Key study design characteristics of the six selected randomised controlled trials in chronic obstructive pulmonary disease (COPD)
| First author [ref.] (study period) | Patients randomised n | Treatment arms | Duration | Key inclusion criteria | Key exclusion criteria | Primary end-point | Study visits after randomisation n | Withdrawal rate % |
| Sharafkhaneh [23] (2007–2009) | 1219 | BUD/FM 320/9 µg pMDI; BUD/FM 160/9 µg pMDI; FM 12 µg DPI | 1 year | Age ≥40 years; smoking history ≥10 pack-years; symptomatic COPD >2 years (mMRC ≥2 and BCSS ≥2); pre-BD FEV1 ≤50%; pre-BD FEV1/FVC <0.70; history ≥1 moderate exacerbation in prior 12 months | Asthma history, allergy rhinitis; subjects taking oral corticosteroid, non-cardio-selective β-blockers, leukotriene antagonists; pulmonary rehabilitation <60 days; significant/unstable cardiovascular disorder; clinically significant respiratory tract disorder other than COPD and α1-AT deficiency; any significant comorbidities that may jeopardise subject safety | Exacerbation (requiring oral or systemic corticosteroid and/or hospitalisation) (post hoc analysis: oral or systemic corticosteroid and/or antibiotics and/or hospitalisation) | 6 | 30 |
| Wedzicha [24] (2009–2011) | 1199 | BDP/FM 100/6 µg pMDI; FM 12 µg pMDI | 48 weeks | Age ≥40 years; smoking history ≥10 pack-years; mMRC ≥2; post-BD FEV1 ≥30% to <50%; post-BD FEV1/FVC <0.7; history ≥1 exacerbation in prior 12 months | Current or past diagnosis of asthma, allergy or other atopic disease; clinically significant or unstable concurrent diseases, including clinically significant laboratory abnormalities; evidence of heart failure | Pre-dose arm FEV1 at 12 weeks; exacerbations at 48 weeks | 5 | 15 |
| Dransfield [6] (2009–2011) | 3255 | FF/VI 50/25 µg DPI; FF/VI 100/25 µg DPI; FF/VI 200/25 µg DPI; VI 25 µg DPI | 1 year | Age ≥40 years; smoking history ≥10 pack-years; post-BD FEV1 ≤70%; post-BD FEV1/FVC ≤0.7; history ≥1 moderate/severe exacerbation in prior 12 months | Exacerbation in prior 2 weeks; current asthma, atopy; other respiratory disorders (lung cancer, bronchiectasis, sarcoidosis, active TB, etc.); α1-AT deficiency, lung volume reduction surgery in prior year; risk factors for pneumonia/chest radiograph with evidence of pneumonia; LTOT ≥12 h·day–1; β-blocker treatment; clinically significant uncontrolled diseases (cardiovascular, neurological, renal, etc.); alcohol or drug abuse | Exacerbations | 9 | 26 |
| Wedzicha [7] (2010–2012) | 2224 | IND/GLY 110/50 µg DPI; GLY 50 µg DPI; TIO 18 µg DPI | 64 weeks | Age ≥40 years; smoking history ≥10 pack-years; post-BD FEV1 <50%; post-BD FEV1/FVC <0.7; history ≥1 moderate exacerbation in prior 12 months | Moderate/severe exacerbation in prior 6 weeks or during run-in; RTI in prior 4 weeks; daily LTOT; concomitant pulmonary disease (PAH, active TB, etc.); lung lobectomy or lung volume reduction; α1-AT deficiency; clinically significant condition or laboratory/ECG abnormalities (heart disease, malignancy, narrow angle glaucoma, long QT, etc.); diabetes; history or current asthma, allergic rhinitis, atopy or blood EOS count >600 mm–3 | Exacerbations | 5 | 25 |
| Wedzicha [8] (2013–2015) | 3362 | IND/GLY 110/50 µg DPI; FP/S 500/50 µg DPI | 1 year | Age ≥40 years; smoking history ≥10 pack-years; mMRC ≥2; post-BD FEV1 ≥25% to <60%; post-BD FEV1/FVC <0.7; history ≥1 moderate exacerbation in prior 12 months | Exacerbation in prior 6 weeks or during run-in; RTI in prior 4 weeks; LTOT >12 h·day–1; concomitant pulmonary disease (PAH, fibrosis, sarcoidosis, active TB, etc.), lung lobectomy or lung volume reduction; α1-AT deficiency; clinically significant condition or laboratory/ECG abnormalities (heart disease, malignancy, narrow angle glaucoma, long QT, etc.); diabetes; history asthma, atopy or blood EOS count >600 mm–3 | Exacerbations | 12 | 18 |
| Vestbo [25] (2014–2016) | 2691 | BDP/FF/GB 100/6/12.5 µg pMDI; BDP/FF 100/6 µg pMDI+TIO 18 µg DPI; TIO 18 µg DPI | 1 year | Age ≥40 years; smoking history ≥10 pack-years; CAT ≥10; post-BD FEV1 <50%; post-BD FEV1/FVC <0.7; history ≥1 moderate/severe exacerbation in prior 12 months; patients receiving ICS/LABA or ICS+LAMA or LAMA/LABA; or LAMA alone >2 months | Asthma diagnosis, allergy or atopy history; exacerbation in prior 4 weeks and during run-in; patients treated with triple therapy (ICS/LABA+LAMA); concomitant pulmonary disease (PAH, fibrosis, active TB, etc.), lung lobectomy or lung volume reduction; α1-AT deficiency; clinically significant cardiovascular conditions or laboratory/ECG abnormalities (heart disease, malignancy, narrow angle glaucoma, long QT, etc.); β-blockers, long-acting anti-H1 treatment; LTOT >12 h·day–1; other unstable concurrent diseases; alcohol or drug abuse history | Exacerbations | 5 | 11 |
BUD/FM: budesonide/formoterol; pMDI: pressurised metered dose inhaler; FM: formoterol; DPI: dry powder inhaler; BDP/FM: beclometasone dipropionate/formoterol; FF/VI: fluticasone furoate/vilanterol; VI: vilanterol; IND/GLY: indacaterol/glycopyrronium; GLY: glycopyrronium; TIO: tiotropium; FP/S: fluticasone propionate/salmeterol; BDP/FF/GB: beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide; BDP/FF: beclometasone dipropionate/formoterol fumarate; mMRC: modified Medical Research Council Dyspnoea scale; BCSS: breathlessness, cough and sputum score; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; CAT: COPD Assessment Test; ICS: inhaled corticosteroid; LABA: long-acting β-agonist; LAMA: long-acting muscarinic antagonist; α1-AT: α1-antitrypsin; LTOT: long-term oxygen therapy; RTI: respiratory tract infection; PAH: pulmonary arterial hypertension; TB: tuberculosis; EOS; eosinophil.