Evaluation of Dupilumab on Nasal Epithelial Barrier Function in Chronic Rhinosinusitis with Nasal Polyps: An Exploratory Pilot Study

The primary objective of this study is to evaluate the **barrier function** of the nasal epithelium in patients with Chronic Rhinosinusitis with nasal polyps (CRSwNP) and Chronic Rhinosinusitis without nasal polyps (CRSsNP), in the absence of monoclonal antibody therapy, compared to disease controls. Additionally, the study aims to assess the effect of **dupilumab** treatment on the nasal epithelial barrier function in patients with CRSwNP. Understanding these differences is clinically relevant as it may provide insights into the pathophysiology of these conditions and the therapeutic impact of dupilumab.

Secondary objectives include: - Characterizing differences in barrier function of the nasal epithelium in response to harmful substances in cultured primary nasal- and polyp-derived epithelial cells. - Analyzing epithelial integrity by staining for tight junction proteins in biopsies of polyps and/or nasal mucosa. - Evaluating cytokine profiles in selected nasal secretions. - Investigating transcriptome and cytokine profiles in cultured cells. - Analyzing nasal microbiome composition. - Associating experimental changes with clinical data such as TPS and SNOT-22 scores.

The clinical trial involves participants diagnosed with **chronic rhinosinusitis**, both with and without nasal polyps. The study population includes adults aged 18 to 99 years, encompassing both male and female subjects. The total number of participants is not specified by the sponsor. Participants were selected based on their diagnosis of chronic rhinosinusitis as defined by EPOS 2020 criteria, with specific groups identified: Group 1 consists of individuals with chronic rhinosinusitis without nasal polyps (CRSsNP), and Group 2 includes those with chronic rhinosinusitis with nasal polyps (CRSwNP), confirmed by endoscopy or CT, and who are planned for therapy with dupilumab. The trial considers the presence or absence of non-steroidal anti-inflammatory drug (NSAID)-Exacerbated Respiratory Disease (N-ERD) and requires a washout period of at least six months for patients with a history of treatment with monoclonal antibodies for asthma or polyps. The study does not provide specific information on lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the effect of **dupilumab** on nasal epithelial barrier function in patients with **chronic rhinosinusitis with nasal polyps** (CRSwNP). This exploratory pilot study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to commence in April 2024 and conclude by April 2026, with a total duration of approximately two years. Participants will be involved for a maximum treatment period of six months, during which they will receive a maximum daily dose of 300 mg of Dupixent, administered subcutaneously.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will involve screening participants aged 18 to 99 years who meet the EPOS 2020 criteria for chronic rhinosinusitis. Participants will be divided into two groups: those with CRSwNP and those with chronic rhinosinusitis without nasal polyps (CRSsNP). The primary endpoint is the change in barrier sensitivity at baseline and after six months of treatment. Secondary endpoints include changes in barrier sensitivity over time, expression levels of tight junction proteins, cytokine levels, microbiome diversity, and transcriptome analysis.

Follow-up visits will occur at baseline, three months, and six months to monitor changes in barrier sensitivity and other secondary endpoints. The end-of-study visit will assess the overall impact of dupilumab treatment on nasal epithelial barrier function. Participants may be terminated early from the study if they experience adverse effects or fail to comply with the study protocol. The trial is classified as low-intervention, as Dupixent is an authorized drug, and the procedures involved pose minimal additional risk compared to standard clinical practice.

The clinical trial involves the administration of **Dupilumab**, an experimental medication, to evaluate its effect on nasal epithelial barrier function in patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). **Dupilumab** is provided in two pharmaceutical forms: a solution for injection in a pre-filled syringe and a solution for injection in a pre-filled pen. Both forms contain 300 mg of the active substance **Dupilumab**, which is a protein of other origin. The medication is administered via the subcutaneous route. The maximum daily dose is 300 mg, with a total maximum dose of 3600 mg over a treatment period of up to 6 months. The administration frequency is determined based on the study protocol, ensuring adherence to the specified dosing schedule.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the effects of **Dupilumab**. Participant compliance with the dosing schedule is monitored throughout the trial to ensure accurate assessment of the medication's efficacy and safety. The trial aims to provide insights into the potential benefits of **Dupilumab** in improving nasal epithelial barrier function in the target patient population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating the impact of **dupilumab** treatment on nasal epithelial barrier function in patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). The primary endpoint is the change in barrier sensitivity, measured as the Cell index, at baseline (visit 1) and after 6 months of treatment (visit 3) in stimulated versus unstimulated cells of patients with CRSwNP compared to disease controls. This assessment will provide insights into the therapeutic effect of dupilumab on the nasal epithelium.

Secondary endpoints include the change in barrier sensitivity over time at 0, 3, and 6 months, and the expression levels of tight junction proteins in selected biopsies and cultured primary cells, analyzed through mass cytometry imaging. Additionally, cytokine levels in nasal mucosal lining fluids, microbiome diversity, and transcriptome analysis in cultured cells will be evaluated. These parameters will be compared between diseased patients and disease controls to establish associations between barrier sensitivity, cytokine levels, microbiome composition, and clinical data such as Total Polyp Score (TPS) and Sino-Nasal Outcome Test (SNOT-22). The study will utilize various laboratory techniques and validated scales to ensure accurate and reliable data collection and analysis throughout the trial duration.