Background
Initial studies with tiotropium inhalation powder
Dose response and comparison with ipratropium
Pivotal trials
Effect on lung hyperinflation, exercise endurance, exertional dyspnea, and HRQoL
Effect on exacerbations
Study | Comparator | Patients (N) | Study duration | Change from baseline in number of exacerbations | Change from baseline in patients with ≥ 1 exacerbation | Increase in time to first exacerbation |
---|---|---|---|---|---|---|
Casaburi 2002 [22] | Placebo | 921 | 1 year | −20% (p = 0.045) | − 14% (p < 0.05) | p = 0.011 |
Vincken 2002 [34] | Ipratropium | 535 | 1 year | −24% (p = 0.006) | −24% (p = 0.014) | p = 0.008 |
Brusasco 2003 [36] | Placebo | 802a | 6 months | −28% (p < 0.05) | −18% (p > 0.05) | p ≤ 0.01 |
Niewoehner 2005 [37] | Placebo | 1829 | 6 months | −19% (p = 0.031) | −14% (p = 0.037) | p = 0.028 |
Dusser 2006 [24] | Placebo | 1010 | 1 year | −35% (p < 0.001) | − 17% (p < 0.01) | p < 0.001 |
Tashkin 2008 [26] | Placebo | 5993 | 4 years | − 14% (p < 0.001) | −2% (p = 0.35) | p < 0.001 |
Tonnel 2008 [23] | Placebo | 554 | 9 months | −43% (p = 0.0287) | − 16% (p = 0.1013) | p = 0.0081 |
Bateman 2010 [28] | Placebo | 1990 | 1 year | p < 0.01** | −16% (p < 0.01)b | p < 0.0001b |
Bateman 2010 [29] | Placebo | 3991 | 48 weeks | −21% (p < 0.0001) | − 18% (p < 0.0001) | p < 0.0001 |
Vogelmeier 2011 [39] | Salmeterol | 7376 | 1 year | −11% (p = 0.002)c | −11% (p < 0.001)c | p < 0.001 |
Longer-term studies
Efficacy and safety vs other therapies
Tiotropium vs ICS/LABA
Tiotropium vs short-acting muscarinic antagonist/short-acting β2-agonist (SAMA/SABA) combinations
Tiotropium vs QD LABA
Tiotropium vs other LAMAs
Clinical development of tiotropium Respimat®
Soft mist inhaler
Dose response
Pivotal studies
Observational studies
Landmark safety trial
Study | Patients (N) | Treatment arms | Primary endpoint results* | Proportion of patients with adverse events | Conclusion of the study |
---|---|---|---|---|---|
Casaburi 2000 [21] | 470 | • Tiotropium 18 μg QD • Placebo | Trough FEV1 response: 0.11 L vs − 0.04 L (p < 0.001) | Overall adverse events: 61.6% vs 66.5% Dry mouth: 9.3% vs 1.6% (p < 0.05) | Tiotropium was safe and effective |
Casaburi 2002 [22] | 921 | • Tiotropium 18 μg QD • Placebo | Trough FEV1 response: 0.11 L to 0.13 L (tiotropium; p < 0.01 vs placebo) | Overall adverse events: 90.0% vs 91.1% Dry mouth: 16.0% vs 2.7% (p < 0.05) | Tiotropium significantly improved lung function and HRQoL and reduced dyspnea, COPD exacerbations, and hospitalizations |
Vincken 2002 [34] | 535 | • Tiotropium 18 μg QD • Ipratropium 40 μg QID | Trough FEV1 response: 0.12 L vs − 0.03 L (p < 0.001) | Adverse events leading to discontinuation: 10.1% vs 12.8% Dry mouth: 12.1% vs 6.1% (p = 0.03) | Tiotropium significantly improved lung function and HRQoL and reduced dyspnea and COPD exacerbations compared with ipratropium |
Donohue 2002 [35] | 623** | • Tiotropium 18 μg QD • Salmeterol 50 μg BID | Trough FEV1 response: 0.14 L vs 0.09 L (p < 0.01) | Dry mouth: 10% vs NA | Tiotropium significantly improved lung function and reduced dyspnea compared with salmeterol |
Brusasco 2003 [36] | 1207 | • Tiotropium 18 μg QD • Salmeterol 50 μg BID • Placebo | COPD exacerbation rate: 1.07 vs 1.23 vs 1.49 (p < 0.05 for tiotropium vs placebo) | Dry mouth: 8.2% vs 1.7% vs 2.3% | Tiotropium significantly improved lung function compared with salmeterol; improved HRQoL and reduced dyspnea and COPD exacerbations compared with placebo |
