A Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus LABA

Study Overview
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Brief Summary
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The purpose of this study is to characterize the safety profile of benralizumab administration in asthma patients who have completed one of the three predecessor studies: D3250C00017, D3250C00018 or D3250C00020.

Detailed Description
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After a minimum of 1200 patients have been enrolled in this study, subsequent patients (up to a maximum of 2200 total for the study), who complete a minimum of 16 weeks, and no more than 40 weeks, in this study, will be given the option to transition to an open-label safety extension study, Study D3250C00037 (MELTEMI). Adolescent patients, patients from Japan and South Korea, and any patient who chooses not to enter Study D3250C00037 will remain in this study through IPD or EOT and FU. At the time of the first interim analysis in Japanese patients, the study regimen for all patients will become unblinded to AstraZeneca for data analysis purposes. Study conduct and blinding at the site and patient level will remain unchanged.

Official Title
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A Multicentre, Double-blind, Randomized, Parallel Group, Phase 3 Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus Long-acting β2 Agonist (BORA)

Conditions
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Asthma

Intervention / Treatment
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* Biological: Benralizumab
* Biological: Benralizumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Informed consent (and/or assent as applicable locally) for study participation must be obtained prior to any study related procedures being performed (local regulations are to be followed in determining the assent/consent requirements for children and parent(s)/guardian(s)) and according to international guidelines and/or applicable European Union guidelines. Female and male patients who completed the double-blind treatment period in a predecessor study on benralizumab or matching placebo. Women of childbearing potential (WOCBP) must agree to use an effective form of birth control throughout the study duration and for 16 weeks after last dose of Investigational Product (IP). For WOCBP only: Have a negative urine pregnancy test prior to administration of Investigational Product (IP) at Visit 1. All male patients who are sexually active must agree to use a double barrier method of contraception (condom with spermicide) from the first dose of IP until 16 weeks after their last dose. Exclusion criteria 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 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 A helminth parasitic infection diagnosed during a predecessor study that has either not been treated, has been incompletely treated or has failed to respond to standard of care therapy Any clinically significant change in physical examination, vital signs, electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during a predecessor study which in the opinion of the investigator may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or interfere with the patient's ability to complete the entire duration of the study Current malignancy or malignancy that developed during a predecessor study (subjects that had basal cell carcinoma, localized squamous cell carcinoma of the skin which was resected for cure, or in situ carcinoma of the cervix that has been treated/cured will not be excluded). Receipt of live attenuated vaccines within 30 days prior to initiation of treatment in this study, during the treatment period, and for 16 weeks (5 half-lives) after the last dose of the investigational product Receipt of immunoglobulin or blood products within 30 days prior to Visit 1 Planned major surgical procedures during the conduct of the study Previous participation in the present study Concurrent enrolment in another clinical trial AstraZeneca staff involved in the planning and/or conduct of the study Employees of the study centre or any other individuals involved with the conduct of the study or immediate family members of such individuals Patients with major protocol deviations in any of the predecessor studies at the discretion of the Sponsor

