An international team led by Stefan Zielen of Goethe University Frankfurt has now reported the results of the TIPP trial, the first study to evaluate a full year of tiotropium treatment as an add-on to inhaled corticosteroids in children aged one to five with severe, partially controlled or uncontrolled preschool asthma. The trial was investigator-initiated and funded by the German Federal Ministry of Education and Research, with Boehringer Ingelheim supplying medication but having no role in design, analysis, or reporting. Published in eClinicalMedicine, the phase III, multicentre, randomised, double-blind, placebo-controlled study enrolled children at twelve German hospitals and one specialised practice. To qualify, each child must have experienced at least one severe exacerbation requiring hospitalisation or at least two courses of systemic corticosteroids in the preceding two years, and their asthma had to remain partly controlled or uncontrolled despite at least four weeks of inhaled corticosteroid therapy, according to Global Initiative for Asthma criteria.

The design was deliberately conservative. Children received two puffs of 1.25 micrograms of tiotropium, a total daily dose of 2.5 micrograms, delivered by Respimat soft-mist inhaler with a spacer and mask, or an identical placebo, once daily for 52 weeks. The dose was chosen from earlier paediatric data showing that both 2.5 and 5 micrograms were well tolerated in this age range, with the lower dose preferred for prolonged use. Of 100 children screened, 86 were randomised, 44 to tiotropium plus inhaled corticosteroids and 42 to placebo plus inhaled corticosteroids. Randomisation used permuted blocks stratified by site, generated independently at the Interdisciplinary Centre for Clinical Trials in Mainz, and everyone involved—families, clinicians, and analysts—remained blinded throughout. Caregivers logged symptoms daily through a purpose-built smartphone diary, and visits at weeks 6, 16, 28, 40, and 52 tracked height, weight, spirometry in children old enough to cooperate, and a battery of immunological markers including total IgE, eosinophil counts, and allergen-specific IgE.

The cohort itself tells a story of how severe preschool asthma really is. The children, with a mean age of 3.3 years, had experienced a median of 3.5 severe exacerbations in the year before enrolment. Eighty-six percent reported daytime symptoms, 78 percent suffered nocturnal awakenings, and 65 percent met the definition of uncontrolled asthma despite a heavy background of controller medication: 52 percent were already on inhaled corticosteroids plus a long-acting beta agonist, and another 14 percent were on that combination plus a leukotriene receptor antagonist. Bronchitis, cough, and respiratory infections dominated the symptom landscape, as they do in real-world clinics. Recruitment, however, proved punishing. The original plan called for 204 children, later revised to 152, but pandemic-era reductions in acute presentations, a brutal influenza and respiratory syncytial virus season in late 2022, and Germany’s high standard of fully insured routine care left the team with 100 screened patients. The authors candidly attribute part of the shortfall to inconsistent nomenclature—many of these children are labelled with recurrent obstructive bronchitis rather than asthma and are treated in family practices rather than specialist centres.

The primary result was unambiguous in its null finding. Time to first severe exacerbation—defined as hospitalisation, at least three days of systemic steroids, or one day of rectal prednisolone—was statistically indistinguishable between groups, with a hazard ratio of 0.99 and a confidence interval spanning unity. A model for recurrent severe exacerbations reached the same conclusion. The secondary endpoints followed suit: severe exacerbations per patient-year (0.8 versus 1.1), hospitalisations, systemic steroid rescue, salbutamol use, symptom-free days, physician visits, missed daycare days, antibiotic prescriptions, lung function, and biomarker-based subgroups all failed to separate the treatments. Younger children, aged one to three, fared worse than four-to-five-year-olds regardless of treatment, with a significantly higher rate of mild exacerbations—an age effect, the authors stress, not a treatment interaction.

