MEDI-563

To provide benralizumab to participants who continue to benefit at the end of the parent clinical study while monitoring long-term safety and tolerability of benralizumab

The safety and tolerability of benralizumab will be evaluated.

The PK of benralizumab will be evaluated.

To assess asthma exacerbation rate.

Main outcomes: Proportion of patients with at least one controller medication category reduction at end of reduction phase * discontinuation of LTRA, or * discontinuation of LAMA, or * getting to MD ICS/LABA or * getting to LD ICS/LABA Supportive outcomes: * Proportion of patients with individual category reduction at end of reduction phase * Proportion of patients with ≥2 category reductions in controller medication * In sub-group of patients who meet reduction criteria * proportion of patients with at least one controller medication category reduction, * proportion of patients with individual category reduction * proportion of patients with ≥2 reductions in controller medication at end of reduction phase

The effect of benralizumab on asthma exacerbations in paediatric and adolescent patients with uncontrolled asthma will be evaluated.

The time to first HES worsening/flare is calculated as: start date of the first HES worsening - date of randomisation + 1. For participants who do not experience a HES worsening/flare, the time to first HES worsening/flare is right censored at the end of the DB period corresponding to the earliest date (date of the first of Benra open label dose, study day 183, date of last contact, and data cut-off date). The number of participants with events and censored observations is presented.

Blood samples were collected to determine the clearance of benralizumab. This was an empirical Bayesian estimate (EBE) derived posthoc using population PK analysis.

Blood samples were collected to determine the AUC0-28 of benralizumab and it was calculated by linear up/log down trapezoidal summation. The PK parameters were estimated using non-compartmental analysis method.

Blood samples were collected to determine Cmax of benralizumab and it was directly calculated from the individual concentration-time curve. The PK parameters were estimated using non-compartmental analysis method.

Blood samples were collected to determine the t1/2 of benralizumab and it was calculated as natural logarithm of 2 \[ln(2)\]/terminal rate constant (λZ). This was an EBE derived posthoc using population PK analysis.

Blood samples were collected to determine the tmax of benralizumab and it was directly calculated from the individual concentration-time curve. The PK parameters were estimated using non-compartmental analysis method.

Blood samples were collected to determine the trough concentration at Week 16, the lowest concentration reached by benralizumab before the next dose was administered. The PK parameters were estimated using non-compartmental analysis method.

Blood samples were collected for determination of eosinophil count levels and were assessed in a central laboratory. Baseline is the last non-missing measurement prior to the first dose of study treatment.

Percentage of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS = 0 and OCS dose ≤ 4 mg/day (main remission definition) at both Weeks 36 and 48.

Supportive endpoint: Proportion of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS = 0 and OCS dose ≤ 7.5 mg/day (supportive remission definition) at both Weeks 36 and 48.

Moderate or severe COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD

Patients who achieve 100% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma

Patients who achieve 100% reduction or a daily OCS dose of \<=5mg, if reason for no further OCS reduction is Adrenal Insufficiency, that are sustained over at least 4 weeks without worsening of asthma

Change from baseline in total nasal polyps score (NPS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The total NPS was the sum of the right and left nostril scores and maximum total NPS is 8, as evaluated by nasal endoscopy and the left and right score were based on central read with scale from 0 to 4 where higher score reflects heavier bilateral nasal polyp burden. Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS\_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS\_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS\_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in nasal blockage score (NBS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The NBS was captured by an item in NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0-none; 1-mild; 2-moderate; 3-severe. The NBS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS\_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS\_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS\_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups

An asthma exacerbation was defined as a worsening of asthma that led to any of the following: * Use of systemic corticosteroids (or temporary increase in stable oral corticosteroids \[OCS\] background dose) for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. * An emergency room/urgent care visit (defined as evaluation and treatment for \< 24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above). * An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. Annual exacerbation rate = 365.25\*total number of exacerbations / total duration of follow-up within the treatment group. Annual asthma exacerbation rates over the 24-week period were estimated using a negative binomial model.

