Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis
Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis
The aim of this present study is to investigate the use of benralizumab as treatment for
 severe nasal polyposis. The effect of benralizumab on nasal polyps will be assessed over a 56
 weeks of treatment period in patients with severe bilateral nasal polyposis who are still
 symptomatic despite standard of care therapy, i.e current use of intranasal corticosteroids
 (INCS) and prior surgery and/or use of systemic corticosteroids. The first 200 patients that
 complete the 56-week treatment will have a 6 month follow-up (FU) period without dosing.
Inclusion Criteria:

 1. Capable of giving signed informed consent, which includes compliance with the
 requirements and restrictions, listed in the informed consent form (ICF) and in
 protocol.

 2. Provision of signed and dated, written informed consent form (ICF) prior to any
 mandatory study specific procedures, sampling, and analyses and according to
 international guidelines and/or applicable European Union (EU) guidelines.

 3. Provision of signed and dated written genetic informed consent in patients that agree
 to participate in the genetic sampling, prior to collection of sample for genetic
 analysis.

 4. Female or male patients aged 18 to 75 years inclusive, at the time of signing the ICF.

 5. Patients with bilateral sinonasal polyposis that, despite treatment with a stable dose
 of intranasal corticosteroids (INCS) for at least 4 weeks prior to V1, in addition to
 history of treatment with systemic (SCS -oral, parenteral) or prior surgery for nasal
 polyposis (NP), have severity consistent with a need for surgery as described by:

 -  A minimum total Nasal Polyp Score (NPS) of 5 out of a maximum score of 8 (with a
 unilateral score of at least 2 for each nostril) at V1, and continuously
 maintained at V2 to meet the randomization criterion, as determined by the study
 Imaging Core Lab;

 -  Ongoing symptoms for at least 12 weeks prior to V1;

 -  Patient-reported moderate to severe nasal blockage score (NBS) 2 or 3 over the
 2-weeks prior to V1 (2-week recall assessment of symptoms, scores 0-none to
 3-severe).

 6. SNOT-22 total score ≥ 30 at enrolment.

 Patient must meet the following criteria (points 7-10) at the randomization visit:

 7. At least 8 days of evaluable daily diary data in the 14-day period prior to
 randomization (baseline bi-weekly mean score collected from study Day -13 to study Day
 0).

 8. At randomization, a bi-weekly mean NBS ≥ 1.5.

 9. SNOT-22 total score ≥ 30 at randomization.

 10. At least 70% compliance with INCS during the run-in period based on daily diary.

 11. Patients with a minimum weight of 40kg.

 12. Negative serum pregnancy test result and a negative urine pregnancy test at
 randomization for female patients of childbearing potential.

 13. Women of childbearing potential (WOCBP) must use an effective form of birth control as
 defined in the Clinical Study Protocol (CSP).

 15. Male subjects who are sexually active must be surgically sterile at least one year
 prior to Visit 1 or must use an adequate method of contraception (condom or condom with
 spermicide depending on local regulations) from the first dose of IP until 16 weeks after
 their last dose. Men with a partner or partners who is (are) not of childbearing potential
 are exempt of these requirements

 Exclusion Criteria:

 1. Patients who have undergone any nasal and/or sinus surgery within 3 months prior to
 V1.

 2. Patients with conditions or concomitant disease that makes them non evaluable for the
 co-primary efficacy endpoint such as:

 -  Unilateral antrochoanal polyps;

 -  Nasal septal deviation that occludes at least one nostril;

 -  Acute sinusitis, nasal infection, or upper respiratory infection at screening or
 in the 2 weeks before screening;

 -  Current rhinitis medicamentosa;

 -  Allergic fungal rhinosinusitis (AFRS) or Allergic fungal sinusitis (AFS);

 -  Nasal cavity tumors.

 3. Clinically important comorbidities that could confound interpretation of clinical
 efficacy results including, but not limited to: active upper or lower respiratory
 tract infection, cystic fibrosis, primary ciliary dyskinesia, eosinophilic diseases
 other than asthma (e.g. allergic bronchopulmonary aspergillosis/mycosis, eosinophilic
 granulomatosis with polyangitis [Churg-Strauss syndrome], hypereosinophilic
 syndromes), granulomatosis with polyangitis (Wegener's granulomatosis), Young's
 syndrome, etc.

