Severe eosinophilic asthma MedDRA version: 21.1 Level: LLT Classification code 10068462 Term: Eosinophilic asthma System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders MedDRA version: 21.1 Level: LLT Classification code 10068462 Term: Eosinophilic asthma System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Conditions
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Able to understand and give written informed consent and has signed a written informed consent form (ICF) approved by the Investigator’s Institutional Review Board (IRB)/Ethics Committee (EC), prior to conducting any study related procedures (including withholding of any asthma medications required for procedures). 2. Male or female aged 18 through 70 years at the time of Visit 1. 3. History of physician-diagnosed asthma requiring continuous treatment with medium- or high-dose ICS (>250µg fluticasone propionate dry powder formulation equivalents total daily dose) plus LABA with or without additional controller medication for at least 12 months prior to Visit 1. 4. Documented current treatment with high-dose ICS plus LABA for at least 3 months prior to Visit 1 with or without additional asthma maintenance medication. If the participant is taking ICS plus LABA, the ICS and LABA can be parts of a combination product or given by separate inhalers. -For ICS plus LABA combination preparations, highest-strength maintenance doses approved in the given country will meet this criterion. -If the ICS and LABA are given by separate inhalers, then the participant must be on a high daily ICS dose during the last 3 months prior to Visit 1(see Appendix D for high daily ICS doses by formulation). 5. Morning pre-BD FEV1 = 50 to < 80% of PNV and = 1 L at Visit 2, or morning pre-BD FEV1 = 50 to < 90% of PNV, if documented historical pre-BD FEV1 value (within 12 months prior to screening visit) was < 80% of PNV. One retest is allowed, 6. A blood eosinophil count meeting any of 3 criteria below: - = 300 cells/µL during screening at Visit 1 or Visit 2, OR - = 220 to < 300 cells/µL during screening at Visit 1 or Visit 2 and documented eosinophil count of = 300 cells/µL in the past 12 months, OR - = 150 to < 300 cells/µL during screening at Visit 1 or Visit 2 PLUS one of the following: Presence of nasal polyps, or Pre-BD FVC < 65% predicted at Visit 2. 7. Weight of =40 kg. 8. Negative serum pregnancy test for female participants of childbearing potential at Visit 1. 9. Negative urine pregnancy test in female participants of childbearing potential prior to randomization and administration of IP. 10. Women are authorized to participate if they meet the following criteria: Female participants who cannot bear children as evidenced by: 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 considered postmenopausal if they have been amenorrhoeic for =12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply - Women <50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range. Until FSH is documented to be within menopausal range treat the participant as WOCBP - Women =50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment If criteria not met, participant should be regarded as having child bearing potential. Female participant capable of having children and both of the following conditions are met: - Have a negative urine pregnancy test prior to administration of the IP
Exclusion criteria
Exclusion criteria: 1.Clinically important pulmonary disease other than asthma or participants who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts. 2.Life-threatening asthma, defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1. 3.In participants undergoing bronchoscopy, a history of allergies or adverse drug reactions to medications used for pre-bronchoscopy procedures. 4.Any disorders that is not stable in the opinion of the investigator and could affect the safety of the participant during the study, influence the findings of the studies or their interpretations, or impede the participant’s ability to complete the entire duration of the study. 5.Current smokers. Ex-smokers must not have smoked for a minimum of 12 months and should not have a smoking history >15 pack-years at Visit 1. Participants who use e-cigarettes or smoke marijuana will also be excluded from the study. 6.Alcohol or drug abuse (past or present) or any conditions associated with poor compliance. 7.Participants who are scheduled to be admitted to hospital or undergo inpatient surgery during the study. 8.History of anaphylaxis to any biologic therapy. 9.Known history of allergy or reaction to any component of the IP formulation. 10.History of cancer: - Participants who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the participant curative therapy was completed at least 12 months prior to the date informed consent is obtained - Participants who have had other malignancies are eligible provided that the participant curative therapy was completed at least 5 years prior to the date informed consent is obtained 11.A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy 12.A history of known immunodeficiency disorder including a positive human immunodeficiency virus test. 13.Current active liver disease, except for chronic stable hepatitis B and C, or other stable chronic liver disease are acceptable if participant otherwise meets eligibility criteria. 