥10 pack-years) Age ≥40 years COPD dx and symptoms >2 years ≥1 COPD exacerbation within 1 year of study Use of SABA as rescue medication Prebronchodilator FEV1 ≤50% FEV1/FVC <70% mMRC dyspnea ≥2	BUD/FF HFA pMDI 2 doses: 320/9 μg BID (n=277) 160/9 μg BID (n=281) vs Monocomponents (BUD [n=275] or FF [n=284] alone or in combination via separate inhalers BUD + FF [n=287]) vs Placebo (n=300) × 26 weeks	BUD/FF 320/9 μg significantly improved predose FEV1 (p≤0.026) and 1-hour postdose FEV1 (p≤0.039) vs BUD, FF, placebo BUD/FF 160/9 μg significantly improved predose FEV1 (p≤0.002) and 1-hour postdose FEV1 (p<0.001) vs BUD, placebo FF alone significantly improved predose FEV1 (p=0.039) and 1-hour postdose FEV1 vs placebo (p<0.001) Both BUD/FF doses significantly improved COPD-related symptoms and decreased daily rescue medication use vs placebo Most common AEs: COPD (highest in FF group), nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and diarrhea; no difference in pneumonia between treatment groups
SUN^Citation20 US, EU, Mexico	Current or ex-smokers (≥10 pack-years) Age ≥40 years COPD dx and symptoms >2 years ≥1 COPD exacerbation within 1 year of study Use of SABA as rescue medication Prebronchodilator FEV1 ≤50% FEV1/FVC <70% mMRC dyspnea ≥2	BUD/FF HFA pMDI 2 doses: 320/9 μg BID (n=494) 160/9 μg BID (n=494) vs FF DPI 9 μg BID (n=495) vs Placebo (n=481) × 52 weeks	BUD/FF 320/9 μg significantly improved predose FEV1 and 1-hour postdose FEV1 vs FF (p≤0.023) and placebo (p<0.001) BUD/FF 160/9 μg significantly improved predose FEV1 and 1-hour postdose FEV1 vs placebo (p<0.001) The number of exacerbations per patient-treatment year was reduced by 37% and 41%, respectively, with BUD/FF 320/9 μg and 160/9 μg vs placebo (p<0.001) and by 25% and 29% vs FF alone (p≤0.004) Most common AEs: oral candidiasis, COPD, dysphonia; incidence of pneumonia-related AEs similar between treatment groups
RISE^Citation21 US, Mexico, South America, EU, South Africa	Current or ex-smokers (≥10 pack-years) Age ≥40 years COPD dx and symptoms >1 year ≥1 moderate/severe COPD exacerbation within 1 year of study Use of SABA as rescue medication Postbronchodilator FEV1 ≤70% FEV1/FVC <70% mMRC dyspnea ≥2	BUD/FF pMDI 320/9 μg BID (n=606) vs FF DPI 9 μg BID (n=613) × 26 weeks	The annual rate of exacerbations (per patient-year) was significantly reduced by 24% with BUD/FF vs FF (0.85 vs 1.12; p=0.006) Time to first exacerbation was significantly reduced by 22% with BUD/FF vs FF (p=0.0164) BUD/FF also significantly reduced nighttime awakenings and rescue medication use Incidence of AEs was similar between treatment groups; most common AEs were COPD, nasopharyngitis
TELOS^Citation22 US, Canada, EU	Current or ex-smokers (≥10 pack-years) Age 40–80 years Symptomatic COPD (CAT score ≥10) despite treatment with ≥1 bronchodilator for ≥6 weeks Postbronchodilator FEV1 ≥30% but <80% FEV1/FVC <70%	BUD/FF MDI (co-suspension delivery) 320/10 μg BID (n=655) vs BUD/FF MDI (co-suspension delivery) 160/10 μg BID (n=637) vs BUD MDI 320 μg BID (n=206) vs FF MDI 10 μg BID (n=644) vs BUD/FF DPI 400/12 μg BID (n=219) × 24 weeks	BUD/FF 320/10 μg significantly improved morning predose trough FEV1 vs FF (LSM 39 mL; p=0.0018); differences between BUD/FF 160/10 μg vs FF were numerically but not significantly improved Differences in predose FEV1 were greater for patients with eosinophils ≥150 cells/mm^3 between BUD/FF 320/10 and 160/10 μg vs FF MDI BUD/FF 320/9 μg and BUD/FF 160/9 μg significantly improved FEV1 AUC0–4h vs BUD (p<0.0001) The adjusted annual rate of exacerbations (per-patient per-year) was significantly reduced with BUD/FF 320/10 and 160/10 μg vs FF MDI (0.44 and 0.50 vs 0.69; p≤0.0094) AEs were similar across treatment groups, with a low incidence of pneumonia in all groups
Calverley et al^Citation23 EU	Current or ex-smokers (≥20 pack-years) Age ≥40 years COPD dx and symptoms >2 years ≥1 COPD exacerbation within 1 year of study Postbronchodilator FEV1 30% to 50% FEV1/FVC <70%	Extrafine BDP/FF pMDI 200/12 μg BID (n=232) vs BUD/FF DPI 400/12 μg BID (n=238) vs FF DPI 12 μg BID (n=233) × 48 weeks	BDP/FF and BUD/FF significantly improved predose morning FEV1 vs FF (77 mL and 80 mL vs 26 mL; p=0.046) The mean rate of exacerbations (per-patient per-year) was similar between treatments: BDP/FF, 0.41; BUD/FF, 0.42; and FF, 0.43 Rates of hospitalization due to exacerbation were significantly higher with BDP/FF vs BUD/FF and FF: 0.074, 0.033, and 0.040 (p≤0.008) AEs were similar between treatment groups; most common AE: COPD exacerbation/worsening
FORWARD^Citation16 EU	Current or ex-smokers (≥10 pack-years) Age ≥40 years Severe COPD dx ≥1 COPD exacerbation within 1 year of study Postbronchodilator FEV1 30% to 50% FEV1/FVC <70%	Extrafine BDP/FF pMDI 200/12 μg BID (n=595) vs FF pMDI 12 μg BID (n=591) × 48 weeks	The adjusted rate of exacerbations (per patient-year) was significantly reduced by 28% with BDP/FF vs FF (0.80 vs 1.12; p<0.001) Time to first exacerbation was significantly reduced by 20% BDP/FF significantly improved predose morning FEV1 at week 12 vs FF (81 mL vs 12 mL; mean difference, 69 mL; p<0.001) AEs were similar between groups; the most common AE was oral candidiasis (2.2% vs 0.3%); pneumonia occurred in 3.8% in BDP/FF group and 1.8% in FF group
Tashkin et al^Citation24 Two studies of identical design were pooled North, Central, and South America; EU; Africa; Asia	Current or ex-smokers (≥10 pack-years) Age ≥40 years COPD dx and symptoms >2 years Prebronchodilator FEV1/FVC ≤70% Postbronchodilator FEV1 25% to 60%	MF/FF 400/10 μg BID (n=442) vs MF/FF 200/10 μg BID (n=446) vs MF 400 μg BID (n=463) vs FF 10 μg BID (n=452) vs Placebo (n=448) × 52 weeks	MF/FF 400/10 μg and 200/10 μg significantly improved FEV1 AUC0–12h vs MF 400 μg and placebo at week 13 (both p<0.001) and all endpoints; FF 10 μg was also superior to placebo MF/FF 400/10 μg significantly improved predose morning FEV1 vs FF (p≤0.008) and placebo (p<0.001); MF/FF 200/10 was significantly superior to placebo Exacerbation rates (per patient-year) were lower in MF/FF and MF groups: MF/FF 400/10, 0.33; MF/FF 200/10, 0.34; MF 400, 0.35; FF 10, 0.42 Most common AEs: headache, COPD, nasopharyngitis, upper respiratory tract infection, and hypertension; pneumonia was infrequently reported: MF/FF 400/10, 2.0%; MF/FF 200/10, 1.1%; MF 400, 1.1%; FF 10, 1.3%; placebo, 0.7%

