NAsal Polyps: Inflammatory & Molecular Phenotyping of Responders to Benralizumab (NAPPREB)

Background and rationale: Phase III-b study. Population and patient selection criteria: Adult patients with Chronic Rhinosinusitis with Nasal Polyps (allergic and non-allergic) requiring at least 1000 mg oral prednisone over the previous twelve months to control symptoms of rhinosinusitis, and with: Nasal polyps score (Meltzer et al.) ≥ 5 Symptoms VAS scores (for nasal obstruction, hyposmia, post-nasal drip, sneezing, rhinorrea; 0-10 for each symptom) > 24 Sample size: 20 subjects. Study design and study duration: This is a pilot, prospective, double-blind placebo-controlled (DBPC) phase III-b trial with Benralizumab 30 mg administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks, for a treatment-period of 16 weeks (followed up at 32 and 52 weeks) in patients with chronic rhinosinusinusitis with nasal polyps (CRSwNP). Description of study treatment/product/intervention: Benralizumab, 30 mg subcutaneously every 4 week for the first 3 doses, and then every 8 weeks. Objectives: Primary objective: To assess the clinical efficacy of Benralizumab on CRSwNP at week 24 (vs baseline) after the beginning of treatment, and to correlate the presence of baseline biomarkers with nasal polyp (NP) score improvement, in order to identify any possible predictive biomarker of response to Benralizumab. Secondary objective: In the follow up phase we will monitor all the biomarkers at 32 and 52 weeks , this monitoring will ascertain if any of those will predict relapse of nasal polyps and consequently when Benralizumab treatment has to be reinstalled. Safety objective: To evaluate the safety and tolerability of Benralizumab in patients with CRSwNP Statistical methods, data analysis: Descriptive analysis of all collected variables at all time-points will be performed. Patients will be classified into "responders" and "non responders", for primary endopoint variable. Continuous variables will be evaluated with the normality test of Kolmogorov-Smirnov and compared with ANOVA or the Mann-Whitney test, depending on the normality of distribution. Categorical variables will be compared using Fisher's exact test. Ethical considerations: The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory requirements and the Sponsor policy on Bioethics and Human Biological Samples.

Double-blind, placebo-controlled clinical trial. Patients will be divided in two arms with 1:1 randomization to Treatment or Placebo.

Randomization will occur by assigning a unique sequential study code to a balanced number of randomly assorted treatment vials. An online open source randomization software will be used to assign treatment groups, and this will be done by an external person from those who will follow and treat the patients. Patients randomization will be blinded to the patients themselves and to all the personnel that will have contact with them during the trial

Benralizumab 30 mg administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks, for a treatment-period of 16 weeks

Placebo administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks, for a treatment-period of 16 weeks

Benralizumab 30 mg administered subcutaneously Q4W for the first 3 doses and then Q8W, for a 16 weeks treatment-period

Placebo administered subcutaneously Q4W for the first 3 doses and then Q8W, for a 16 weeks treatment-period

Significant reduction of the Nasal polyps Score (range: 0-8; higher values mean larger nasal polyps size)

Improvement of Sino-Nasal Outcome Test (SNOT-22; range: 0-110; higher values mean poorer disease-related quality of life)

Inclusion Criteria: Adult patients with Chronic Rhinosinusitis with Nasal Polyps (allergic and non-allergic) requiring at least 1000 mg oral prednisone over the previous twelve months to control symptoms of rhinosinusitis, and with: Nasal polyps score (Meltzer et al.) > 5 Symptoms VAS scores (for nasal obstruction, hyposmia, post-nasal drip, sneezing, rhinorrea; 0-10 for each symptom) > 24 Provision of informed consent prior to any study specific procedure Exclusion Criteria: Patients < 18 years age Pregnant women Biologic therapy in the past 6 months (or at least a period corresponding to 5 half-life of used drugs) (eg: omalizumab, mepolizumab, reslizumab, dupilumab) Previous treatment with Benralizumab Known hypersensitivity to benralizumab or any of its excipients Immunosuppression other than oral steroids in the past 3 months Allergen immunotherapy in the past 6 months Serious life threatening cardiopulmonary disorders Systemic immunologic disorder in the last 12 months Positive history for malignant tumors ever in patient's life Patients with conditions or concomitant diseases making them non evaluable at visit 1 or for the primary efficacy endpoint: Ongoing rhinitis medicamentosa Nasal septal deviation occluding at least one nostril Acute sinusitis, nasal infection, upper respiratory infections Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis Eosinophilic Granulomatosis with Polyangiitis (previously named Churg-Strauss Syndrome) Granulomatosis with Polyangiitis (previously named Wegener's granulomatosis) Young's Syndrome Kartagener's Syndrome all ciliary dyskinesia Cystic Fibrosis Systemic corticosteroid treatment for other chronic conditions (i.e.: autoimmune disorders, tumors,….) Evidence of active systemic immunedepression (i.e..: primary or secondary immunodeficiency) Patients with severe asthma, defined according to ERS/ATS definition

Chong LY, Piromchai P, Sharp S, Snidvongs K, Webster KE, Philpott C, Hopkins C, Burton MJ. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2021 Mar 12;3(3):CD013513. doi: 10.1002/14651858.CD013513.pub3.