Study protocol for a A randomized double-blinded placebo-controlled trial on mepolizumab for patients with chronic rhinosinusitis with nasal polyps, NSAID exacerbated respiratory disease and asthma

Annina Lyly ¹ Johanna Sahlman ² Karoliina Pajala ² Maija Salminen ³ Saara Sillanpää ³ Jura Numminen ³ Tanzeela Hanif ¹ Anu Laulajainen-Hongisto ⁴ Mika J. Mäkelä ¹ Paula Kauppi ⁵ Iiris Kangasniemi ² Markus Lilja ¹ Sari Hammaren-Malmi ⁴ Paula Virkkula ⁴ Sanna Katriina Toppila-Salmi ^6*

• ¹ Department of Allergy, Helsinki University Hospital and University of Helsinki, Helsinki, Finland, Helsinki, Finland
• ² Department of Otorhinolaryngology, Wellbeing services county of Pohjois-Savo, Kuopio, Finland, Kuopio, Northern Savonia, Finland
• ³ Department of Otorhinolaryngology, Head and neck Surgery, Tampere University Hospital, Wellbeing Services County of Pirkanmaa, Faculty of Medicine and Heealth Technology, Tampere University, Finland, Tampere, Finland
• ⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, Helsinki, Uusimaa, Finland
• ⁵ Heart and Lung Center, Department of Pulmonary Diseases and Allergology, Helsinki University Hospital and University of Helsinki, Finland, Helsinki, Finland
• ⁶ University of Helsinki, Helsinki, Finland

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the nose and paranasal sinuses that significantly impactsaccompanying decreased healthrelated quality of life. Nonsteroidal anti-inflammatory drug (NSAID) -exacerbated respiratory disease (N-ERD) affects approximately one fifth of CRSwNP patients. N-ERD and asthma increase the risk of uncontrolled CRSwNP as measured by frequent sinus surgeries and rescue treatment. Compared to non-N-ERD patients, those with N-ERD N-ERD patients also have higher risk of asthma exacerbations, severe allergic reactions, and anosmia. Mepolizumab is a humanized monoclonal anti-IL-5 antibody shown to be effective in the treatment treating of severe eosinophilic asthma and chronic polypotic rhinosinusitisCRSwNP.While evidence suggests that mepolizumab alleviates respiratory symptoms in N-ERD patients, placebo-controlled studies remain limited.There is evidence showing that mepolizumab is effective against respiratory symptoms in N-ERD patients, but placebo-controlled study evidence is limited.The aim of this prospective randomized, placebo-controlled, multicenter study is to investigate whether mepolizumab reduces polyp size, symptom scores, and exacerbations more than placebo during the 16-week treatment period in patients with uncontrolled CRSwNP, N-ERD and asthma. Additionally, we will examine We will also investigate the effect of mepolizumab on drug dosage and lung and nasal function and evaluate predictive biomarkers.We will recruit 120 patients with N-ERD, nasal polyposis and asthma in three centers in Finland. Patients will be randomized into two 16-week treatment groups in 1:1 ratio (placebo or mepolizumab 100mg every 4 weeks). The study lasts for 6 months, including recruitment visit 2-4 weeks before randomization. Subjects Participants will attendhave 6 visits, duringon four of which they will receive a subcutaneous injection of the study product is administered. During visitsAt each visit, patient-reported outcome tests, as well as clinical examination, airway function tests, and nasal, blood, urine, and stool samples are takenwill be conducted.The efficacy of the 16-week anti-IL-5-treatment in this severe patient group will be analyzed, as well as possible predictive biomarkers.