Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis
Condition: Nasal Polyposis
MeSH terms: Colorectal Neoplasms; Nasopharyngeal Neoplasms; Nasal Polyps
Intervention: Benralizumab 30 mg SC + Mometasone Furoate; Matching placebo SC + Mometasone Furoate
Intervention description: Benralizumab injection is 30mg/ml SC clear to opalescent, colourless to yellow solution in accessorized pre-filled syringe.
Benralizumab 30 mg SC will be injected every 4 weeks for the first 3 doses - Weeks 0 , 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. Total of 8 doses.
Mometasone Furoate Nasal Spray (MFNS) - intranasal corticosteroid - 2 doses (1 dose = 50 micrograms/actuation) in each nostril twice daily. Total daily dose of 400mcg. MFNS will be used for a minimum of 4 weeks prior to randomization and will be continued throughout the study.; Matching placebo injection is SC clear to opalescent, colourless to yellow solution in accessorized pre-filled syringe.
Matching placebo SC will be injected every 4 weeks for the first 3 doses - Weeks 0 , 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. Total of 8 doses.
Mometasone Furoate Nasal Spray (MFNS) - intranasal corticosteroid - 2 doses (1 dose = 50 micrograms/actuation) in each nostril twice daily. Total daily dose of 400mcg. MFNS will be used for a minimum of 4 weeks prior to randomization and will be continued throughout the study.
Intervention MeSH terms: Mometasone Furoate; Benralizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 413.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Polyps; Nasal polyps; Nasal polyposis; Nose diseases; Respiratory tract diseases; Otorhinolaryngologic diseases; Benralizumab; Mometasone furoate

Summary:

      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.
    

Eligibility criteria:

        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.