Abbreviations: AE, adverse event; AUC_0–4h, area under the curve from 0 to 4 hours; AUC_0–12h, area under the curve from 0 to 12 hours; BDP, beclomethasone dipropionate; BID, twice daily; BUD, budesonide; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; dx, diagnosis; EU, European Union; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; FVC, forced vital capacity; HFA, hydrofluoroalkane; LSM, least squares mean; MDI, metered-dose inhaler; MF, mometasone furoate; mMRC, modified Medical Research Council dyspnea scale; pMDI, pressurized metered-dose inhaler; SABA, short-acting β₂-agonist; US, United States.

Note: ^aBold font indicates trial duration.

Figure 2 Time to first moderate or severe exacerbation^a in the RISE study.

Notes:^aBetween-treatment difference in time to first moderate or severe exacerbation, p<0.016; Cox regression model. Reprinted from Respiratory Medicine, Vol 132, Ferguson et al, Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: the 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study, pages 31–41, Copyright 2017, with permission from Elsevier.²¹

Abbreviations: B/f, budesonide/formoterol; BID, twice daily; DPI, dry powder inhaler; f, formoterol; pMDI, pressurized metered-dose inhaler.

Table 4 Efficacy of Formoterol in Combination with LAMAs

Clinical Trial	Patient Population	Treatments and Duration^a	Key Findings
PINNACLE-1^Citation30 US, Australia, New Zealand	Current or ex-smokers (≥10 pack-years) Age 40–80 years Moderate to very severe COPD Postbronchodilator FEV1 <80% FEV1/FVC <70%	GFF pMDI 18/9.6 μg BID (n=526) vs GP pMDI 18 μg BID (n=451) vs FF pMDI 9.6 μg BID (n=449) vs OL tiotropium 18 μg QD (n=451) vs Placebo BID (n=219) × 24 weeks	GFF, GP, and FF pMDI significantly improved predose morning trough FEV1 at week 24 vs placebo (all p<0.0001) GFF showed significant differences of 59 mL and 64 mL vs GP and FF, respectively GFF significantly improved 2-hour postdose change from baseline FEV1 at week 24 vs monocomponents (all p<0.0001) Across both studies, most common AEs were nasopharyngitis, cough, upper respiratory tract infection, sinusitis, dyspnea; all occurred with similar frequency in active vs placebo groups
PINNACLE-2^Citation30 US	Same as above	GFF pMDI 18/9.6 μg BID (n=510) vs GP pMDI 18 μg BID (n=439) vs FF pMDI 9.6 μg BID (n=437) vs Placebo BID (n=223) × 24 weeks	GFF, GP, and FF pMDI significantly improved predose morning trough FEV1 at week 24 vs placebo (all p<0.02) GFF showed significant differences of 54 mL and 56 mL vs GP and FF, respectively GFF significantly improved 2-hour postdose change from baseline FEV1 at week 24 vs monocomponents (all p<0.0001)
PINNACLE-3^Citation31 US, Australia, New Zealand	Extension study of PINNACLE-1, −2 Patients receiving GFF, GP, FF, or tiotropium were eligible to continue Patients receiving placebo were not eligible	GFF pMDI 18/9.6 μg BID (n=1035) vs GP pMDI 18 μg BID (n=888) vs FF pMDI 9.6 μg BID (n=884) vs OL tiotropium 18 μg QD (n=450) × 28 weeks	GFF pMDI significantly improved predose morning trough FEV1 over 52 weeks vs GP, FF, and tiotropium (p<0.0001 vs GP, FF and p=0.0117 vs tiotropium) GFF also significantly improved 2-hour postdose FEV1 over 52 weeks vs both monocomponents and tiotropium (all p<0.0001) Dyspnea scores improved significantly for GFF vs monocomponents No new safety risks were identified for GFF pMDI vs monocomponents