Two exploratory signals flickered at the margins. Caregivers using the electronic diary reported fewer night-time awakenings in the tiotropium group, a median of 5 percent of nights versus 9 percent, a nominally significant difference the authors insist requires confirmation in adequately powered trials with multiplicity control. And in a post-hoc analysis, the median time to first exacerbation of any severity was longer with tiotropium, 61 days versus 35 days, yielding a nominal hazard ratio of 0.60—yet the corresponding log-rank test was not significant, and the investigators rightly decline to claim efficacy from exploratory statistics. Spirometry, restricted to the minority of children aged four and older who could perform acceptable manoeuvres, showed a numerical average FEV1 gain of 131 millilitres at week 24 in the tiotropium arm, a clinically relevant magnitude echoing findings in older children, but the difference did not reach statistical significance in the small subgroup.

What the trial did deliver was reassurance on safety. Eighty-three of the 86 children experienced at least one adverse event, a total of 847, ranging from nasopharyngitis and bronchitis to pneumonia—unsurprising in a cohort of wheezing toddlers followed through a full year of respiratory-virus seasons. Crucially, the distribution was balanced, and if anything favoured tiotropium: upper respiratory infections and pneumonia were both more frequent in the placebo group, and none of the severe adverse events were judged causally related to the study drug. No new safety signals emerged, consistent with the established tolerability profile of tiotropium in paediatric populations. For a medication acting on muscarinic receptors in very young airways, this absence of harm carries genuine weight, even in the absence of demonstrated benefit.

The authors place their null result in context with an honest accounting of limitations. The trial was substantially underpowered relative to its original ambition; the sample size calculation assumed 90 percent of placebo children would suffer a severe exacerbation within a year against 75 percent on tiotropium, and the smaller-than-planned cohort eroded precision for the primary endpoint and especially for secondary and subgroup analyses. No correction for multiple testing was applied, so the nominally significant secondary findings must be read as exploratory. Preschool asthma is phenotypically heterogeneous, and heterogeneous background therapy may have diluted any true treatment effect. Lung function data were confined to a small, older subset, and the sample was far too small to detect rare adverse events. Still, the investigators argue that adequately powered studies, not dismissal, are the appropriate response to these data.

For clinicians and families, the practical message is measured. Tiotropium cannot currently be recommended as routine add-on therapy for preschool children with partially controlled or uncontrolled asthma on inhaled corticosteroids; the evidence is simply insufficient to support that step. But neither has it been excluded as potentially helpful in a suitably selected subgroup. The trial underscores a broader and uncomfortable truth: children under five with severe asthma remain one of the most under-evidenced populations in respiratory medicine, where diagnostic inconsistency, licensing gaps, and recruitment difficulties converge to leave treatment decisions resting on extrapolation from older children. TIPP, despite its underpowered outcome, has mapped that terrain carefully—establishing feasibility of a year-long placebo-controlled inhaler trial in toddlers, confirming safety, and defining the exacerbation-prone phenotype that future studies must target. Until adequately powered trials arrive, the standard armamentarium of inhaled corticosteroids, careful trigger management, and vigilant exacerbation planning remains the best available defence for these smallest patients.

Subject of Research: A phase III randomised trial of tiotropium add-on therapy for preschool children with partial or uncontrolled asthma

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

Article References: Zielen, S., Wollscheid, N., Nickolay, T., Grimmel, C., Scheele, D., Sattler, F., Prenzel, F., Lorenz, M., Schaub, B., Lex, C., Stieglitz, F., Trischler, J., Donath, H., Lau, S., Hamelmann, E., Vogelberg, C., Gerstlauer, M., Grychtol, R., Schubert, R., … Wosniok, J. (2026). Efficacy and safety of tiotropium in partial and uncontrolled preschool asthma (TIPP): a phase III, multicentre, randomised, double-blind, placebo-controlled trial. eClinicalMedicine, 99, Article 104172. https://doi.org/10.1016/j.eclinm.2026.104172

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104172

Keywords: preschool asthma, tiotropium, long-acting muscarinic antagonist, inhaled corticosteroids, severe exacerbations, phase III trial, Respimat, paediatric pulmonology, randomised controlled trial, asthma control, placebo, drug safety