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

Table 3.

Efficacy of Formoterol in Combination with ICS

Clinical Trial	Patient Population	Treatments and Duration^a	Key Findings
SHINE¹⁹ 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
SUN²⁰ 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
RISE²¹ 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
TELOS²² 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/mm³ 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 AUC_0–4h 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 al²³ 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
FORWARD¹⁶ 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 al²⁴ 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 AUC_0–12h 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.