PINNACLE-4^Citation32 Asia, EU, US	Same as PINNACLE-1 and −2	GFF pMDI 18/9.6 μg BID (n=555) vs GP pMDI 18 μg BID (n=480) vs FF pMDI 9.6 μg BID (n=483) vs Placebo BID (n=238) × 24 weeks	GFF pMDI significantly improved predose morning trough FEV1 at week 24 vs GP, FF, and placebo (all p<0.0001) GFF significantly improved 2-hour postdose change from baseline FEV1 at week 24 vs monocomponents and placebo (all p<0.0001) Significant improvement in TDI over 24 weeks for GFF vs GP (LSM difference, 0.33; p=0.0125) and placebo (LSM difference, 0.80; p<0.001) GFF improved SGRQ total score vs placebo (LSM difference, −5.33; p=0.0011)
AUGMENT^Citation34 North America, Australia, New Zealand	Current or ex-smokers (≥10 pack-years) Age ≥40 years Postbronchodilator FEV1 ≥30% to <80% FEV1/FVC <70%	ACL/FF DPI 400/12 μg BID (n=335) vs ACL/FF DPI 400/6 μg BID (n=333) vs ACL DPI 400 μg BID (n=337) vs FF DPI 12 μg BID (n=332) vs Placebo DPI (n=331) × 24 weeks	Both doses of ACL/FF significantly improved 1-hour postdose FEV1 change from baseline to week 24 vs ACL (LSM difference, 108 mL and 87 mL, respectively p<0.0001) ACL/FF 400/12 μg significantly improved predose morning trough FEV1 from baseline to week 24 vs FF (LSM difference, 45 mL; p=0.01) Numerically greater improvements in FEV1 measurements were observed for the higher dose of ACL/FF vs the lower dose TDI focal scores were significantly improved with ACL/FF vs ACL, FF (p≤0.01), and placebo (p<0.0001) SGRQ total scores were significantly improved at week 24 for ACL/FF and monocomponents vs placebo (p<0.05) Most common AEs were cough and nasopharyngitis
ACLIFORM-COPD^Citation35 EU, South Africa, South Korea	Current or ex-smokers (≥10 pack-years) Age ≥40 years Postbronchodilator FEV1 ≥30% -<80% FEV1/FVC <70%	ACL/FF DPI 400/12 μg BID (n=385) vs ACL/FF DPI 400/6 μg BID (n=381) vs ACL DPI 400 μg BID (n=385) vs FF DPI 12 μg BID (n=384) vs Placebo DPI (n=194) × 24 weeks	Both doses of ACL/FF significantly improved 1-hour postdose FEV1 change from baseline to week 24 vs ACL and FF (p<0.001), with the 400/12 μg dose superior to the 400/6 μg dose TDI focal scores improved above 1-unit threshold for both doses of ACL/FF (1.29 and 1.16) Incidences of AEs were similar across combination, monotherapy, and placebo arms
AFFIRM-COPD^Citation25 EU, Canada, South Africa	Current or ex-smokers (≥10 pack-years) Age ≥40 years Postbronchodilator FEV1 <80% FEV1/FVC <70% CAT score ≥10	ACL/FF DPI 400/12 μg BID (n=468) vs Salmeterol/fluticasone DPI 50/500 μg BID (n=463) × 24 weeks	Peak FEV1 was significantly greater with ACL/FF vs salmeterol/fluticasone at week 24, with significant differences observed after first dose (p<0.0001) Mean increase in peak FEV1 at week 24 was 93 mL greater with ACL/FF No significant differences in changes in TDI scores, CAT total scores, or exacerbations between groups Most common AEs were COPD exacerbation, headache, and nasopharyngitis and were similar between groups
AMPLIFY^Citation39 EU, Israel, US	Current or ex-smokers (≥10 pack-years) Age ≥40 years Postbronchodilator FEV1 <80% FEV1/FVC <70% CAT score ≥10	ACL/FF DPI 400/12 μg BID (n=314) vs ACL DPI 400 μg BID (n=475) vs FF DPI 12 μg BID (n=319) vs Tiotropium DPI 18 μg QD (n=475) × 24 weeks	ACL/FF significantly improved 1-hour postdose FEV1 from baseline at week 24 vs ACL, FF, and tiotropium (all p<0.0001) ACL/FF significantly improved predose morning trough FEV1 vs FF (p<0.001) SGRQ total score improved vs baseline >MCID for ACL/FF (4.68), ACL (4.95), and tiotropium (5.58); improvement for FF was 3.96 Early morning symptom severity was significantly improved with ACL/FF vs tiotropium (p<0.05) Most common AEs: COPD exacerbation, nasopharyngitis, and headache