Patients who are still in the study is defined as patients who had been treated for the specified timepoint. A successful administration is defined as an injection completed, an answer of "Yes" to all 5 questions in the Questionnaire, and adequately passed the visual inspection and function tests.

AI evaluated as functional is defined as the device having adequately passed the visual inspection and function tests.

Number (%) of AI used to administer benralizumab at home or in the clinic and have been reported as malfunctioning (Product Complaints). The percentage is calculated based on AI dispensed for patients who were treated for the specific time point. This excludes AIs dispensed but never used for the treatment or the device not returned for evaluation.

The average over the mean differences between benralizumab and placebo for change from baseline in pre-BD FEV1 is used to determine if the study is positive and to determine maintenance of effect. The first post baseline time point where the p-value for the mean difference between benralizumab and placebo is less than or equal to 0.05 is used to determine time to onset of effect.

Body plethysmography was performed for sub-study patients. Lung volume subdivisions measures were performed by the investigator or qualified designee according to ATS/ERS guidelines.

To evaluate the effect of benralizumab on allergen-induced increases in eosinophils in induced sputum

To evaluate the effect of benralizumab on the allergen-induced late (3-7 hours post challenge) asthmatic response (LAR)

To compare the geometric mean fold rises in influenza strain-specific hemagglutination-inhibition responses from Week 8 to Week 12 between patients receiving benralizumab 30mg and patients receiving placebo. Geometric mean fold rise was defined as antilog(z) (mean \[log(z) x\]), where "x" is the postdose HAI antibody titer fold rise from Week 8 and "z" is the natural logarithm.

To compare the geometric mean titers of hemagglutination-inhibition antibody as a measure of influenza strain-specific response at Week 12 between patients receiving benralizumab 30mg and patients receiving placebo.

To compare the proportions of patients experiencing influenza strain-specific responses as measured by ≥4-fold rises in hemagglutination-inhibition antibody titer from Week 8 to Week 12 between patients receiving benralizumab 30mg and patients receiving placebo.

To compare the proportions of patients experiencing influenza strain-specific responses as measured by ≥40-fold rises in hemagglutination-inhibition antibody titer at Week 12 between patients receiving benralizumab 30mg and patients receiving placebo.

Change from baseline in hematologic lab parameter of Basophils.

Change from baseline in hematologic lab parameter of Leukocytes.

Change from baseline in hematologic lab parameter of Lymphocytes.

Change from baseline in hematologic lab parameter of Neutrophils.

Change from baseline in hematologic lab parameter of Monocytes.

Change from baseline in hematologic lab parameter of Platelets.

Change from baseline in hematologic lab parameter of Hematocrit.

Change from baseline in hematologic lab parameter of Erythrocytes.

Change from baseline in hematologic lab parameter of Hemoglobin.

Change from baseline in chemistry test ALT.

Change from baseline in chemistry test AST.

Change from baseline in chemistry test Bilirubin.

Number (%) of patients/caregivers who successfully administered benralizumab with an APFS at home among those who have been deemed by the Principal Investigator to be suitable for at-home administration and are still in the study. A successful administration is defined as an injection completed, an answer of "Yes" to all 5 questions in the Functioning Device Return Questionnaire for the GREGALE Clinical Study (Appendix to the Clinical Study Protocol), and adequately passed the visual inspection and function tests. The percentage is calculated among all patients/caregivers who had been deemed by the Principal Investigator to be suitable for at home administration and were still in the study at the time point.

Number (%) of returned APFS used to administer benralizumab at home that have been evaluated as functional among all returned APFS used to administer benralizumab at home. A functional APFS is defined as an answer of "Yes" to all the questions in the visual inspection and function tests. The percentage is calculated among all returned APFS at the specified time point.

Number (%) of APFS used to administer benralizumab at home or in the clinic and have been reported as malfunctioning (Product Complaints). The percentage is calculated based on APFS dispensed and used for the specified time point.