14.In participants undergoing bronchoscopy, any medical condition that requires chronic treatment with chronic anti-coagulation, chronic aspirin, or anti-platelet therapy. 15.In participants undergoing bronchoscopy, use of anticoagulants within 4 weeks prior to randomization into the study. 16.In participants undergoing bronchoscopy, use of non-steroidal anti-inflammatory drugs within 72 hours before or aspirin within 7 days of randomization. 17.Use of chronic (i.e. >4 weeks) immunosuppressive medication within 3 months prior to the date informed consent is obtained. 18.Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained. 19.Receipt of any marketed or investigational biologic for the treatment of asthma within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer. 20.Previously received benralizumab. Participants that participated in other studies with benralizumab but have been confirmed to have received placebo are eligible. 21.Receipt of live attenuated vaccines 30 days prior to the date of randomization.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - to evaluate the effect of benralizumab on submucosal eosinophils in endobronchial biopsies as measured by major basic protein (MBP) staining - to evaluate the effect of treatment with benralizumab on airway wall dimensions as measured by quantitative computed tomography (QCT) imaging;Secondary Objective: To evaluate: - the effect of benralizumab on eosinophils in endobronchial biopsies as measured by MBP staining - the effect of benralizumab on small airway obstruction as measured by QCT - the effect of benralizumab on computational fluid dynamics by QCT - the effect of benralizumab on mucus plugging as measured by QCT - the effect of benralizumab on large airway remodeling as measured by histology and immunohistochemistry (IHC) - the effect of benralizumab on small airway obstruction as measured by airwave oscillometry (AO) - the effect of benralizumab on change in lung function as measured by pre-bronchodilator (BD) and post-BD whole body plethysmography (WBP) - the effect of benralizumab on airway function as measured by spirometry - the effect of benralizumab on basophil numbers in endobronchial biopsies as measured by IHC - the short-term (anti-inflammatory) effect of benralizumab on changes in the primary and secondary endpoints measured by QCT, AO, WBP, and spirometry;Primary end point(s): 1. The change, expressed as a percentage from baseline to end of treatment (EOT) in eosinophil numbers, expressed as number/mm2 in submucosa. 2. The change, expressed as a percentage, from baseline to EOT in airway WA% as the overall median for airway generations 3 and 4 combined. Supportive measure: Change, expressed as a percentage, from baseline to EOT in airway lumen area (LA), airway wall area (WA) and airway wall thickness (WT).;Timepoint(s) of evaluation of this end point: End of treatment (EOT) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. The change, expressed as a percentage, from baseline to EOT in eosinophil numbers, expressed as number/mm2 in: - Epithelium - Epithelium and submucosa 2. Absolute change from baseline to EOT in: - Air trapping expressed as percentage of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans - Air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory CT scans 3. Change, expressed as a percentage, from baseline to EOT in: - Airway lumen volume - Airway resistance 4. Absolute change from baseline to EOT in mucus score. 5. Change, expressed as a percentage, from baseline to EOT in endobronchial biopsies on: - Airway epithelial cell integrity - RBM thickening - Vascularization of the sub-mucosa - Airway smooth muscle mass percentage - Mucus glands, goblet cells and mucin 5AC,oligomeric mucus/gel-forming (MUC5AC) 6. Absolute change from baseline to EOT in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) and area under the reactance curve (AX). 7. Absolute change from baseline to EOT in pre-BD whole body plethysmography (WBP), post-BD WBP, and change from pre-BD WBP to post-BD WBP: Residual volume (RV), Total lung capacity (TLC), Inspiratory capacity (IC), RV/TLC ratio, Functional residual capacity (FRC) and Vital capacity (VC). 8. Change, expressed as a percentage, from baseline to EOT in post-BD forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC 9. Change, expressed as a percentage, from baseline to EOT in basophil number (number/mm2) in endobronchial biopsies 10. Change from baseline to Week 8 in the primary and secondary variables measured by quantitative computed tomography (QCT), airwave oscillometry (AO), whole body plethysmography (WBP | — |
Countries
Canada, Denmark, Sweden, United Kingdom, United States
Contacts
Public ContactInformation Center
AstraZeneca AB
Outcome results
None listed