Efficacy of Dupilumab with Medium-Dose ICS/LABA vs. High-Dose ICS/LABA in Adolescents and Adults with Uncontrolled Asthma

The primary objective of this study is to evaluate the **efficacy** of dupilumab when added to medium dose inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) in reducing severe asthma exacerbations compared to the escalation of ICS to high dose ICS/LABA in patients with uncontrolled **asthma**. This is clinically relevant as it aims to determine a more effective treatment strategy for managing severe asthma exacerbations, which are a significant concern in asthma management.

Secondary objectives include:

• Evaluating the effect of dupilumab added to medium dose ICS/LABA versus ICS dose escalation on lung function.
• Assessing the impact on annualized cumulative systemic corticosteroid exposure for treating severe asthma exacerbations.
• Evaluating changes in asthma control and the proportion of participants achieving a minimal clinically important difference in asthma control.
• Comparing the time to the first severe exacerbation event between the two treatment strategies.
• Assessing the safety and tolerability of dupilumab added to medium dose ICS/LABA versus high dose ICS/LABA.

The clinical trial involves a total of **188 participants** diagnosed with **asthma**. The study population includes both male and female subjects, aged between 12 and 80 years, who have been diagnosed with asthma for at least 12 months. Participants were selected based on their existing treatment with medium dose ICS/LABA for a minimum of three months, with a stable dose for at least one month prior to the initial visit. The trial includes individuals who require a maximum of three controllers for their asthma management. Participants must demonstrate adherence to their treatment regimen on at least 80% of days during the run-in period. The study population is characterized by a history of at least one severe exacerbation in the previous year, excluding the 30 days immediately before the first visit. Additionally, a baseline blood eosinophil count of at least 300 cells/μL is a common feature among approximately 90% of the participants. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.

The clinical trial is designed to evaluate the efficacy of **dupilumab** added to medium-dose inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) therapy in reducing severe asthma exacerbations compared to escalating the ICS dose to a high-dose ICS/LABA regimen in patients with uncontrolled **asthma**. This study is a randomized, double-blind, controlled trial, categorized as a Phase IV study. The trial is expected to commence recruitment on October 15, 2024, and conclude by December 7, 2026. Participants will be involved in the study for a maximum treatment period of 52 weeks.

The trial will include several study visits, beginning with a screening visit to assess eligibility based on criteria such as age, existing asthma treatment, and lung function parameters. Participants must be aged 12 to 80 years and have a physician diagnosis of asthma for at least 12 months. They should be on a stable medium-dose ICS/LABA regimen for at least one month prior to the screening visit. The inclusion visit will confirm adherence to the treatment regimen and assess baseline characteristics, including blood eosinophil count and asthma control questionnaire scores.

Following the inclusion visit, participants will be randomized to receive either dupilumab or a placebo, in addition to their existing ICS/LABA therapy. The trial will involve regular follow-up visits to monitor treatment efficacy and safety, including assessments of lung function, asthma control, and any adverse events. The primary endpoint is the annualized rate of severe asthma exacerbations, while secondary endpoints include changes in lung function parameters and asthma control scores.

The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the overall efficacy and safety of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the treatment protocol, or if the investigator deems it necessary for their safety. The study aims to provide valuable insights into the management of uncontrolled asthma and the potential benefits of adding dupilumab to existing treatment regimens.

The clinical trial involves the administration of **Dupixent** (dupilumab), a monoclonal antibody, as the experimental medication. Dupixent is provided as a 300 mg solution for injection in a pre-filled syringe. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous use**. The maximum daily dose is 600 mg, with a total maximum dose of 8100 mg over a treatment period of 52 weeks. Dupixent is manufactured by Sanofi Winthrop Industrie and is authorized under the marketing authorization number EU/1/17/1229/002.

In addition to the experimental treatment, the trial includes a **placebo** that matches the formulation of dupilumab. The placebo is used to maintain blinding in the study and is administered in the same manner as Dupixent, although specific details regarding its pharmaceutical form and administration route are not available.

The trial also utilizes **Advair HFA** as a comparator treatment. Advair HFA is available in two dosages: 115 mcg/21 mcg and 230 mcg/21 mcg, both in the form of a pressurised inhalation suspension. The active substances in Advair HFA are **fluticasone propionate** and **salmeterol**, both of which are chemical in origin. The maximum daily dose for the 115 mcg/21 mcg formulation is 230 µg, with a total maximum dose of 90390 µg over 56 days. For the 230 mcg/21 mcg formulation, the maximum daily dose is 460 µg, with a total maximum dose of 174340 µg over the same period. Advair HFA is manufactured by Regeneron Pharmaceuticals, Inc. and is administered via inhalation.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **annualized severe asthma exacerbation rate**, which will be used to evaluate the effectiveness of dupilumab when added to medium dose ICS/LABA compared to ICS dose escalation to high dose ICS/LABA in patients with uncontrolled asthma. Secondary endpoints include changes in pre-bronchodilator Forced Expiratory Volume in the first second (FEV1), annualized cumulative dose of systemic corticosteroid exposure to treat severe asthma exacerbations, and changes in the Asthma Control Questionnaire (ACQ-5) scores. Additional secondary endpoints involve the proportion of participants achieving an ACQ-5 score of less than 1.5, changes in percent of predicted FEV1, peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25-75%, FEV1:FVC ratio, and post-bronchodilator FEV1. The time to first severe exacerbation event and the proportion of participants achieving a 0.5-point improvement in ACQ-5, which is considered a minimal clinically important difference (MCID), will also be evaluated. The incidence of treatment-emergent adverse events (TEAEs) will be monitored as part of the safety assessment.