Main characteristics and results of the studies included in the systematic review
| Study, year, reference | clinicaltrials.gov identifier | Study characteristics | Treatment duration (weeks) | Number of analysed patients | Drugs, doses and regimen of administration# | Inhaler device (brand) | Patient characteristics | Age (years) | Male (%) | Current smokers (%) | Smoking history (pack-years) | Post-bronchodilator FEV1 (% predicted) | Outcome measurements of the impact on airway mucus | Jadad score | Main results |
| Smith et al. 2019 [37] | NCT02375724 | Multicentre, phase IV, randomised, double-blind, PCB-controlled, parallel-group | 8 | 269 | ACL 400 μg twice daily versus PCB | ACL: multidose DPI (Genuair/Pressair) | Moderate COPD | 62.0 | 60.2 | 64.0 | NA | 64.2 | E-RS cough and sputum domain score and LCQ total score | 2 | ACL significantly improved cough and sputum production in symptomatic patients with moderate COPD compared to placebo |
| Beier et al. 2017 [27] | NCT01462929 | Post hoc analysis of a multicentre, phase IIIB, randomised, double-blind, double-dummy, PCB- and active-controlled, parallel-group | 6 | 277 | ACL 400 μg twice daily versus TIO 18 μg once daily versus PCB | ACL: MDI (Genuair/Pressair); TIO: DPI (HandiHaler) | Symptomatic moderate to severe COPD (FEV1 ≥30% and <80% of predicted; post- bronchodilator FEV1/FVC<0.7; E-RS in COPD baseline score ≥10 units) | 62.1 | 64.1 | 54.1 | 41.0 | 54.6 | E-RS cough and sputum domain score and in severity of early-morning cough and phlegm symptoms | 5 | ACL provided additional improvements compared to TIO in E-RS cough and sputum symptoms in patients with moderate to severe COPD |
| Tagaya et al. 2016 [28] | NA | Open-label, non-controlled | 8 | 22 | TIO 18 μg once daily | DPI (HandiHaler) | COPD | 67.0 | 81.8 | 0.0 | NA | 59.0 | CASA-Q score, nasal clearance time, and level of mucin concentration in sputum | NA | TIO decreased symptoms associated with sputum in COPD patients |
| Jones et al. 2016 [38] | NCT01001494 (ATTAIN study) [46]; NCT01437397 (AUGMENT COPD I study) [47] | Post hoc pooled analysis of two multicentre, phase III, randomised, double-blind, PCB-controlled, parallel-group studies | 24 | 1161 | ACL 400 μg twice daily versus PCB | MDI (Genuair/Pressair); | Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) | 63.2 | 60.6 | 51.9 | 47.1 | 54.4 | E-RS cough and sputum domain score | ATTAIN: 5; AUGMENT COPD I: 5 | ACL significantly improved E-RS cough and sputum symptoms regardless of the patients’ level of symptoms at baseline |
| Lange et al. 2016 [39] | NA | Multicentre, real-life, prospective, non-interventional | ≃24 | 874 | ACL 400 μg twice daily (either as initial therapy, switch of treatment or as add-on therapy) | MDI (Genuair) | COPD (NA) | 69.3 | 46.0 | 36.0 | NA | 54.9 | CAT score for cough and mucus | NA | ACL was associated with a significant improvement in CAT score for cough and mucus, an effect more pronounced in the LAMA naïve group |
| McGarvey et al. 2016 [29] | NCT00891462 (ACCORD COPD I study) [42]; NCT01001494 (ATTAIN study) [46]; NCT01462929 [31] | Post hoc analysis of three multicentre, phase III, randomised, double-blind, PCB-controlled (and active-controlled for NCT01462929), parallel-group studies | 12 (ACCORD COPD I study), 24 (ATTAIN study), 6 NCT01462929 | 1792 | ACL 400 μg twice daily versus TIO 18 μg once daily versus PCB | ACL: multidose DPI (Genuair/Pressair); TIO: DPI (HandiHaler) | Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) | 63.1 | 62.5 | 51.4 | 45.3 | 55.6 | E-RS cough and sputum domain score and frequency/severity of morning and night-time cough and sputum symptoms | ACCORD COPD I: 5; ATTAIN: 5; NCT01462929: 5 | ACL improved cough and sputum expectoration compared to PCB in stable COPD |
| Bateman et al. 2015 [40] | NCT01462942 (ACLIFORM-COPD study) [43]; NCT01437397 (AUGMENT COPD I study) [47] | Post hoc pooled analysis of two multicentre, phase III, randomised, double-blind, PCB-controlled, parallel-group studies | 24 | 2680 | ACL/FOR 400/12 μg twice daily versus ACL 400 μg twice daily versus FOR 12 μg twice daily versus PCB | Multidose DPI (Genuair/Pressair) | Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) | 63.6 | 60.0 | 49.3 | ≥10.0 | 53.6 | E-RS cough and sputum domain score and in early-morning and night-time cough and difficulty in bringing up phlegm symptoms score | ACLIFORM-COPD: 5; AUGMENT COPD I: 5 | ACL/FOR significantly improved the early-morning and night-time difficulty in bringing up phlegm compared to PCB in patients with moderate to severe COPD |
| Marth et al. 2015 [41] | NA | Multicentre, real-life, prospective, non-interventional | ≃12 | 795 | ACL 400 μg twice daily (either as initial therapy, switch of treatment or as add-on therapy) | Multidose DPI (Eklira Genuair) | COPD (NA) | 63.2 | 56.0 | 44.0 | ≥10.0 | NA | CAT score for cough and phlegm | NA | ACL significantly reduced the CAT score for phlegm and cough in COPD patients |
