Efficacy and Safety of Dupilumab in Pediatric Patients Aged 2 to <6 Years with Uncontrolled Asthma and/or Recurrent Severe Asthmatic Wheeze

The primary objective of this study is to evaluate the **efficacy** of dupilumab in reducing the annualized rate of severe asthma exacerbations at Week 52 compared to placebo in children aged 2 to <6 years with uncontrolled asthma and/or recurrent severe asthmatic wheeze. This is clinically relevant as it aims to address the frequency of severe exacerbations, which are critical events in asthma management, potentially leading to improved long-term outcomes and reduced healthcare utilization.

Secondary objectives include:

• Assessing the efficacy of dupilumab in decreasing the need for hospitalization, emergency room, or urgent care visits at Week 52 compared to placebo.
• Evaluating the efficacy of dupilumab in reducing the need for increased inhaled corticosteroid doses and reliever use compared to placebo.
• Assessing the improvement in asthma symptoms and the safety and tolerability of dupilumab in the specified pediatric population.
• Evaluating the effect of dupilumab on health-related quality of life, global impression of asthma severity and control from both caregiver's and clinician's perspectives.
• Exploring baseline and on-treatment levels of biomarkers for their potential to predict and associate with treatment response.
• Evaluating the pharmacokinetics, immunogenicity, and the association between dupilumab treatment and immune response to non-live vaccines in the pediatric population.

The clinical trial involves a total of **77 participants** who are children aged between **2 to <6 years**. The study population includes both **male and female** subjects diagnosed with **asthma** or recurrent severe asthmatic wheeze that is not controlled with chronic inhaled corticosteroids (ICS) for at least three months. Participants were selected based on specific criteria, including evidence of uncontrolled asthma and/or recurrent severe asthmatic wheeze, and at least one major criterion from the modified asthma predictive index, such as physician-diagnosed atopic dermatitis or allergic sensitization to at least one aeroallergen. The trial population is considered vulnerable due to the young age of the participants. Lifestyle considerations such as diet or physical activity are not specified, but the study requires that participants have a body weight at screening and randomization between 5 kg and 30 kg. The trial aims to assess the efficacy and safety of dupilumab in reducing severe asthma exacerbations and is conducted with the consent and cooperation of the participants' parents or legal guardians.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel group study** to evaluate the efficacy and long-term safety of **dupilumab** in children aged 2 to less than 6 years with uncontrolled **asthma** and/or recurrent severe asthmatic wheeze. The trial is divided into two parts: Part A focuses on assessing the efficacy of dupilumab in reducing the annualized rate of severe asthma exacerbations over a 52-week treatment period, while Part B evaluates the safety and tolerability of dupilumab in the same population. The trial is expected to commence recruitment on January 3, 2024, and conclude by December 21, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of asthma or recurrent severe asthmatic wheeze, and evidence of uncontrolled asthma despite chronic inhaled corticosteroid (ICS) use. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of asthma exacerbations, medication use, and quality of life. The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final evaluations will be conducted.

The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including the occurrence of serious adverse events, non-compliance with study procedures, or withdrawal of consent by the participant's parent or legal guardian. The primary endpoints include the annualized rate of severe asthma exacerbations and the incidence of treatment-emergent adverse events. Secondary endpoints encompass hospitalization rates, medication usage, and changes in asthma control and quality of life metrics. The study aims to provide comprehensive data on the efficacy and safety of dupilumab in this pediatric population.

The clinical trial involves the administration of **Dupilumab**, a solution for injection in a pre-filled syringe. Dupilumab is a protein-based medication developed by Sanofi Aventis Recherche et Développement (SAR). It is administered subcutaneously with a maximum daily dose of 300 mg for the high dose and 200 mg for the low dose. The treatment period extends up to 104 weeks. Participant compliance is monitored through regular follow-ups and assessments to ensure adherence to the dosing schedule.

In addition to the experimental medication, the trial includes a **matched placebo** for both high and low doses of Dupilumab. The placebo is designed to mimic the appearance and administration method of the active treatment, ensuring the study remains double-blind. The placebo is administered with the same frequency and route as Dupilumab, maintaining consistency in the trial protocol.

Other auxiliary treatments in the study include **Salbutamol** and **Ipratropium Bromide**, which are administered via an unknown route. These medications are used as needed to manage acute symptoms, with dosing adjusted based on individual patient requirements. The pharmaceutical form is coded as PHF00154MIG, and the maximum treatment period is one day.

**Fluticasone** and **Salmeterol** are also included as auxiliary treatments, administered via inhalation. The maximum daily dose is 100 µg, with a treatment period of one day. The pharmaceutical form is coded as PHF00207MIG. These medications are used to manage chronic symptoms and are part of the standard care for asthma management.

**Montelukast** is administered orally, either as a chewable tablet or sprinkles, with a maximum daily dose of 4 mg. The treatment period is one day, and the pharmaceutical form is coded as PHF00082MIG. Montelukast is used to manage chronic asthma symptoms and is part of the standard care regimen.

Additional auxiliary treatments include **Budesonide** and **Beclometasone**, both with unknown routes of administration. These medications are used as needed, with dosing adjusted based on individual patient requirements. The pharmaceutical form for Budesonide is coded as PHF00110MIG, and for Beclometasone, it is also PHF00110MIG. The maximum treatment period for both is one day.

The efficacy of dupilumab in the clinical trial will be assessed primarily by evaluating the **annualized rate of severe asthma exacerbations** during the 52-week treatment period in Part A. Secondary endpoints include the annualized rate of hospitalization, emergency room, or urgent care visits for asthma exacerbations, the annualized rate of moderate asthma exacerbations, and the cumulative inhaled corticosteroid (ICS) dose during the same period. Additional secondary measures involve changes from baseline in the weekly average use of reliever medication, the mean number of days without asthma symptoms using the Pediatric Asthma Caregiver Diary (PACD), and changes in daytime symptom scores using the PACD. The trial will also assess the change from baseline to Week 52 in the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Scale, Caregiver Global Impression of Change in asthma control, and Physician Global Assessment of Change in asthma control.

Further assessments include changes in blood eosinophil levels at Weeks 24 and 52, the concentration of dupilumab in serum over time, and the incidence of treatment-emergent anti-drug antibodies (ADAs) against dupilumab. The IgG response to non-live vaccination will also be evaluated. The efficacy parameters will be measured and collected at specified time points throughout the trial, with data analysis conducted to determine the impact of dupilumab on the specified endpoints. The trial will utilize validated scales and patient-reported outcomes to ensure accurate and reliable efficacy assessments.