Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Itepekimab in Adults with Inadequately-Controlled Chronic Rhinosinusitis with Nasal Polyps

The primary objective of this study is to evaluate the **efficacy** of itepekimab compared with placebo on nasal polyps size and nasal congestion in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). This is clinically relevant as CRSwNP is a condition that significantly impacts patients' quality of life, and effective management of nasal polyps and congestion can lead to improved patient outcomes.

Secondary objectives include: - Evaluating the long-term efficacy of itepekimab compared with placebo on nasal polyps size and nasal congestion. - Assessing the efficacy of itepekimab on sinus opacification, symptoms of CRSwNP, sense of smell, health-related quality of life, and sleep disturbance. - Evaluating the ability of itepekimab to reduce the risk of worsening or acute sinusitis requiring treatment with systemic corticosteroids or sinus surgery. - Assessing the effect of itepekimab on asthma in participants with comorbid asthma and in those with aspirin-exacerbated respiratory disease (AERD). - Evaluating the safety and tolerability of itepekimab in participants with CRSwNP. - Assessing the pharmacokinetics and immunogenicity of itepekimab over time compared to placebo.

The clinical trial involves a total of **247 participants** diagnosed with **chronic rhinosinusitis with nasal polyps**. The study population includes both male and female subjects, aged 18 years and older, reflecting a diverse adult demographic. Participants were selected based on specific criteria, including a history of chronic rhinosinusitis with nasal polyps for at least one year prior to screening, and ongoing symptoms such as nasal congestion, loss of smell, or rhinorrhea. The trial also considers individuals who have undergone prior sinonasal surgery or required systemic corticosteroid treatment for worsening symptoms within the past year. The health status of participants is characterized by the presence of nasal polyps, with an endoscopic bilateral Nasal Polyp Score of at least 5 out of a maximum of 8. Lifestyle factors such as diet and physical activity are not specified, but female participants must adhere to contraceptive guidelines if of childbearing potential. The trial includes a vulnerable population, ensuring comprehensive representation in the study. The selection process ensures that participants meet the necessary health and demographic criteria to evaluate the efficacy of itepekimab compared to placebo in reducing nasal polyp size and alleviating nasal congestion.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group study to evaluate the efficacy, safety, and tolerability of **itepekimab** in adult participants with inadequately-controlled **chronic rhinosinusitis with nasal polyps**. The trial will span a duration of 52 weeks, with the primary objective being to assess the change from baseline in the endoscopic Nasal Polyp Score (NPS) and Nasal Congestion Score (NCS). Secondary endpoints include changes in sinus opacification assessed by CT scan, total symptom scores, and the incidence of treatment-emergent adverse events.

Participants will be involved in the study for the entire 52-week period unless early termination is warranted due to adverse events, withdrawal of consent, or non-compliance with the study protocol. The study will commence with a screening visit to confirm eligibility based on criteria such as age, history of chronic rhinosinusitis with nasal polyps, and symptom severity. Following successful screening, participants will be randomized to receive either itepekimab or a matched placebo administered as a solution for injection in a pre-filled syringe.

Study visits will be scheduled at regular intervals to monitor the participants' health status, adherence to the treatment regimen, and to collect data on primary and secondary endpoints. The end-of-study visit will involve a comprehensive assessment to evaluate the overall outcomes of the treatment. Participants are expected to adhere to the study protocol, including the use of effective contraception for women of childbearing potential, to ensure the integrity of the trial results. The trial is anticipated to conclude by December 2027, with recruitment starting in March 2025.

The clinical trial involves the administration of **Itepekimab**, an experimental medication, to evaluate its efficacy, safety, and tolerability in adult participants with inadequately-controlled chronic rhinosinusitis with nasal polyps. **Itepekimab** is a **human monoclonal antibody IgG4** targeting **interleukin-33**. It is provided as a **solution for injection in a pre-filled syringe**. The maximum daily dose is 150 mg, and the treatment period extends up to 52 weeks. The route of administration is via injection, and the frequency of administration is determined by the study protocol. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

The study also includes a **matched placebo** for the test product, which serves as a comparator treatment. The placebo is designed to mimic the experimental medication in appearance and administration method, ensuring the study remains double-blind. The placebo does not contain any active substance and is used to assess the efficacy of **Itepekimab** by providing a baseline for comparison. Participants are randomly assigned to receive either the experimental medication or the placebo, and the administration schedule is consistent with that of the active treatment group.

The efficacy of **itepekimab** in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will be assessed through a randomized, double-blind, placebo-controlled, parallel-group Phase 3 clinical trial. The primary endpoints for evaluating efficacy include the change from baseline in the endoscopic Nasal Polyp Score (NPS) and the Nasal Congestion Score (NCS). Secondary endpoints encompass a range of measures such as changes from baseline in sinus opacification assessed by CT scan using the Lund-Mackay (LMK) score, Total Symptom Score (TSS), loss of smell severity score using the daily CRSwNP sinonasal symptom eDiary, and the University of Pennsylvania Smell Identification Test (UPSIT) score. Additional secondary endpoints include changes in the Sino-Nasal Outcome Test (SNOT-22) total score, Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD-SF-8b) scores, and the proportion of participants requiring systemic corticosteroids (SCS) or surgery for CRS.

Data collection will occur at various timepoints throughout the 52-week treatment period. The trial will utilize validated scales and instruments for measuring these endpoints, ensuring the reliability and accuracy of the data collected. The analysis will focus on comparing the changes from baseline between the itepekimab and placebo groups, providing insights into the drug's efficacy in reducing nasal polyp size and alleviating nasal congestion. The trial will also monitor the incidence of treatment-emergent adverse events and the concentration of itepekimab in serum, alongside the incidence of treatment-emergent anti-itepekimab antibody responses, to ensure a comprehensive evaluation of both efficacy and safety.