Efficacy and Safety of Tiotropium Bromide Monohydrate in Preventing Severe Asthma Exacerbations in Preschool Children with Partial and Uncontrolled Asthma

The primary objective of this study is to evaluate whether the addition of **Tiotropium** via Respimat® to inhaled corticosteroids (ICS) prevents severe asthma exacerbations in children with partial or uncontrolled preschool asthma. This is clinically relevant as severe asthma exacerbations can lead to significant morbidity, increased healthcare utilization, and impact the quality of life in this population. By potentially reducing the frequency of these exacerbations, the study aims to improve clinical outcomes and reduce the burden of asthma management in young children.

The secondary objective is to assess whether the addition of Tiotropium via Respimat® to ICS reduces health utilization, including hospitalizations, physician visits, and antibiotic use, in cases of partial or uncontrolled preschool asthma. This evaluation is important as it may demonstrate additional benefits of Tiotropium in managing asthma, potentially leading to more efficient healthcare resource utilization and improved patient care.

The clinical trial focuses on evaluating the efficacy of Tiotropium via Respimat® in preventing severe **asthma** exacerbations in preschool children with partial and uncontrolled asthma. The study population comprises both male and female participants aged between 1 and 5 years, with a history of physician-diagnosed asthma symptoms such as wheezing, cough, and shortness of breath for at least six months. Participants must have been on a stable dose of inhaled corticosteroids (ICS) for at least four weeks prior to the study and have experienced hospitalization due to acute severe asthma or required systemic steroids in the past 24 months. The trial includes children who are symptomatic despite ICS treatment, as defined by the GINA guideline for children aged 5 years and younger. Participants must be capable of using the Respimat® inhaler with a spacer. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of **Tiotropium bromide monohydrate** in preventing severe asthma exacerbations in preschool children with partial and uncontrolled asthma. The trial will involve the administration of Tiotropium via the **Respimat Inhaler**, with a maximum daily dose of 2.5 µg and a total dose not exceeding 912.5 µg over a treatment period of up to 12 months. The study is expected to commence recruitment on February 1, 2022, and conclude by February 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, asthma diagnosis, and current treatment regimen. Following randomization, participants will attend regular follow-up visits to monitor their response to treatment and any adverse events. The primary endpoint is the time to the first severe exacerbation, defined by hospitalization or the need for systemic steroids. Secondary endpoints include the number of severe exacerbations, hospitalizations, and asthma-related events, as well as assessments of safety and quality of life.

The expected length of participant involvement is up to 12 months, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that compromise participant safety. The study aims to provide comprehensive data on the potential benefits of Tiotropium in managing severe asthma exacerbations in young children, contributing to improved therapeutic strategies in this population.

The clinical trial involves the administration of **Tiotropium bromide monohydrate**, a **solution for inhalation**. This experimental medication is delivered using the Respimat® inhaler, which is specifically designed for this purpose. The active substance, **Tiotropium bromide monohydrate**, is of chemical origin and is provided by Boehringer Ingelheim International. The inhalation solution is administered at a dosage of 2.5 µg per actuation, with a maximum daily dose of 2.5 µg. The treatment period extends up to 12 weeks. The Respimat® inhaler is equipped to deliver 60 actuations per cartridge, ensuring precise dosing. Compliance with the dosing schedule is monitored through regular assessments and device usage tracking.

The study also includes a **placebo** group, utilizing the Respimat® inhaler with a cartridge containing a placebo solution. The placebo is administered in the same manner as the active treatment, ensuring blinding and maintaining the integrity of the trial. The placebo inhaler is indistinguishable from the active treatment inhaler in appearance and usage, providing a reliable comparator for evaluating the efficacy and safety of Tiotropium in preventing severe asthma exacerbations in preschool children with partial and uncontrolled asthma.

The efficacy of Tiotropium bromide monohydrate in preventing severe asthma exacerbations in preschool children with partial and uncontrolled asthma will be assessed through a prospective multicenter placebo-controlled trial. The primary endpoint for evaluating efficacy is the time to first severe exacerbation, defined by hospitalization and/or the requirement of at least three days of systemic steroids or one day of rectal prednisolone (Rectodelt®). Secondary endpoints include the number of severe exacerbations, number of hospitalizations due to severe exacerbations, exacerbation-free survival time, and the number of asthma-related events defined by the use of antibiotics.

Additional secondary endpoints involve the percentage of night-time awakenings due to asthma symptoms, percentage of days without asthma symptoms, and the use of PRN salbutamol rescue medication, all assessed via electronic patient diaries and the TIPP diary App (PACD). Health utilization metrics such as the number of physician visits and missed days in daycare will also be recorded. The study will further evaluate the results of the TRACK questionnaire, CGI-C at the end of treatment, and potential biomarkers for treatment response, including eosinophils, IgE, and specific IgE to common allergens.

Data collection will be facilitated by the use of the Respimat® inhaler, which delivers the Tiotropium solution for inhalation. The trial will ensure safety by analyzing symptom scores, rescue medication use, and adverse events through electronic diaries. The study is designed to provide comprehensive insights into the efficacy of Tiotropium in managing severe asthma exacerbations in the specified pediatric population.