| D’Urzo et al. 2014 [30] | NCT01005901 (GLOW1) [44]; NCT00929110 (GLOW2) [45] | Post hoc pooled analysis of two phase III, multicentre, randomised, double-blind (open-label TIO in GLOW2), PCB-controlled, active-controlled (only GLOW2), parallel-group studies | 26 (GLOW1); 52 (GLOW2) | 1854 | GLY 50 μg once daily versus PCB (GLOW1); GLY 50 μg once daily versus PCB versus open-label TIO 18 μg once daily (GLOW2) | GLY: DPI (Breezhaler); TIO: DPI (HandiHaler) | Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) | 63.8 | 71.0 | 40.5 | 47.3 | 55.4 | Symptom score for cough, sputum production, and sputum colour | GLOW1: 3; GLOW2: 3 | TIO and GLY significantly improved the sputum production in moderate to severe COPD patients |
| Beier et al. 2013 [31] | NCT01462929 | Multicentre, phase IIIB, randomised, double-blind, double-dummy, PCB- and active-controlled, parallel-group | 6 | 414 | ACL 400 μg twice daily versus TIO 18 μg once daily versus PCB | ACL: MDI (Genuair/Pressair); TIO: DPI (HandiHaler) | Moderate to severe COPD (FEV1 ≥30% and <80% of predicted; post- bronchodilator FEV1/FVC<0.7) | 62.3 | 65.5 | 53.6 | 42.0 | 55.8 | E-RS cough and sputum domain score | 5 | Improvement in E-RS cough and sputum symptoms were significantly greater for ACL and TIO compared to PCB |
| Kerwin et al. 2012 [42] (ACCORD COPD I study) | NCT00891462 | Multicentre, phase III, randomised, double-blind, PCB-controlled, parallel-group | 12 | 560 | ACL 200 μg twice daily versus ACL 400 μg twice daily versus PCB | ACL: MDI (Genuair/Pressair) | Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) | 64.3 | 53.0 | 44.8 | 54.3 | 47.2 | Frequency of night-time cough and sputum production, and severity of cough | 5 | Treatment of moderate-to-severe COPD patients with ACL was associated with significant improvements in night-time symptoms due to cough and sputum production, and severity of cough, compared to PCB |
| Welte et al. 2009 [32] | NCT00496470 | Multicentre, phase IV, randomised, double-blind, parallel-group | 24 | 660 | TIO 18 μg once daily+BUD/FOR 320/9 μg twice daily versus TIO 18 μg once daily+PCB | TIO: DPI (HandiHaler); BUD/FOR: DPI (Turbuhaler) | COPD (pre- bronchodilator FEV1 ≤50% of predicted; history of exacerbations requiring systemic steroids and/or antibiotics) | 62.5 | 75.0 | NA | 37.0 | 37.9 | Symptom score for cough | 4 | In patients with COPD TIO added to BUD/FOR FDC provided rapid and sustained improvement in symptom score for cough compared to TIO alone |
| Powrie et al. 2007 [33] | NCT00405236 | Single-centre, randomised, double-blind, PCB-controlled, parallel-group | 52 | 142 | TIO 18 μg once daily versus PCB | TIO: DPI (HandiHaler) | COPD (FEV1 <80% of predicted and FEV1/FVC<0.7) | 66.4 | 62.9 | 58.5 | 55.2 | 50.1 | Sputum reduction | 3 | Administration of TIO was significantly associated with a subjective decrease in sputum production compared to COPD patients treated with PCB |
| Hasani et al. 2004 [34] | NA | Single-centre, randomised, double-blind, PCB-controlled, parallel-group | 3 | 34 | TIO 18 μg once daily versus PCB | TIO: DPI (HandiHaler) | COPD (FEV1 ≥30% and ≤65% of predicted; post- bronchodilator FEV1/FVC≤0.7) | 66.0 | 79.4 | 58.8 | 52.0 | 44.0 | Number of coughs | 4 | Cough frequency was reduced with TIO compared to PCB during 6 h post administration |
| Casaburi et al. 2002 [35] | NA | Two multicentre, randomised, double-blind, PCB-controlled studies | 52 | 921 | TIO 18 μg once daily versus PCB | TIO: DPI (HandiHaler) | COPD (FEV1 ≤65% of predicted; post- bronchodilator FEV1/FVC≤0.7) | 65.2 | 65.0 | NA | 61.0 | 38.6 | Symptom score for cough | 5 | In patients with stable COPD, TIO did not modulate the symptom score for cough after 52 weeks of treatment compared to PCB |
| Casaburi et al. 2000 [36] | NA | Multicentre, randomised, double-blind, PCB-controlled, parallel-group | 13 | 470 | TIO 18 μg once daily versus PCB | TIO: DPI (HandiHaler) | COPD (FEV1 ≤65% of predicted; post- bronchodilator FEV1/FVC<0.7) | 65.2 | 65.3 | NA | 62.9 | 39.0 | Symptom score for cough | 4 | In patients with stable COPD, TIO reduced the symptom score for cough after 8 days of treatment but not at week 13, compared to PCB |
#: All studies analysed long-acting muscarinic antagonists (LAMAs) administered through oral inhalation. ACL: aclidinium bromide; BUD: budesonide; CASA-Q: Cough and Sputum Assessment - Questionnaire; CAT: COPD Assessment Test; DPI: dry powder inhaler; E-RS: Exacerbations of Chronic Pulmonary Disease Tool–Respiratory Symptoms; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 s; FOR: formoterol; FVC: forced vital capacity; GLY: glycopyrronium; LCQ: Leicester Cough Questionnaire; MDI: metered-dose inhaler; NA: not available; PCB: placebo; pMDI: pressurised metered dose inhaler; TIO: tiotropium bromide.