E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Nasal polyposis (NP) is a chronic inflammatory disease of the nasal mucosa characterized by the presence of polyps in the upper nasal cavity. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028754 |
E.1.2 | Term | Nasal polyp |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of benralizumab on nasal polyp burden and patient-reported nasal blockage |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of benralizumab on: - disease specific health-related quality of life (HRQoL) - nasal polyp surgery and/or SCS use - sense of smell - systemic corticosteroids (SCS) use for relief of nasal symptoms - symptoms associated with nasal polyps - sinus opacification by computed tomography (CT) scan (subset of patients) - proportion of NP surgery - patient-reported general health status
Safety objectives: - to assess the safety of benralizumab - to assess the pharmacokinetics and immunogenicity of benralizumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 a history of treatment with systemic corticosteroids (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 (V1). Patient must meet the following criteria (points 7-10) at the randomization visit (V3): 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 (V3). 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 at V1 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 (confirmed by the Investigator) eg, total sexual abstinence, a vasectomized sexual partner, Implanon. Female sterilization by tubal occlusion, any effective IUD intrauterine device/IUS levonorgestrel Intrauterine system, Depo-ProveraTM injections, oral contraceptive, Evra PatchTM, or NuvaringTM. Women of childbearing potential must agree to use highly effective method of birth control, as defined above, from enrolment, throughout the study duration and for 16 weeks after the last dose of investigational product (IP). 14. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considerd postmenopausal if they have been amenorrheic for 12 months prior to the planned date of the randomization without alternative medical cause. The following age specific requirements apply: - Women <50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and if follicle stimulating hormone (FSH) levels are in the postmenopausal range; - Women ≥ 50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment. 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. |
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E.4 | Principal exclusion criteria |
1. Patients who have undergone any nasal and/or sinus surgery within 3months 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 (eg, 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 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 with specific exceptions 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 enrol) 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, whichever is longer, prior to V1. 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 AERD (aspirin exacerbated respiratory disease) 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
- change from baseline in endoscopic total nasal polyp score - change from baseline in mean nasal blockage score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- change from baseline at Week 56 |
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E.5.2 | Secondary end point(s) |
- change from baseline in SinoNasal Outcome Test (SNOT-22) score - time to first NP surgery - time to first NP surgery and/or SCS use for NP - sense of smell captured as change from baseline in mean difficulty with sense of smell (DSS) score - sense of smell captured as change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score - change from baseline in Lund Mackay score and sinus severity score by Quantitative CT analysis (subset of patients) - proportion of patients with surgery for NP - proportion of patients with SCS use for NP - time to first SCS course for NP, number of courses of SCS for NP, total SCS dose used and total duration of SCS use for NP - change from baseline in nasal symptom score(s) as captured in the daily diary - change from baseline in Short Form 36-item Health survey, Version 2 (SF-36v2), Physical Component Score (PCS), Mental Component Score (MCS) and domains - adverse events and serious adverse events - laboratory variables - serum PK - benralizumab anti-drug antibodies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- following the first administration of study drug through week 56 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Approx.1st 200Pts who complete treatment enter 6mths FollowUP.CT done in Pts subset at chosen sites |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
Denmark |
Hungary |
Poland |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last expected visit/contact of the last patient undergoing the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 12 |