Abbreviations: ACL, aclidinium; AE, adverse event; BID, twice daily; CAT, COPD Assessment Test; 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; LAMA, long-acting muscarinic antagonist; LSM, least squares mean; MCID, minimal clinically important difference; OL, open-label; pMDI, pressurized metered-dose inhaler; QD, once daily; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; US, United States.

Note: ^aBold font indicates trial duration.

Figure 3 Relative bioavailability for glycopyrronium/formoterol combination versus glycopyrronium or formoterol monotherapy. Reprinted from International Journal of Chronic Obstructive Pulmonary Disease, Vol 13, Ferguson et al, Pharmacokinetics of glycopyrronium/formoterol fumarate dihydrate delivered via metered-dose inhaler using co-suspension delivery technology in patients with moderate-to-very severe COPD, pages 945–593, Copyright 2018, with permission from Dove Medical Press.²⁶

Abbreviations: AUC_0–12, area under the curve from 0 to 12 hours; C_max, maximum concentration achieved; FF, formoterol fumarate; GFF, glycopyrronium/formoterol fumarate; GP, glycopyrronium; LSM, least squares mean; MDI, metered-dose inhaler.

Figure 4 Effects of fixed-dose glycopyrrolate/formoterol combination on change from baseline in (A) Predose morning trough FEV₁ and (B) Peak change in FEV₁ within 2 hours postdose over 52 weeks versus monocomponents and open-label tiotropium. Reprinted from Respiratory Medicine, Vol 126, Hanania et al, Long-term safety and efficacy of glycopyrrolate/formoterol metered-dose inhaler using novel Co-Suspension^TM Delivery Technology in patients with chronic obstructive pulmonary disease, pages 105–115, Copyright 2017, with permission from Elsevier.³¹

Abbreviations: FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrronium; LSM, least squares mean; MDI, metered-dose inhaler; SE, standard error.

Table 5 Efficacy of Formoterol in Triple Therapy Combinations

Clinical Trial	Patient Population	Treatments and Duration^a	Key Findings
TRILOGY^Citation40 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
TRINITY^Citation41 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%)
TRIBUTE^Citation42 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
KRONOS^Citation51 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 AUC0–4h 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%
ETHOS^Citation44,Citation45 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.

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