Treatment of rhinosinusitis with nasal polyposis with dupilumab and mepolizumab: A randomized, multi-centre, head-to-head comparison in real-world Danish patients

The primary objective of this study is to compare the **efficacy** of mepolizumab versus dupilumab in treating **chronic rhinosinusitis with nasal polyposis** (CRSwNP). The study aims to evaluate both objective and subjective symptoms, as well as related comorbidities, to determine whether mepolizumab is non-inferior to dupilumab or if dupilumab demonstrates superiority. This comparison is clinically relevant as it may guide treatment decisions for CRSwNP, potentially improving patient outcomes by identifying the more effective biologic therapy.

The secondary objective is to explore additional differences between mepolizumab and dupilumab, focusing on the frequency of adverse events (AEs), the need for rescue treatments, and variations in outcomes based on endotype, comorbidity, or other factors. These insights could contribute to a patient-centered approach when selecting treatment options for CRSwNP.

The clinical trial involves participants diagnosed with **chronic rhinosinusitis with nasal polyposis**. The study population includes both male and female subjects, aged 18 years and older, who are in general good health but have specific medical conditions related to type 2 inflammation, such as eosinophilia or late-onset eosinophilic asthma. Participants are required to have undergone at least one endoscopic sinus surgery within the past seven years or be unfit for such surgery. They must adhere to a regimen of nasal steroid spray and nasal douches twice daily for at least three months prior to the start of treatment. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Key lifestyle considerations include the need for systemic corticosteroids, a high Sino-nasal outcome test score, reduced sense of smell, a significant nasal polyp score, and asthma requiring inhaled corticosteroids. Participants must be able to read and/or speak Danish. The selection criteria ensure that the study population is well-defined and relevant to the trial's objectives.

The clinical trial is designed to evaluate the efficacy of **mepolizumab** versus **dupilumab** in treating **chronic rhinosinusitis with nasal polyposis** (CRSwNP). This is a randomized, double-blind, controlled trial conducted over an estimated duration of 24 months, with recruitment starting on March 21, 2023, and expected completion by February 1, 2025. The trial aims to determine the non-inferiority or potential superiority of dupilumab over mepolizumab in improving both objective and subjective symptoms of CRSwNP and related comorbidities.

Participants will be randomly assigned to receive either mepolizumab or dupilumab, with the trial employing a double-blind methodology to ensure unbiased results. The primary endpoints include changes in the nasal polyp score (NPS) and the Sino-nasal outcome test 22 (SNOT-22) score at 24 weeks. Secondary endpoints encompass improvements in smell, asthma, quality of life, and other related measures over a 52-week period.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age above 18 years, evidence of type 2 inflammation, and a history of endoscopic sinus surgery. Follow-up visits will occur at regular intervals to monitor treatment efficacy and safety, with assessments of primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, summarizing the overall treatment outcomes.

Participant involvement is expected to last up to 52 weeks, with conditions for early termination including adverse reactions, non-compliance with study protocols, or withdrawal of consent. The trial is categorized as low-intervention, focusing on the optimal use of already authorized investigational medicinal products (IMPs) in a real-world setting. The study's rigorous design and comprehensive endpoints aim to provide valuable insights into the comparative effectiveness of these biologic treatments for CRSwNP.

The clinical trial involves the administration of several treatments to evaluate their efficacy in the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). The **experimental medication** Dupixent, containing the active substance **dupilumab**, is provided as a 300 mg solution for injection in a pre-filled syringe. This medication is administered via the **subcutaneous** route. The maximum daily dose is 300 mg, with a treatment period extending up to 99 weeks. Dupilumab is a protein-based therapeutic agent, and its administration is monitored to ensure compliance with the dosing schedule.

Another experimental treatment in the trial is Nucala, which contains the active substance **mepolizumab**. It is supplied as a 100 mg powder for solution for injection. Similar to Dupixent, Nucala is administered subcutaneously. The maximum daily dose is 100 mg, and the treatment period is also up to 99 weeks. Mepolizumab is a protein-based therapeutic agent, and participant adherence to the dosing regimen is closely monitored.

In addition to the experimental treatments, the trial includes the use of Nasonex, a nasal spray suspension containing **mometasone furoate**. This auxiliary treatment is administered intranasally. The maximum daily dose is 0.25 mg, with a total dose limit of 1000 mg over the treatment period, which can extend up to 999 days. Mometasone furoate is a chemically derived substance, and its administration is intended to complement the primary treatments.

Prednisolon Alternova, containing the active substance **prednisolone**, is also used as an auxiliary treatment. It is provided in tablet form, with each tablet containing 5 mg of prednisolone. The medication is administered orally, with a maximum daily dose of 37.5 mg and a total dose limit of 375 mg over a 12-week treatment period. Prednisolone is a chemically derived substance, and adherence to the dosing schedule is monitored to ensure participant compliance.

The efficacy of the clinical trial comparing **mepolizumab** and **dupilumab** for the treatment of Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) will be assessed using both objective and subjective measures. The primary endpoints include the change in Nasal Polyp Score (NPS) and the Sino-Nasal Outcome Test 22 (SNOT-22) score at 24 weeks. These endpoints will provide insights into the reduction of nasal polyps and improvement in nasal symptoms, respectively.

Secondary endpoints will further evaluate efficacy through various parameters, such as the change in loss of smell, improvement in asthma control, and quality of life impacts measured by visual analog scales. Additional assessments include tympanometry, expired nitrous oxide levels, and changes in radiologic sinus opacification using the Lund-Mackey score. The trial will also monitor the proportion of subjects needing rescue treatment, such as systemic corticosteroids or sinus surgery, and changes in the Nasal Congestion Score (NCS) and FEV1.

Data collection will occur at specified intervals, with primary assessments at 24 weeks and additional evaluations extending to 52 weeks. The trial aims to determine the non-inferiority or potential superiority of dupilumab over mepolizumab, providing a comprehensive analysis of treatment efficacy in real-world settings.