Tiotropium add-on may be safe in children 1–5 years with asthma
Adding tiotropium to inhaled corticosteroids (ICS) appeared safe and well tolerated in preschool children with persistent asthmatic symptoms, reveals an exploratory, regulatory trial—suggesting that tiotropium may be a complementary strategy for managing this young population for whom treatment options are scarce.
Tiotropium add-on also demonstrated a potential to reduce asthma exacerbations in young children, although it did not improve daytime asthma symptom score.
“Children are not small adults … [T]heir study brings much-needed preliminary evidence of the safety and efficacy of a new controller medication to add on to ICS in young children with uncontrolled asthma,” wrote Dr Alvaro Cruz of the Federal University of Bahia School of Medicine in Salvador, Brazil, in a commentary. [Lancet Respir Med 2018;6:80-82] “Whether their data is sufficient for the approval of tiotropium for use in children aged 1–5 years merits discussion.”
The exploratory, multinational, double-blind, phase II/III, regulatory trial included 102 children aged 1–5 years with persistent asthmatic symptoms for ≥6 months and required ICS. They were randomized to receive either once-daily tiotropium 2.5 µg, 5 µg, or placebo, which was added on to ICS with or without additional controller medication. [Lancet Respir Med 2018;6:127-137]
At 12 weeks, the primary safety outcome of adverse event rate was lower with tiotropium than with placebo add-on (56 percent and 58 percent vs 74 percent for tiotropium 2.5 µg and 5 µg vs placebo, respectively). The most common adverse events (AEs) were asthma exacerbations and nasopharyngitis (17 percent and 14 percent, respectively), which according to the researchers, were mild or moderate in intensity.
Although the assessment was descriptive and formal statistical comparison between groups was not done due to limited sample size, Cruz noted that the data are consistent with findings from older children aged 6–11 years. [J Allergy Clin Immunol 2017;140:1277-1287]
Also, an exploratory analysis revealed that fewer children in the tiotropium groups reported asthma exacerbations than in the placebo group (14 percent and 6 percent vs 29 percent). By Kaplan-Meier estimates, the risk of asthma exacerbations or worsening was 52 percent and 63 percent lower with tiotropium 2.5 µg and 5 µg, respectively vs placebo.
“The Kaplan-Meier curves for exacerbations reported as AEs showed significantly differing trends in the tiotropium and placebo groups after approximately 10 days of treatment … These findings suggest that patient-relevant outcomes can be observed within a short time after initiation of tiotropium add-on treatment,” observed the researchers.
Three serious AEs requiring hospitalization were reported, with all cases occurring in the placebo arm. There were no AEs leading to treatment discontinuation or death.
However, the changes from baseline to week 12 in weekly mean combined daytime asthma symptom scores—the primary efficacy endpoint—were not significantly different with either dose of tiotropium vs placebo (adjusted mean difference vs placebo, -0.080 for tiotropium 2.5 µg and -0.048 for tiotropium 5 µg). This efficacy endpoint was chosen because of the difficulty in performing spirometry in young children and hence, inability to use lung function as an efficacy endpoint.
“Regardless, their ambitious trial was successful in bringing preliminary evidence that tiotropium is safe in young children,” remarked Cruz.
As the number of patients in the study was small, the researchers recommended further studies to confirm the potential of tiotropium in reducing exacerbation risk.
“The important observation of a tiotropium effect on asthma exacerbations in preschool children is encouraging and provides a starting point for future prospective clinical trials to show the observed effect in a confirmatory design,” said the researchers.