Phase 3 Randomized Double-Blind Placebo-Controlled Study of Tezepelumab in Pediatric Patients Aged 5 to <12 Years with Severe Uncontrolled Asthma

The primary objective of this study is to evaluate the effect of **tezepelumab** on severe asthma exacerbations in children aged 5 to less than 12 years with severe uncontrolled asthma, compared with placebo. This is clinically relevant as severe asthma exacerbations can significantly impact the quality of life and overall health of pediatric patients, and finding effective treatments is crucial for managing this condition.

Secondary objectives include assessing the effect of tezepelumab compared with placebo on various clinical parameters:

• Pulmonary function (FEV1) in children with severe uncontrolled asthma.
• Severe asthma exacerbations in children with allergic asthma.
• Other endpoints associated with severe asthma exacerbations.
• Cumulative exposure to systemic corticosteroids.
• Health status and health-related quality of life.
• Asthma symptoms and asthma control.
• Other asthma control metrics.
• Biomarkers such as blood eosinophil count, FeNO, and total serum IgE.
• Health resource utilization (HRU) and productivity loss due to asthma.
• Pharmacokinetics (PK) and immunogenicity of tezepelumab.
• Safety of tezepelumab.

The clinical trial involves a total of **311 participants** who are children aged **5 to less than 12 years** with **severe uncontrolled asthma**. The study population includes both male and female subjects, and it is noted that the participants are considered a vulnerable population due to their age and health condition. Participants were selected based on specific criteria, including a documented physician diagnosis of severe asthma for at least six months prior to the study, and a history of at least two severe asthma exacerbation events requiring systemic corticosteroid treatment or one event resulting in hospitalization within the past year. The trial also requires participants to have been on a stable dose of medium or high-dose inhaled corticosteroids and additional asthma controller medication for at least three months. Lifestyle considerations such as diet and physical activity are not specified, but the trial focuses on children with evidence of uncontrolled asthma, as indicated by frequent use of reliever medication, sleep disturbances due to asthma symptoms, or asthma symptoms occurring multiple days per week. The study aims to assess the effect of **tezepelumab** on severe asthma exacerbations compared to a placebo.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of **tezepelumab** in children aged 5 to less than 12 years with severe uncontrolled **asthma**. The trial aims to assess the effect of tezepelumab on severe asthma exacerbations compared to a placebo. The study is expected to commence recruitment on November 28, 2023, and conclude by November 10, 2027, with a total duration of approximately four years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented severe asthma, historical evidence of asthma exacerbations, and current asthma control status. Following the screening, eligible participants will be randomized to receive either tezepelumab or a matching placebo via subcutaneous injection. The treatment period will last for 52 weeks, during which participants will attend regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will include assessments such as lung function tests, asthma control questionnaires, and blood sample collections for biomarker analysis.

The primary endpoint of the study is the annualized asthma exacerbation rate (AAER), while secondary endpoints include changes in lung function, time to first severe exacerbation, and health-related quality of life measures. Participants' involvement in the study is expected to last for the entire 52-week treatment period, with an additional follow-up period to assess long-term outcomes. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures.

The clinical trial involves the administration of **Tezepelumab**, a solution for injection, as the experimental medication. Tezepelumab is a biological product of biotechnological origin, specifically a protein of other origin. It is provided in vials and administered via **subcutaneous use**. The dosing schedule for Tezepelumab is not explicitly detailed in the provided data, but the maximum treatment period is specified as 76 weeks. The trial aims to assess the efficacy and safety of Tezepelumab in children aged 5 to less than 12 years with severe uncontrolled asthma. The product is identified with the sponsor product code MEDI9929 (AMG157) and is registered in the EU, although the investigational medicinal product (IMP) used in this study will be provided in a different primary container.

The study also includes a **matching placebo** for Tezepelumab, which is used as a comparator treatment in this double-blind, placebo-controlled trial. The placebo is designed to match the Tezepelumab solution for injection in appearance and administration route, ensuring the blinding of participants and investigators. The placebo is administered subcutaneously, similar to the active treatment, to maintain consistency in the administration process. The placebo serves as a control to evaluate the true efficacy and safety of Tezepelumab in the target population.

The efficacy of **tezepelumab** in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the Annualised Asthma Exacerbation Rate (AAER), which will be used to evaluate the frequency of severe asthma exacerbations in children aged 5 to less than 12 years with severe uncontrolled asthma. Secondary endpoints include changes from baseline to Week 52 in pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1% predicted normal), AAER associated with allergic asthma, time to first severe asthma exacerbation, and the proportion of participants with at least one severe asthma exacerbation. Additional secondary endpoints involve AAER associated with emergency room visits or hospitalizations, cumulative exposure to systemic corticosteroids, and changes in various patient-reported outcomes and biomarkers.

These efficacy parameters will be measured and collected at specified timepoints throughout the trial, including baseline and Week 52. The assessments will utilize validated tools and instruments, such as spirometry for FEV1 measurements and patient-reported outcome measures like the Pediatric Asthma Quality of Life Questionnaire (PAQLQ-IA) and the Asthma Control Questionnaire (ACQ-IA). Biomarker levels, including blood eosinophil count, fractional exhaled nitric oxide (FeNO), and total serum IgE, will also be evaluated. The analysis of these endpoints will provide comprehensive data on the efficacy of tezepelumab in reducing asthma exacerbations and improving asthma control in the pediatric population.