 4. Any disorder, including but not limited to: cardiovascular, gastrointestinal, hepatic,
 renal, neurological, musculoskeletal, infectious, endocrine, metabolic,
 haematological, psychiatric, or major physical impairment that is not stable in the
 opinion of the Investigator or AstraZeneca and could:

 -  Affect the safety of the patient throughout the study;

 -  Influence the findings of the studies or their interpretations;

 -  Impede the patient's ability to complete the entire duration of study.

 5. Patients experiencing an asthma exacerbation requiring systemic (oral and/or
 parenteral) corticosteroids treatment or hospitalization (>24hrs) for treatment of
 asthma within 4 weeks prior to V1.

 6. History of anaphylaxis to any biologic therapy or vaccine.

 7. Known history of allergy or reaction to any component of the Investigational Product
 (IP) formulation.

 8. History of Guillain-Barré syndrome.

 9. A helminth parasitic infection diagnosed within 24 weeks prior to V1 and has not been
 treated with, or has failed to respond to standard of care therapy.

 10. Current malignancy, or history of malignancy, except for: - Patients who have had
 basal cell carcinoma, localized squamous cell carcinoma of the skin, or in situ
 carcinoma of the cervix are eligible provided that patient is in remission and
 curative therapy was completed at least 12 months prior to V1; - Patients who have had
 other malignancies are eligible provided that the patient is in remission and curative
 therapy was completed at least 5 years prior to V1.

 NOTE: Hormonal therapy is allowed. As long as the cancer is in remission for 5 years,
 the patient is eligible.

 11. Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality
 obtained during the screening/run-in period, which may put the patient at risk or
 interfere with study assessments.

 12. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology
 (confirmed by additional testing, e.g. hepatitis C RNA test, if indicated), or a
 positive medical history for hepatitis B or C (Note: Patients with history of
 hepatitis B vaccination without history of hepatitis B are allowed to enroll).

 13. History of known immunodeficiency disorder, including a positive human
 immunodeficiency virus (HIV) test.

 14. Infection requiring systemic antibiotics (Ab) within 14 days prior to V1

 15. Use of immunosuppressive medication (including but not limited to: methotrexate,
 troleandomycin, cyclosporine, azathioprine, or any experimental anti-inflammatory
 therapy) within 3 months prior to V1.

 16. Receipt of any marketed or investigational biologic products (monoclonal or polyclonal
 antibody) within 6 months or 5 half-lives prior to the date informed consent, is
 obtained, whichever is longer, prior to V1 and during the study period. This also
 applies to patients who previously participated in clinical studies and were treated
 with monoclonal antibodies (e.g. mepolizumab, reslizumab, dupilumab, omalizumab). Note
 that this restriction do not apply to patients, who are confirmed to have only
 received treatment with placebo.

 17. Previous receipt of benralizumab.

 18. Receipt of immunoglobulin or blood products within 30 days prior to V1.

 19. Receipt of live attenuated vaccines 30 days prior to the date of randomization.

 20. Receipt of any investigational drug within 30 days or 5 half-lives whichever is longer
 prior to randomization.

 21. Receipt of systemic corticosteroid 4 weeks prior to V1, or a scheduled systemic
 corticosteroid treatment during the study period.

 NOTE: Sustained release steroids (e.g. Kenalog [Triamcinolone acetonide]) or depot
 injections require minimum 6 weeks washout prior to V1.

 22. Receipt of leukotriene antagonist/modifiers for patients who were not on a continuous
 stable dose for ≥30 days prior to V1.

 23. Concurrent enrolment in another clinical drug interventional trial.

 24. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 3 times the
 upper limit of normal (ULN) confirmed during screening period.

 25. Previous randomization in the present study.

 26. Planned major surgical procedures or scheduled NP surgery at the time of the study
 enrolment and randomization.

 27. Initiated or is being maintained on an aspirin desensitization regimen for the
 management of aspirin exacerbated respiratory disease (AERD) at the time of study
 enrolment or during the run-in period.

 28. For women only - currently pregnant (or intend to become pregnant), breastfeeding or
 lactating.