The FEV1 (L) change from baseline are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) analysis with baseline blood eosinophil count (≥300 cells/μL or \<300 cells/μL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment\*visit interaction as fixed effects and baseline pre-bronchodilator FEV1 (L) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.

Change from baseline in hematologic lab parameter of Basophils.

Change from baseline in hematologic lab parameter of Basophils.

Change from baseline in hematologic lab parameter of Leukocytes.

Change from baseline in hematologic lab parameter of Leukocytes.

Change from baseline in hematologic lab parameter of Lymphocytes.

Change from baseline in hematologic lab parameter of Lymphocytes.

Change from baseline in hematologic lab parameter of Neutrophils.

Change from baseline in hematologic lab parameter of Neutrophils.

Change from baseline in hematologic lab parameter of Eosinophils.

Change from baseline in hematologic lab parameter of Eosinophils.

Change from baseline in chemistry tests ALT.

Change from baseline in hematologic lab parameter of ALT.

Change from baseline in chemistry tests AST.

Change from baseline in hematologic lab parameter of AST.

Change from baseline in chemistry test Bilirubin.

Change from baseline in hematologic lab parameter of Bilirubin.

A COPD exacerbation is defined by symptomatic worsening of COPD requiring: * Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or * Use of antibiotics; and/or * An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}\*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF

The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.

The primary objective is to evaluate the effect of benralizumab on the allergen-induced number of eosinophils in the skin assessed by histological examination compared to placebo. Intradermal saline challenge will be used as a control.

The annual asthma exacerbation rate (AER) was calculated as the total number of observed exacerbations in each group up to week 52, divided by total duration of person-year follow-up in each group. An asthma exacerbation is defined as a progressive increase of asthma symptoms (cough, wheeze, chest tightness, and/or shortness of breath) that does not resolve after the initiation of rescue medications and remains troublesome for the participant resulting in either 1) use of systemic corticosteroids or increase of a stable systemic maintenance dose for a duration of at least 3 days as prescribed or administered by the investigator or healthcare provider; or 2) participant initiation of systemic corticosteroids (tablets, suspension or injection) for a duration of at least 3 days as outlined in the Asthma Action Plan provided to the participant by the investigator on Day 1.

An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. Annualized Incidence Rate of Moderate or Severe AECOPD was assessed based on AECOPD data up to Day 393 (Rate = total number of moderate or severe AECOPD in each group/total person-year follow-up in each group). The severity of an exacerbation of COPD is defined as: a) Mild exacerbations, which require treatment with an increase in usual therapy, example (eg), increase use of short acting bronchodilators, b) Moderate exacerbations which require treatment with systemic corticosteroids, and or antibiotics and c) Severe exacerbations which require hospitalization.

Percentage of participants who required urgent healthcare visit for treatment of acute asthma exacerbation were reported. As per protocol, asthma exacerbation (relapse/de novo) was defined as either 1) increase of asthma symptoms (cough, wheeze, chest tightness, and/or shortness of breath) that did not resolve within 2 hours after use of rescue albuterol or corticosteroids and required an unscheduled medical visit or 2) during scheduled study visit, participant had acute worsening of asthma symptoms and a reduction of greater than or equal to (\>=) 20 percent (%) in Peak Expiratory Flow (PEF) or Forced Expiratory Volume in 1 Second (FEV1), which in the opinion of the investigator required treatment with systemic corticosteroids. Asthma exacerbations were analyzed in a non-adjudicated manner (by investigator), which were then adjudicated in a blinded fashion by the sponsor medical monitor prior to database lock to determine whether the reported exacerbation met the protocol definition.

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to Day 161 that were absent before treatment or that worsened relative to pre-treatment state.

To compare the AUCinf following single SC administration of Benralizumab by using APFS or AI devices

To compare the AUClast following single SC administration of Benralizumab by using APFS or AI devices

To compare the Cmax following single SC administration of Benralizumab by using APFS or AI devices