Table 3.
Phase III RCTs that evaluated efficacy and safety of tiotropium in asthma
| Authors | Year | Main inclusion criteria | Age | Number | Treatment | Duration | Primary outcome | Secondary outcomes | Conclusions |
|---|---|---|---|---|---|---|---|---|---|
| Children and adolescents | |||||||||
| Szefler SJ et al. [133] | 2017 | FEV1 60–90%pred ACQ-7 > 1.5 and high dose ICS + 1 controller therapy or medium dose ICS + 2 controller therapies |
6–11 | 392 | Add on tiotropium 5 μg, 2.5 μg or placebo to chronic medium dose ICS (200–400 μg budesonide or eq.) + 2 controller or high dose ICS (≥400 μg) plus one controller | 12 weeks | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) Peak FVC (0–3 h) 3) ACQ–IA score and responder rate 4) trough FVC 5) FEV1AUC (0–3h) 6) rescue medication use 7) time to first exacerbation 8) time to first severe exacerbation 9) ACQ-6 and ACQ-7 10) FEF25–75 11) weekly evening PEF 12) Tolerability |
Primary and key secondary outcomes were significantly improved only for tiotropium 5 μg. Peak FVC (0–3 h) and trough FVC did not reach significance for any tiotropium dose. |
| Huang J et al. [134] | 2016 | Moderate persistent asthma | 6–14 | 80 | 125 μg fluticasone propionate aerosol TD + placebo OD vs 125 μg fluticasone propionate aerosol TD + tiotropium 18 μg dry-powder OD | 12 weeks | (not clearly stated) | 1) FEV1, FVC and PEF at week 12. 2) Asthma exacerbation 3) Rescue medication use 4) Night time symptoms 5) Tolerability |
Tiotropium 18 as add-on to maintenance therapy significantly improved lung function compared to maintenance therapy alone. |
| Hamelmann E et al. [131] | 2016 | FEV1 60–90%pred ACQ-7 > 1.5 and chronic treatment with ICS (200–800 μg for 12–14 years; 400–800 μg for 15–17 years) +/−LABA +/− LTRA |
12–17 | 376 | Add on tiotropium 5 μg, 2.5 μg or placebo to maintenance therapy, with ICS +/− LTRA (LABA not permitted) + open label SABA as rescue medication | 48 weeks | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) Peak FVC (0–3 h) 3) FVC AUC (0–3h) 4) Trough FVC 5) FEV1AUC (0–3h) 6) time to first exacerbation 7) time to first severe exacerbation 8) ACQ-7 and ACQ-6 9) AQLQ (S) score and responder rate 10) Tolerability |
All functional outcomes were significantly improved compared to placebo for all tiotropium doses. Greatest overall benefit was found for tiotropium 5 μg. A trend towards improvements was present for ACQ-7 |
| Hamelmann E et al. [132] | 2016 | ACQ-7 > 1.5 and high dose ICS + 1 controller therapy or medium dose ICS + 2 controller therapies | 12–17 | 388 | Add on tiotropium 5 μg, 2.5 μg or placebo to chronic ICS plus one or more controller therapies. | 12 weeks | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) Peak FVC (0–3 h) 3) FVC AUC (0–3h) 4) trough FVC 5) FEV1AUC (0–3h) 6) rescue medication use 7) time to first exacerbation 8) time to first severe exacerbation 9) ACQ-6 and ACQ-7 10) FEF25–75 11) evening and morning PEF 12) Tolerability |
Primary and secondary endpoint not met. Numerical greater response with tiotropium 5 μg compared to placebo. |
| Adults | |||||||||
| Peters SP et al. [137] “TALC study” | 2010 | Symptomatic despite 160 μg daily beclomethasone with FEV1 < 70%pred | ≥18 | 174 | Tiotropium 18 μg + placebo vs beclomethasone 320 μg + placebo vs salmeterol 50 TD + beclomethasone 160 μg + placebo | 14 weeks – 3 period | Morning PEF | 1) Trough FEV1
2) asthma control days 3) rescue medication use 4) asthma symptoms 5) exacerbations 6) use of health care service 7) inflammatory biomarkers 8) ACQ 9) Tolerability |
