Non-Inferiority Trial on Dupilumab Withdrawal Versus Continuation in Patients with Controlled Severe Asthma

The primary objective of this study is to demonstrate the **non-inferiority** regarding strategy failure at 24 months of stopping **dupilumab** (intervention group) compared with its continuation (control group) in patients with controlled **severe asthma** who have been receiving this drug for at least 36 months. This is clinically relevant as it may inform treatment strategies for long-term management of severe asthma, potentially reducing medication burden and associated costs without compromising asthma control.

Secondary objectives include:

• Comparing stopping dupilumab with its continuation regarding changes in asthma control, time to loss of control, time to first exacerbation, number of exacerbations, and proportion of patients with exacerbations at 6, 12, and 24 months.
• Evaluating changes in quality of life, lung function, and daily doses of oral and inhaled corticosteroids, as well as the effect on nasal polyposis at 6, 12, and 24 months.
• Determining the proportion of patients in the intervention group who resume dupilumab at 6, 12, and 24 months.
• Assessing safety in both groups.
• Exploratory objectives include identifying baseline factors and biomarkers associated with asthma loss of control over 24 months.

The clinical trial involves participants diagnosed with **severe asthma** who have been receiving dupilumab treatment for at least 36 months. The study population includes both male and female adults aged 18 years and older. Participants are required to have well-controlled asthma, as indicated by an ACT score of 18 or higher, with no more than one exacerbation in the year prior to randomization. The trial does not include a vulnerable population. Participants must be affiliated with a social security scheme and provide free, informed, and written consent. Women of childbearing age are required to use effective contraception. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **non-inferiority** of stopping **dupilumab** compared to its continuation in patients with well-controlled severe asthma. This is a randomized, non-inferiority-controlled trial with a double-blind design. The trial will span a total duration of 24 months, with the estimated recruitment start date set for December 2, 2024, and an estimated end date of December 1, 2029. Participants will be randomly assigned to either the intervention group, where dupilumab is discontinued, or the control group, where dupilumab treatment is continued. The primary endpoint is the proportion of patients experiencing strategy failure, defined as having two or more asthma exacerbations annually or requiring the resumption of dupilumab or a switch to another biologic within 24 months post-randomization.

Study visits are structured to include an initial inclusion (screening) visit, followed by regular follow-up visits at 6, 12, and 24 months, and a final end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as age (≥18 years), prior treatment with dupilumab for at least 36 months, and well-controlled asthma as indicated by an ACT score of ≥18. Follow-up visits will assess changes in asthma control, the time to loss of control, and the number of exacerbations. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced during the trial.

Participant involvement is expected to last for the entire 24-month duration of the trial. However, conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or the need for alternative treatment due to worsening asthma control. The trial aims to provide valuable insights into the management of severe asthma and the potential implications of discontinuing dupilumab in patients with controlled symptoms.

The clinical trial involves the use of **Dupilumab**, marketed under the name Dupixent, as the experimental medication. Dupixent is formulated as a **solution for injection** in a pre-filled syringe, with each syringe containing 300 mg of the active substance. The pharmaceutical form is specifically designed for **subcutaneous injection**. The administration of Dupixent is conducted at a maximum daily dose of 300 mg, with a total maximum dose of 144 grams over the course of the treatment period. The maximum treatment period is set at 24 months. Dupilumab is a protein-based therapeutic agent, classified under the ATC code D11AH05, and is produced by Sanofi Winthrop Industrie. The trial aims to assess the non-inferiority of stopping Dupilumab compared to its continuation in patients with controlled severe asthma who have been receiving the drug for at least 36 months.

In addition to the experimental treatment, the study may involve the use of a **comparator treatment** or placebo, as is standard in non-inferiority trials. However, specific details regarding non-experimental treatments, such as standard-of-care therapy or placebo, are not provided in the available data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial's main objective is to evaluate the strategy failure at 24 months, comparing the outcomes of patients who discontinue Dupilumab with those who continue its use.

Efficacy in the clinical trial titled "Withdrawal of Dupilumab in Severe Asthma: a randomised non-inferiority-controlled trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients experiencing strategy failure, defined as having an annualized number of asthma exacerbations of two or more, and/or the resumption of **dupilumab** or a switch to another biologic within 24 months following randomization. Secondary endpoints include several measures: the change in the asthma control test (ACT) score at 6, 12, and 24 months compared to baseline; the time from baseline to loss of control, defined as a reduction of 5 points or more on the ACT score; the time from baseline to the first exacerbation; the number of exacerbations within 24 months; and the proportion of patients with one or more exacerbations and one or more severe exacerbations at 6, 12, and 24 months. Additionally, the trial will assess the proportion of patients in the interventional group (stopping dupilumab) who resume dupilumab at 6, 12, and 24 months, as well as the proportion of patients experiencing adverse events (AE) or serious adverse events (SAE) in both groups. These efficacy parameters will be measured and collected at specified time points throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on severe asthma management.