A Randomised Dose-ranging Study of Tiotropium Respimat® in Children With Symptomatic Asthma Despite Inhaled Corticosteroids

Christian Vogelberg; Petra Moroni-Zentgraf; Migle Leonaviciute-Klimantaviciene; Ralf Sigmund; Eckard Hamelmann; Michael Engel; Stanley Szefler


Respiratory Research. 2015;16(20) 

In This Article


In the present study, once-daily tiotropium Respimat® add-on to medium-dose ICS, with or without a leukotriene modifier, improved lung function in children with symptomatic asthma. For the primary end point, statistically significant improvements in peak FEV1(0–3h) response after 4 weeks of treatment were observed for all tiotropium Respimat® dose groups versus placebo Respimat®.

Analyses of secondary and additional efficacy end points also generally demonstrated the superiority of all tiotropium Respimat® doses tested, with statistically significant improvements in trough FEV1, FEV1 AUC(0–3h) and peak FEV1 at all time points up to 3 hours post-dosing observed with all doses of tiotropium Respimat®, compared with placebo Respimat®. The observed improvements in FVC were generally not significantly different from those observed with placebo Respimat®, which is an expected observation given the age of this patient population.

PEF monitoring is an important tool for measuring airway changes, particularly in patients who may not accurately perceive their worsening symptoms.[25] PEF results, which represent a weekly average of daily values, may provide more reliable data compared with FEV1 measurements, which represent a single value taken on 1 day in a clinic outside of a patient's real-life setting. Data from the study presented here demonstrate that all doses of tiotropium Respimat® were superior to placebo Respimat® for morning PEF. For evening PEF, which represents a true 24-hour value, the tiotropium Respimat® 5 μg dose also showed superiority when compared with placebo Respimat®, and demonstrated higher values than the 2.5 μg and 1.25 μg doses.

With regard to patient-reported outcomes, a positive trend for improvements in ACQ-7 and PAQLQ(S) scores was observed in this study following treatment with all three doses of tiotropium Respimat®. Additional analyses from parallel-group trials of longer duration and with larger patient numbers are required to further investigate the effect of tiotropium Respimat® on asthma control and quality of life in children with symptomatic asthma.

The study presented here demonstrates that once-daily tiotropium Respimat® add-on to medium-dose ICS, with or without a leukotriene modifier, has safety and tolerability that are comparable with those of placebo Respimat® in children aged 6–11 years with symptomatic asthma. This parallels and further reinforces the data in adult patients, where once-daily tiotropium Respimat® was shown to have similar safety and tolerability when compared with placebo Respimat® in patients with symptomatic asthma on ICS with or without a LABA.[20,26,27]

Although the comparison between the tiotropium Respimat® doses was descriptive only, we note that there was no clear dose-dependent response seen for either the primary or any of the secondary or additional efficacy end points. The results of Phase II studies in adult and adolescent patients with asthma have clearly demonstrated a greater response with the 5 μg dose. In these Phase II studies, the once-daily doses of 10 μg, 5 μg, 2.5 μg or 1.25 μg all improved lung function and were well tolerated, with the 5 μg dose achieving the greatest bronchodilation.[17,18,22,28] The long-term clinical efficacy and safety of tiotropium Respimat® 5 μg have been demonstrated in two large Phase III studies in adult patients with symptomatic asthma receiving ICS plus LABA.[20]

The Respimat® SoftMist™ inhaler may provide advantages over pressurised metered-dose inhalers and dry-powder inhalers, particularly in the treatment of children with asthma. The increased aerosol production time with the SoftMist™ inhaler may benefit young patients with low inspiratory capacity or poor timing of inhalation to actuation, although correct technique remains important.[29] A single device with once-daily dosing may also improve patient adherence, which is notably poor in children and adolescents.[11]

It should be noted that this study has some methodological limitations. The incomplete-crossover design means that all patients did not receive all study treatments; however, this study design reduces inter-patient variability and the number of patients required to reach statistical power, with the lack of washout between treatments promoting patient compliance. The short study duration meant that the focus was on assessment of lung function, and did not allow for a full assessment of asthma symptom control or exacerbation rate.

The data presented in this manuscript encourage and warrant future, large Phase III trials in paediatric patients to confirm these results and to examine the impact of tiotropium Respimat® add-on therapy on long-term efficacy, safety and tolerability. Additional studies will help to determine where tiotropium Respimat® will fit in future treatment guidelines, particularly in relation to high-dose ICS maintenance therapy with or without a LABA.