O’Donnell 2004 [45] | 187 | • Tiotropium 18 μg QD • Placebo | Difference in endurance time between tiotropium and placebo: 105 s (p = 0.0098) | Overall adverse events: 36.7% vs 41.0% | Tiotropium significantly reduced lung hyperinflation at rest and exercise and improved exertional dyspnea and endurance time |
Niewoehner 2005 [37] | 1829 | • Tiotropium 18 μg QD • Placebo | Percentage of patients with ≥1 exacerbation: 27.9% vs 32.3% (p = 0.037) Percentage of patients with COPD-related hospitalization: 7.0% vs 9.5% (p = 0.056) | Serious adverse events: 18% vs 17% | Tiotropium reduced COPD exacerbations, COPD-related hospitalization, and healthcare utilization compared with placebo |
Dusser 2006 [24] | 1010 | • Tiotropium 18 μg QD • Placebo | Percentage of patients with ≥1 exacerbation: 49.9% vs 60.3% (p < 0.01) | Overall adverse events: 46.4% vs 45.1% Dry mouth: 4.0% vs 1.4% | Tiotropium significantly improved lung function and reduced COPD exacerbations and COPD-associated health resource use compared with placebo |
Verkindre 2006 [32] | 100 | • Tiotropium 18 μg QD • Placebo | Trough FVC: Difference: 0.20 L (p < 0.05) | Adverse events leading to discontinuation: 2% vs 11% Dry mouth: 2% vs 0% | Tiotropium significantly improved FVC, lung hyperinflation, walking distance, and HRQoL |
Bateman 2008 [66] | 107 | • Tiotropium 18 μg QD • Fluticasone/salmeterol 250/50 μg BID | FEV1 AUC0–12h: 1.55 L vs 1.57 L (p = 0.63) | Overall adverse events: 41.1% vs 43.1% Dry mouth: 3.6% vs 3.9% | Tiotropium improved lung function similar to fluticasone/salmeterol combination |
Tashkin 2008 [26] | 5993 | • Tiotropium 18 μg QD • Placebo | Rate of decline in FEV1 before bronchodilation: 0.030 L vs 0.030 L (p = 0.95) Rate of decline in FEV1 after bronchodilation: 0.040 L vs 0.042 L (p = 0.21) | Overall adverse events: 92.6% vs 92.3% | Tiotropium significantly improved lung function, improved HRQoL, reduced exacerbations, but did not significantly reduce rate of decline in FEV1 compared with placebo |
Tonnel 2008 [23] | 554 | • Tiotropium 18 μg QD • Placebo | Proportion of patients with improvement in HRQoLa: 59.1% vs 48.2% (p = 0.029) | Patients with ≥1 adverse event: 60.9% vs 67.0% Dry mouth: 1.1% vs 0.7% | Tiotropium significantly improved lung function, improved HRQoL, and reduced exacerbations |
Voshaar 2008 [27] | 719 | • Tiotropium 5 μg QD • Tiotropium 10 μg QD • Ipratropium 36 μg QID vs placebo | Trough FEV1 response treatment differences: tiotropium 5 μg − placebo: 0.118 L (p < 0.0001) tiotropium 10 μg − placebo: 0.149 L (p < 0.0001) tiotropium 5 μg − ipratropium: 0.064 L (p = 0.006) tiotropium 10 μg − ipratropium: 0.095 L (p < 0.0001) | Overall adverse events: 52.8% vs 60.0% vs 59.6% vs 59.1% Dry mouth: 8.3% vs 10.0% vs 3.9% vs 2.2% | Tiotropium (via Respimat®) significantly improved lung function compared with ipratropium (pMDI) and placebo |
Wedzicha 2008 [67] | 1323 | • Tiotropium 18 μg QD • Fluticasone/salmeterol 500/50 μg BID | Modeled annual rate of exacerbations: 1.32 vs 1.28 (p = 0.656) | Overall adverse events: 62% vs 66% | Tiotropium was similar to fluticasone/salmeterol in exacerbation efficacy |