Tiotropium 18 μg is superior to doubling the ICS dose and non-inferior to salmeterol in patients with uncontrolled asthma |
| Wang K et al. [138] | 2015 | Moderate asthma. FEV1 60–80%pred, daily use of SABA, PEF and FEV1variability of >30%. ACT 12–20 |
≥18 | 94 | Add on therapy with tiotropium 18 μg, LTRA or double dose ICS on salmeterol/fluticasone dry-powdre 50/250 μg TD | 16 weeks | Asthma control in terms of FeNO; daily PEF variability and ACT score | Not clearly stated | Tiotropium non inferior to doubling doses of ICS. Best response obtained with double dose ICS/LABA but higher risk of pneumonia and RTI. |
| Kerstjens HA et al. [139] “PrimoTinA-asthma 1 & PrimoTinA-asthma 2“ | 2012 | Uncontrolled asthma defined with ACQ-7 > 1.5, FEV1 ≤ 80%pred and/or FVC ≤ 70%pred despite chronic treatment with ≥800 μg budesonide + LABA | 18–75 | 912 (456 per study) | Tiotropium 5 μg add on therapy or matching placebo. Teophylline, OCT and LTRA were permitted if part of maintenance therapy along with LABA/ICS. | Two replicate 48 weeks | 1) Peak FEV1 (0–3 h) 2) Trough FEV1 (24 weeks). 3) Time to first exacerbation (48 weeks) |
At each visit: 1) Trough FEV1 2) Peak FEV1 4) trough FVC 5) Peak FVC 6) FEV1AUC (0–3h) 7) FVC AUC (0–3h) 8) time to first exacerbation 9) morning and evening PEF 10) asthma symptoms 11) ACQ-7 and AQLQ 12) Tolerability |
Add on treatment with tiotropium to ICS/LABA sustained bronchodilation over 24 h, reduces severe exacerbations and episodes of worsening of disease. Improvements in asthma control scores and other secondary outcomes were not met. |
| Kerstjens HA et al. [141] “MezzoTinA-asthma 1 & MezzoTinA-asthma 2“ | 2015 | Uncontrolled asthma defined with ACQ-7 > 1.5, FEV1 60–90%pred despite chronic treatment with 400–800 μg budesonide or eq. +/− LABA or SABA | 18–75 | 1972 (998 & 974 per study) | Tiotropium 5 μg, 2.5 μg, salmeterol 50 μg TD or placebo as add on therapy to 400–800 μg of budesonide or eq. | Two replicate 24 weeks | 1) Peak FEV1 (0–3 h) 2) Trough FEV1 (24 weeks). 3) ACQ-7 responder rate |
1) trough FVC 2) Peak FVC 3) morning weekly PEF 4) ACQ-7 5) time to first exacerbation 6) Tolerability |
Add on treatment with tiotropium significantly improves lung function and asthma control compared with placebo, and has similar efficacy and tolerability to salmeterol |
| Paggiaro P et al. [142] | 2016 | Uncontrolled asthma defined with ACQ-7 > 1.5, FEV1 60–90%pred despite chronic treatment with 200–400 μg budesonide or eq. | 18–75 | 464 | Tiotropium 5 μg or tiotropium 2.5 μg or placebo as add on treatment to chronic low to medium ICS. | 12 week | Peak FEV1 (0–3 h) | 1) Trough FEV1
2) FEV1AUC (0–3h) 3) Use of rescue medication 4) ACQ-7 5) morning and evening PEF 6) Safety |
Both doses of tiotropium were significantly superior to placebo for every lung function outcome. No effect size retrieved. No difference in reduction of ACQ-7 score between active and placebo groups. |
Phase III RCTs that evaluated efficacy and safety of different doses of tiotropium in patients with moderate to severe uncontrolled asthma. RCTs are divided according to the study sample age. N number of patients randomized to treatment, ACQ-IA Interviewer-Administered version of the Asthma Control Questionnaire, RTI respiratory Tract Infections, FeNO Exhaled Fraction of Nitric Oxide, %pred percent predicted, eq. equivalent. For other abbreviations please see text. In all trials adverse effects were not different between groups if not otherwise reported. For other abbreviations, please see text