Safety and Efficacy of Tiotropium Respimat® Add-on Therapy in Pre-school Children with Symptomatic Persistent Asthma

Abstract

Purpose: Asthma is the most common chronic disease of childhood (GINA. Diagnosis and management of asthma in children 5 years and younger. 2015). The preferred controller medication in children aged ≤5 years is a low dose of inhaled corticosteroids (ICS). However, treatment options for these patients are limited if their asthma symptoms are not then well controlled on ICS. The aim of this study was to evaluate the safety and efficacy of once-daily tiotropium Respimat® in patients aged 1-5 years with symptomatic persistent asthma, as add-on to ICS with or without further maintenance therapy. Methods: A Phase II/III, randomized, double-blind, placebo-controlled, parallel-group trial (NCT01634113) in patients aged 1-5 years with symptomatic persistent asthma. Patients received tiotropium 5 µg (two puffs of 2.5 µg), tiotropium 2.5 µg (two puffs of 1.25 µg), or placebo (two puffs), administered once daily in the afternoon for 12 weeks via the Respimat® device, each as add-on to usual maintenance therapy of ICS with or without other controller medication. The primary objective was to determine the safety of tiotropium Respimat®. Safety data included post hoc analyses of three composite exacerbation endpoints derived from adverse events (AEs), with treatment comparisons reported as hazard ratios (95% confidence interval [HR (95% CI)]). The primary efficacy endpoint was change in the weekly mean combined daytime asthma symptom score from baseline at Week 12 (response). The co-primary endpoint in 5-year-olds was peak forced expiratory volume in 1 second within 3 hours post-dose (peak FEV1(0-3h)) response. Treatment comparisons for efficacy endpoints were exploratory, and no formal hypothesis testing was performed. Results: Of the 102 patients randomized, 101 were treated and completed the 12-week treatment period: tiotropium 5 µg, n=31; tiotropium 2.5 µg, n=36; placebo, n=34. Safety results were comparable between all treatment groups, with a lower proportion of patients reporting any AEs in the tiotropium groups (5 µg: 58.1%; 2.5 µg: 55.6%) than in the placebo group (73.5%). No AEs leading to treatment discontinuation or death were reported, and AEs were of mild or moderate intensity. Serious AEs were reported in three patients (8.8%), all in the placebo group. In post hoc analyses, both tiotropium doses reduced the risk of asthmatic exacerbation over 12 weeks compared with placebo (e.g. see exacerbation [broad] with pneumonia plus worsening in the figure). Tiotropium and placebo were associated with comparable improvements in weekly mean combined daytime asthma symptom score and peak FEV1(0-3h) responses (exploratory analyses); treatment comparisons were not performed for peak FEV1(0-3h) response because of insufficient patient numbers in each treatment group. Conclusion: Once-daily tiotropium Respimat® add-on to ICS with or without further maintenance therapy is safe and well tolerated, and may reduce exacerbations in pre-school children with symptomatic persistent asthma.