Bateman 2010 [28] | 1990 | • Tiotropium 5 μg QD • Tiotropium 10 μg QD • Placebo | Trough FEV1 response: tiotropium 5 μg vs placebo: 0.127 L (p < 0.0001) tiotropium 10 μg vs placebo: 0.150 L (p < 0.0001) | Overall adverse events: 75.4% vs 78.7% vs 76.9% | Tiotropium (via Respimat®) significantly improved lung function and HRQoL and reduced dyspnea and exacerbations compared with placebo |
Bateman 2010 [29] | 3991 | • Tiotropium 5 μg QD • Placebo | Trough FEV1 response: 0.119 L vs 0.018 L (p < 0.0001) Time to first exacerbation: 169 days vs 119 days (p < 0.0001) | Overall adverse events: 70.1% vs 69.3%; Dry mouth: 3.1% vs 1.4% | Tiotropium (via Respimat®) significantly improved lung function and HRQoL and reduced exacerbations compared with placebo |
Vogelmeier 2011 [39] | 7376 | • Tiotropium 18 μg QD • Salmeterol 50 μg BID | Time to first exacerbation: 187 days vs 145 days (p < 0.001) | Serious adverse events: 14.7% vs 16.5% | Tiotropium significantly reduced exacerbations compared with salmeterol |
Wise 2013 [81] | 17,135 | • Tiotropium 2.5 μg QD • Tiotropium 5 μg QD • Tiotropium 18 μg QD | Deaths: 7.7% vs 7.4% vs 7.7% Proportion of patients with exacerbations: 49.4% vs 47.9% vs 48.9% | Serious adverse events: 33.8% vs 32.4% vs 32.4% | Tiotropium 2.5 μg or 5 μg (via Respimat®) was similar to tiotropium 18 μg (via HandiHaler®) in safety and exacerbation efficacy |
Clinical development of tiotropium/olodaterol Respimat®
Study | Patients (N) | Treatment arms | Primary endpoint results | Proportion of patients with adverse events | Conclusion of the study |
---|---|---|---|---|---|
Buhl 2015 [95] | 5162 | • Tiotropium+olodaterol 2.5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD • Tiotropium 2.5 μg QD • Tiotropium 5 μg QD • Olodaterol 5 μg QD | • FEV1 AUC0–3 response: o Tiotropium+olodaterol 2.5/5 μg vs olodaterol 5 μg, 0.115 L; vs tiotropium 2.5 μg, 0.111 L; and vs tiotropium 5 μg, 0.097 L (p < 0.0001 for all comparisons) o Tiotropium+olodaterol 5/5 μg vs olodaterol 5 μg, 0.128 L and vs tiotropium 5 μg, 0.110 L (p < 0.0001 for both) • Trough FEV1 response: o Tiotropium+olodaterol 2.5/5 μg: vs olodaterol 5 μg, 0.062 L; vs tiotropium 2.5 μg, 0.045 L; vs tiotropium 5 μg, 0.038 L (p < 0.0001 for all comparisons) o Tiotropium+olodaterol 5/5 μg: vs olodaterol 5 μg, 0.085 L; vs tiotropium 5 μg, 0.060 L (p < 0.0001 for both comparisons) • SGRQ total score: o Tiotropium+olodaterol 5/5 μg: vs olodaterol 5 μg, − 1.693 (p = 0.0022); vs tiotropium 5 μg, − 1.233 (p = 0.0252) o Tiotropium+olodaterol 2.5/5 μg vs individual components was not significant for all comparisons | 74.7% vs 74.0% vs 73.4% vs 73.3% vs 76.6% | Tiotropium+olodaterol improved lung function and HRQoL compared with monocomponents |
Beeh 2015 [96] | 259 | • Tiotropium+olodaterol 2.5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD • Tiotropium 2.5 μg QD • Tiotropium 5 μg QD • Olodaterol 5 μg QD • Placebo | • FEV1 AUC0–24 response: o Tiotropium+olodaterol 2.5/5 μg: vs olodaterol 5 μg, 0.111 L; vs tiotropium 2.5 μg, 0.124 L; vs tiotropium 5 μg, 0.107 L; vs placebo, 0.277 L (p < 0.001 for all comparisons) o Tiotropium+olodaterol 5/5 μg: vs olodaterol 5 μg, 0.115 L; vs tiotropium 2.5 μg, 0.127 L; vs tiotropium 5 μg, 0.110 L; vs placebo, 0.280 L (p < 0.0001 for all comparisons) | 36.0% vs 37.4% vs 39.4% vs 44.2% vs 37.7% vs 46.4% | Tiotropium+olodaterol improved lung function over 24 h compared with monocomponents |
