Evaluation of Omalizumab Discontinuation Versus Continuation in Patients with Well-Controlled Severe Allergic Asthma: A Multicenter Randomized Controlled Trial

The primary objective of this study is to demonstrate the **non-inferiority** of attempting to withdraw **omalizumab** compared to its continuation in patients with well-controlled severe allergic asthma who have been treated for at least 33 months. Clinically, this is significant as it evaluates whether discontinuing omalizumab does not lead to an increase in asthma exacerbations over a 12-month period, which could inform treatment duration decisions and potentially reduce long-term medication use.

Secondary objectives include comparing the effects of omalizumab withdrawal versus continuation on various clinical outcomes at 6 and 12 months. These outcomes include:

• Variation in the Asthma Control Test (ACT) score.
• Changes in Asthma Quality of Life (AQLQ) and St. George's Respiratory Questionnaire scores.
• Alterations in respiratory function.
• Variation in the mean daily dose of oral steroids for steroid-dependent patients.
• Changes in the number of asthma controller drugs and the daily dose of inhaled steroids.
• Time to loss of asthma control and time to the first occurrence of an exacerbation.
• Number of emergency room visits and hospitalizations for asthma in the year following randomization.
• Occurrence of deterioration in ACT.
• Impact of treatment duration and dose of omalizumab before randomization on the number of exacerbations, time to loss of asthma control, and ACT score at 12 months.
• Impact of eosinophilia at randomization on the same outcomes.
• Comparison of allergy symptoms (ocular, rhinitis, atopic dermatitis, food allergies) between the two groups at 6 and 12 months.

The clinical trial involves participants diagnosed with **well-controlled severe allergic asthma**. The study population includes both male and female adults over the age of 18, who have been treated with Omalizumab, prescribed by a pulmonologist, for a minimum of 33 months. Participants are required to have an Asthma Control Test (ACT) score of 18 or higher, indicating well-controlled asthma, and must have experienced no more than one exacerbation in the year prior to inclusion. An exacerbation is defined as requiring an oral or injectable steroid course for at least two days or a minimum doubling of the usual steroid dose for at least two days for steroid-dependent patients. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study focuses on individuals who have maintained asthma control under the specified treatment regimen.

The clinical trial is designed to evaluate the impact of **omalizumab** withdrawal after a three-year treatment duration in patients with well-controlled severe allergic asthma. This is a multicentric, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial aims to demonstrate the non-inferiority of discontinuing omalizumab compared to its continuation in patients who have been treated for at least 33 months. The study is expected to run from May 2021 to May 2027, with participant involvement lasting up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (over 18 years), treatment history with omalizumab, and asthma control status. Following randomization, participants will attend follow-up visits at 6 and 12 months to assess primary and secondary endpoints, including the number of asthma exacerbations, changes in asthma control test (ACT) scores, and quality of life measures. The end-of-study visit will coincide with the 12-month follow-up, marking the conclusion of participant involvement.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The primary endpoint is the number of asthma exacerbations in the year following randomization, while secondary endpoints include changes in ACT scores, asthma quality of life, and respiratory function, among others. The trial will provide valuable insights into the long-term management of severe allergic asthma and the potential for omalizumab withdrawal in well-controlled patients.

The clinical trial involves the use of **omalizumab**, marketed under the name Xolair, as the experimental medication. Xolair is provided as a 75 mg **solution for injection** in a pre-filled syringe. The pharmaceutical form is specifically designed for subcutaneous administration. The maximum daily dose of omalizumab is 600 mg, with a total maximum dose of 15.6 grams over the course of the treatment. The treatment period is capped at 52 weeks. Omalizumab is a protein-based therapeutic agent, classified under the ATC code R03DX05, and is produced by Novartis Europharm Limited. The trial aims to assess the impact of omalizumab withdrawal after a three-year treatment duration in patients with well-controlled severe allergic asthma.

In this study, the experimental group will undergo a withdrawal attempt of omalizumab, while the comparator group will continue the treatment. The primary objective is to demonstrate the non-inferiority of omalizumab withdrawal compared to its continuation, specifically in terms of exacerbation rates at 12 months. The trial does not involve any additional non-experimental treatments such as standard-of-care therapy or placebo. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the number of asthma exacerbations in the year following randomization. An exacerbation is defined as an oral or injectable steroid course for at least two days and/or a minimum doubling of the usual steroid dose for at least two days for steroid-dependent patients.

Secondary endpoints include changes in asthma control test (ACT) scores at 6 and 12 months. The ACT is a self-administered standardized questionnaire consisting of five questions related to the frequency of asthma symptoms and rescue medication use over the previous four weeks. Scores range from 5 (worse control) to 25 (total control), with a minimal change of 5 points considered clinically significant. Additional secondary endpoints involve changes in asthma quality of life (AQLQ) and St. George's Respiratory Questionnaire (SGRQ) scores, changes in FEV1 (in ml) to assess respiratory function, and variations in daily oral steroid doses at 6 and 12 months.

Further assessments include changes in the number of asthma controller drugs, mean daily dose of inhaled steroids, time to loss of asthma control, time to exacerbation, and the number of emergency room visits and hospitalizations for asthma in the year following randomization. The occurrence of deterioration in asthma control, defined by a decrease in ACT score by 5 points or more at 6 and 12 months compared to baseline, will also be evaluated. The effect of **omalizumab** treatment duration and dosage before randomization on asthma control, time to loss of asthma control, and exacerbations will be analyzed, as well as the effect of **omalizumab** eosinophil rate. Occurrence of allergy manifestations such as conjunctivitis, rhinitis, atopic dermatitis, and food allergies will be monitored at 6 and 12 months.