Efficacy and safety of tiotropium in partial and uncontrolled preschool asthma (TIPP): a phase III, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preschool children with asthma are more susceptible to develop acute life-threatening respiratory distress leading to hospital admissions compared to school children and treatment options are limited for this age group. We evaluated the safety and efficacy of tiotropium as add-on therapy to inhaled corticosteroids (ICS) in preschool children with high-risk, partly controlled or uncontrolled asthma. METHODS: TIPP was a phase III, prospective, multicentre, randomised, double-blind, placebo-controlled, parallel-group (investigator-initiated) trial conducted at 13 German centres (12 hospitals, one specialised medical practice). Children aged 1-5 years with physician-diagnosed asthma, partly controlled or uncontrolled symptoms despite ICS, and a history of severe exacerbations were randomly assigned to receive once-daily tiotropium (two puffs of 1.25 μg) via Respimat® inhaler or placebo as add-on to ICS therapy over 52 weeks. The primary outcome was time to first severe asthma exacerbation requiring hospitalisation and/or systemic corticosteroid treatment. All randomised participants were included in the intention-to-treat analysis and analysed by treatment received for safety. No primary or safety data were missing; therefore, no imputation was required. The study was registered in the "EU Clinical Trials Registry" (EudraCT 2021-000190-81). FINDINGS: Between February 2022 and March 2025, 100 of the planned 204 children were enrolled, of whom 86 were randomised to tiotropium + ICS (n = 44) or placebo + ICS (n = 42). Mean age was 3.3 years (Standard deviation (SD) 1.3). The primary outcome time to first severe asthma exacerbation did not differ between groups (Hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.51-1.92; p = 0.98). At least one adverse event was reported in 41 (93%) of 44 children in the tiotropium + ICS group and 42 (100%) of 42 children in the placebo + ICS group. 397 adverse events were reported with tiotropium + ICS group and 450 with placebo + ICS group. Tiotropium was well tolerated, and no new safety signal was identified. INTERPRETATION: Tiotropium did not reduce the risk of a severe asthma exacerbation, but was well tolerated as add-on therapy to ICS in preschool children with high-risk asthma. FUNDING: German Federal Ministry of Education and Research (01KG2030); study medication provided by Boehringer Ingelheim Pharma GmbH & Co. KG (0205-0546).