O’Donnell 2017 [97] | 586 | • Tiotropium+olodaterol 2.5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD • Tiotropium 5 μg QD • Olodaterol 5 μg QD • Placebo | • Inspiratory capacity: o Tiotropium+olodaterol 2.5/5 μg: vs olodaterol 5 μg, 0.090 L; vs tiotropium 5 μg, 0.092 L; vs placebo, 0.245 L (p < 0.0001 for all comparisons) o Tiotropium+olodaterol 5/5 μg: vs olodaterol 5 μg, 0.099 L; vs tiotropium 5 μg, 0.101 L; vs placebo, 0.254 L (p < 0.0001 for all comparisons) • Exercise endurance time during constant work-rate cycle ergometry (improvement): o Tiotropium+olodaterol 2.5/5 μg: vs olodaterol 5 μg, 7.3% (p < 0.01); vs tiotropium 5 μg, 3.5%; vs placebo, 19.2% (p < 0.0001) o Tiotropium+olodaterol 5/5 μg: vs olodaterol 5 μg, 5.6% (p < 0.05); vs tiotropium 5 μg, 1.9%; vs placebo, 17.3% (p < 0.0001) | 36.3% vs 40.0% vs 38.3% vs 40.2% vs 40.8% | Tiotropium+olodaterol improved lung hyperinflation and exercise tolerance compared with monotherapies |
Maltais 2018 [98] | 404 | • Tiotropium+olodaterol 2.5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD • Placebo | • Endurance time during constant work-rate cycle ergometry: o Tiotropium+olodaterol 5/5 μg vs placebo, 14% (p = 0.02) o Tiotropium+olodaterol 2.5/5 μg vs placebo, 9% (p = 0.14) | 54.9% vs 43.9% vs 50.8% | Tiotropium+olodaterol improved endurance time compared with placebo during cycle ergometry |
Singh 2015 [99] | 1621 | • Tiotropium+olodaterol 2.5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD • Tiotropium 5 μg QD • Placebo | • SGRQ total score (difference): o Tiotropium+olodaterol 5/5 μg: vs tiotropium 5 μg, − 2.10 (p < 0.01); vs placebo, − 4.67 (p < 0.0001) o Tiotropium+olodaterol 2.5/5 μg: vs tiotropium 5 μg, − 1.27; vs placebo, − 3.85 (p < 0.0001) • FEV1 AUC0–3 response: o Both tiotropium+olodaterol 2.5/5 μg and 5/5 μg significantly improved (p < 0.0001) FEV1 AUC0–3 response compared with placebo and tiotropium 5 μg | OTEMTO 1: 42.6% vs 44.8% vs 44.3% vs 51.5% OTEMTO 2: 45.5% vs 43.1% vs 45.8% vs 46.0% | Tiotropium+olodaterol improved lung function and QoL compared with placebo and tiotropium |
Beeh 2016 [100] | 229 | • Tiotropium+olodaterol 2.5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD • Salmeterol/fluticasone 50/500 μg BID • Salmeterol/fluticasone 50/250 μg BID | • FEV1 AUC0–12 response: o 0.295 L vs 0.317 L vs 0.188 L vs 0.192 L (p < 0.0001 for comparisons of tiotropium+olodaterol vs salmeterol/fluticasone) | 34.4% vs 33.9% vs 37.0% vs 29.7% | Tiotropium+olodaterol QD provided superior improvement in lung function compared with salmeterol/fluticasone BID |
Troosters 2018 [101] | 303 | • Tiotropium+olodaterol 5/5 μg QD • Tiotropium+olodaterol 5/5 μg QD plus 8 weeks of ExT • Tiotropium 5 μg • Placebo | • Exercise endurance time by shuttle walk test (increase): o Tiotropium+olodaterol 5/5 μg QD vs placebo, 29.2% (p = 0.0109) o Tiotropium+olodaterol 5/5 μg QD plus 8 weeks of ExT vs placebo, 45.8% (p = 0.0002) o Tiotropium 5 μg vs placebo, 4.1% (p = 0.6895) | 57.9% vs 64.5% vs 67.1% vs 61.3% | In patients taking part in a self-management behavior-modification program, tiotropium+olodaterol improved exercise endurance time compared with placebo |
Calverley 2018 [102] | 7880 | • Tiotropium+olodaterol 5/5 μg QD • Tiotropium 5 μg QD | • Rate of moderate and severe COPD exacerbations: o 0.90 vs 0.97 (rate ratio, 0.93; p = 0.0498) | 74% vs 75% | Tiotropium+olodaterol reduced exacerbation rate compared with tiotropium, but not to a significant extent |