Efficacy, Safety, and Tolerability of Itepekimab in Chronic Rhinosinusitis Without Nasal Polyps: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of itepekimab compared with placebo on sinus opacification in participants with inadequately controlled chronic rhinosinusitis without nasal polyps. This is clinically relevant as sinus opacification is a key indicator of disease severity and treatment response in chronic rhinosinusitis, impacting patient management and outcomes.

Secondary objectives include:

• Evaluating the efficacy of itepekimab compared with placebo on sinus symptoms.
• Assessing the efficacy on symptoms of chronic rhinosinusitis without nasal polyps (CRSsNP).
• Evaluating the impact on Health Related Quality of Life (HRQoL).
• Assessing efficacy on additional measures of sinus opacification.
• Evaluating the safety and tolerability of itepekimab compared to placebo in participants with CRSsNP.
• Evaluating the pharmacokinetics (PK) of itepekimab.
• Assessing the immunogenicity of itepekimab.

The clinical trial involves a total of **56 participants** diagnosed with **respiratory tract diseases**, specifically focusing on chronic rhinosinusitis. The study population includes both male and female subjects, aged **18 years or older**, with no upper age limit specified. Participants were selected based on their ongoing symptoms of nasal congestion or obstruction persisting for at least 12 consecutive weeks prior to the initial visit, and a significant nasal congestion score. Additionally, participants must exhibit bilateral inflammation of the paranasal sinuses with specific opacification criteria on a CT scan. The trial includes individuals who have undergone prior sinonasal surgery or have been treated with systemic corticosteroids within the past two years. Participants are required to have a stable dose of mometasone furoate nasal spray for at least three weeks before the second visit. The study population is inclusive of vulnerable groups, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial does not exclude based on gender, and female participants must adhere to specific contraceptive guidelines if of childbearing potential.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, and tolerability of **itepekimab** in participants with inadequately controlled chronic rhinosinusitis without nasal polyps. The trial aims to assess the change from baseline in sinus opacification volume, as measured by CT scan, and other secondary endpoints such as changes in symptom scores and the incidence of treatment-emergent adverse events. The study will involve the administration of itepekimab via **subcutaneous injection** in a solution for injection in a pre-filled syringe, with a matched placebo serving as the control.

The trial is expected to commence recruitment on January 15, 2025, and conclude by February 9, 2027. Participants will be involved in the study for a maximum treatment period of 24 weeks. The study visits will include an initial screening visit to confirm eligibility based on criteria such as age, symptom severity, and CT scan results. Participants must be 18 years or older and have ongoing symptoms of nasal congestion for at least 12 consecutive weeks prior to the screening visit. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the final outcomes and collect data on the primary and secondary endpoints.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will ensure that all participants are not pregnant or breastfeeding and that women of childbearing potential use effective contraception. The study will adhere to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **Itepekimab**, a human monoclonal antibody targeting interleukin-33. Itepekimab is provided as a **solution for injection in a pre-filled syringe**. The pharmaceutical form is specifically designed for **subcutaneous injection**. The dosage is set at a maximum of 150 mg per administration, with a total treatment period extending up to 24 weeks. The administration frequency is determined by the study protocol, ensuring that the maximum daily dose does not exceed 150 mg. The active substance, Itepekimab, is a protein-based therapeutic agent, classified under the category of "Protein - Other." The product is developed by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR440340.

The study also includes a **matched placebo** for the test product, which serves as a comparator treatment to evaluate the efficacy of Itepekimab. The placebo is designed to mimic the test product in appearance and administration method, ensuring the study remains double-blind. The placebo does not contain any active pharmaceutical ingredients and is used to maintain the integrity of the trial's control group. The administration of the placebo follows the same route and frequency as the experimental medication, ensuring consistency across the study arms.

The efficacy of **itepekimab** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in sinus (maxillary, ethmoid) percent opacification volume, which will be evaluated using CT scans. Secondary endpoints include changes from baseline in the sinus Total Symptom Score (sTSS), nasal congestion severity score, anterior/posterior rhinorrhea severity score, facial pain/pressure severity score, and loss of smell severity score, all measured using the CRSsNP daily e-diary. Additionally, changes from baseline in the Sino-Nasal Outcome Test-22-Items (SNOT-22) total score and sinus opacification as measured by the Lund-Mackay (LMK) score and the modified LMK score will be assessed.

Further secondary endpoints involve the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent adverse events of special interest (TEAESIs), treatment-emergent serious adverse events (TESAEs), and treatment-emergent adverse events leading to intervention discontinuation. The concentration of itepekimab in serum and the incidence of treatment-emergent anti-itepekimab antibodies responses will also be evaluated. These efficacy parameters will be collected and analyzed at various timepoints throughout the trial to determine the therapeutic impact of itepekimab compared to placebo in participants with inadequately controlled chronic rhinosinusitis without nasal polyps.