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.

Study Overview

• Status: Recruiting
• Conditions: Nasal Polyps
• Intervention / Treatment: Biological: Benralizumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Giorgio Walter Canonica, MD; Phone Number: +390288247013; Email: giorgio_walter.canonica@hunimed.eu
• Study Contact Backup: Name: Enrico Heffler, MD, PhD; Phone Number: +390288247013; Email: enrico.heffler@hunimed.eu

Study Locations

• Italy
  • MI
    • Rozzano, MI, Italy, 20089
      • Recruiting
      • Humanitas Clinical and Research Hospital
      • Contact: Giorgio Walter Canonica, MD; Phone Number: +390288247013; Email: giorgio_walter.canonica@hunimed.eu
      • Contact: Enrico Heffler, MD, PhD; Phone Number: +390288247013; Email: enrico.heffler@hunimed.eu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Ongoing rhinitis medicamentosa
  2. Nasal septal deviation occluding at least one nostril
  3. Acute sinusitis, nasal infection, upper respiratory infections
  4. Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis
  5. Eosinophilic Granulomatosis with Polyangiitis (previously named Churg-Strauss Syndrome)
  6. Granulomatosis with Polyangiitis (previously named Wegener's granulomatosis)
  7. Young's Syndrome
  8. Kartagener's Syndrome
  9. all ciliary dyskinesia
  10. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Benralizumab; 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	Biological: Benralizumab; Benralizumab 30 mg administered subcutaneously Q4W for the first 3 doses and then Q8W, for a 16 weeks treatment-period
Placebo Comparator: Placebo; Placebo administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks, for a treatment-period of 16 weeks	Biological: Placebo; Placebo administered subcutaneously Q4W for the first 3 doses and then Q8W, for a 16 weeks treatment-period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Significant reduction of the Nasal polyps Score (range: 0-8; higher values mean larger nasal polyps size)	score reduction of 1.5	at week 24 (vs baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Lund-MacKay Score (range: 0-24; higher values mean larger nasal polyps extension)	>50% of baseline	at week 24 (vs baseline)
Improvement of Sino-Nasal Outcome Test (SNOT-22; range: 0-110; higher values mean poorer disease-related quality of life)	>40% of baseline	at week 24 (vs baseline)
Improvement of smell Visual Analogue Scale (VAS; range: 0-10; higher values mean worse smell)	>50% of baseline	at week 24 (vs baseline)

Collaborators and Investigators

• Sponsor: Humanitas Clinical and Research Center
• Collaborators: AstraZeneca

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2020
• Primary Completion (Anticipated): March 28, 2022
• Study Completion (Anticipated): July 30, 2022

Study Registration Dates

• First Submitted: November 29, 2019
• First Submitted That Met QC Criteria: December 2, 2019
• First Posted (Actual): December 4, 2019

Study Record Updates

• Last Update Posted (Actual): November 18, 2021
• Last Update Submitted That Met QC Criteria: November 17, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Biomarkers; Benralizumab; Eosinophils
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Pathological Conditions, Anatomical; Nose Diseases; Nasal Polyps; Polyps; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: NAPPREB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No