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab Arm A<br>Benralizumab administered subcutaneously | Biological: Benralizumab<br>* Benralizumab administered subcutaneously<br>|
| Experimental: Benralizumab Arm B<br>Benralizumab administered subcutaneously | Biological: Benralizumab<br>* Benralizumab administered subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Basophils, Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in hematologic lab parameter of Basophils. | Week 56 | 
| Change From Baseline in Basophils, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of Basophils. | Week 108 | 
| Change From Baseline in Leukocytes, Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in hematologic lab parameter of Leukocytes. | Week 56 | 
| Change From Baseline in Leukocytes, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of Leukocytes. | Week 108 | 
| Change From Baseline in Lymphocytes, Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in hematologic lab parameter of Lymphocytes. | Week 56 | 
| Change From Baseline in Lymphocytes, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of Lymphocytes. | Week 108 | 
| Change From Baseline in Neutrophils, Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in hematologic lab parameter of Neutrophils. | Week 56 | 
| Change From Baseline in Neutrophils, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of Neutrophils. | Week 108 | 
| Change From Baseline in Eosinophils, Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in hematologic lab parameter of Eosinophils. | Week 56 | 
| Change From Baseline in Eosinophils, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of Eosinophils. | Week 108 | 
| Change From Baseline in Alanine Aminotransferase (ALT), Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in chemistry tests ALT. | Week 56 | 
| Change From Baseline in ALT, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of ALT. | Week 108 | 
| Change From Baseline in Aspartate Aminotransferase (AST), Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in chemistry tests AST. | Week 56 | 
| Change From Baseline in AST, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of AST. | Week 108 | 
| Change From Baseline in Bilirubin, Full Analysis Set, Excluding MELTEMI Patients | Change from baseline in chemistry test Bilirubin. | Week 56 | 
| Change From Baseline in Bilirubin, Full Analysis Set, Adolescents Only (SIROCCO/CALIMA) | Change from baseline in hematologic lab parameter of Bilirubin. | Week 108 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Overall Patients With Asthma Exacerbations During Study Period | Annual asthma exacerbation rate, where an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic corticosteroids for at least 3 days, and/or an in patient hospitalization, and/or an emergency department or urgent care visit | From week 0 to week 56 in study treatment period and through the follow up period (16 weeks from day of last dose) | 
| Number of Overall Patients With Asthma Exacerbations During Study Period, Adolescents Only (SIROCCO/CALIMA) | Annual asthma exacerbation rate, where an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic corticosteroids for at least 3 days, and/or an in patient hospitalization, and/or an emergency department or urgent care visit | From week 0 to week 108 in study treatment period and through the follow up period (16 weeks from day of last dose) | 
| Change From Baseline in Pre-bronchodilator FEV1 (L) | Change from baseline to Week 56 in Pre-bronchodilator Forced expiratory volume in 1 second (FEV1). | Week 56 | 
| Change From Baseline in Pre-bronchodilator FEV1 (L), Adolescents Only (SIROCCO/CALIMA) | Change from baseline to Week 108 in Pre-bronchodilator Forced expiratory volume in 1 second (FEV1). | Week 108 | 
| Change From Baseline in Post-bronchodilator FEV1 (L) | Change from baseline to Week 56 in Post-bronchodilator Forced expiratory volume in 1 second (FEV1). | Week 56 | 
| Change From Baseline in Post-bronchodilator FEV1 (L), Adolescents Only (SIROCCO/CALIMA) | Change from baseline to Week 108 in Post-bronchodilator Forced expiratory volume in 1 second (FEV1). | Week 108 | 
| Change From Baseline in Asthma Control Questionnaire (ACQ) as a Measure of Asthma Control in Overall Patients | Asthma Control Questionnaire 6 (ACQ-6) contains 1 bronchodilator use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses. | Week 56 | 
| Change From Baseline in Asthma Control Questionnaire (ACQ) as a Measure of Asthma Control in Overall Patients, Adolescents Only (SIROCCO/CALIMA) | Asthma Control Questionnaire 6 (ACQ-6) contains 1 bronchodilator use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses. | Week 108 | 
| Change From Baseline in Total Score of Asthma Related and General Health-related Quality of Life Questionnaire (AQLQ(S)+12) | Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). It contains 32 questions on a 7 point scale ranging from 7 (no impairment) to 1 (severe impairment); total score is an average of all questions. An increase in score indicates improvement. | Week 56 | 
| Change From Baseline in Total Score of Asthma Related and General Health-related Quality of Life Questionnaire (AQLQ(S)+12), Adolescents Only (SIROCCO/CALIMA) | Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). It contains 32 questions on a 7 point scale ranging from 7 (no impairment) to 1 (severe impairment); total score is an average of all questions. An increase in score indicates improvement. | Week 108 | 
| Change of Blood Eosinophil Levels' Measurement in Overall Patients | Change from baseline to Week 56 in Blood eosinophils | Week 56 | 
| Change of Blood Eosinophil Levels' Measurement in Adolescents Patients (SIROCCO/CALIMA). | Change from baseline to Week 108 in Blood eosinophils. | Week 108 | 
| Change From Baseline in EQ-5D-5L Visual Analog Scale | The questionnaire included a visual analog scale (VAS) score, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state; thus, an increase in VAS score indicated improvement. | Week 56 | 
| Change From Baseline in EQ-5D-5L Visual Analog Scale, Adolescents Only (SIROCCO/CALIMA) | The questionnaire included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state; thus, an increase in VAS score indicated improvement. | Week 108 | 
| Work Productivity Loss in Adults, Using Work Productivity and Activity Impairment Questionnaire (WPAI) | The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. Work productivity loss is calculated with sum of hours missed at work due to health problem and hours that affected due to health problem at work, divided by sum of hours missed due to health problem and hours actually worked, presented by percentage. | Week 68 | 
| Work Productivity Loss in Adults, Using Work Productivity and Activity Impairment Questionnaire (WPAI), Adolescents Only (SIROCCO/CALIMA) | The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. Work productivity loss is calculated with sum of hours missed at work due to health problem and hours that affected due to health problem at work, divided by sum of hours missed due to health problem and hours actually worked, presented by percentage. | Week 108 | 
| Classroom Productivity Loss Using Classroom Impairment Questionnaire (CIQ) | The WPAI (+CIQ) is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. Classroom productivity loss is calculated with sum of hours missed for classes due to health problem and hours that affected due to health problem in classes, divided by sum of hours missed due to health problem and hours actually attended classes, presented by percentage. | Week 56 | 
| Classroom Productivity Loss Using Classroom Impairment Questionnaire (CIQ), Adolescents Only (SIROCCO/CALIMA) | The WPAI (+CIQ) is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. Classroom productivity loss is calculated with sum of hours missed for classes due to health problem and hours that affected due to health problem in classes, divided by sum of hours missed due to health problem and hours actually attended classes, presented by percentage. | Week 108 | 
| Activity Impairment (%), Using Work Productivity and Activity Impairment Questionnaire (WPAI) | The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. The WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. | Week 68 | 
| Activity Impairment (%), Using Work Productivity and Activity Impairment Questionnaire (WPAI), Adolescents Only (SIROCCO/CALIMA) | The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. The WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. | Week 108 | 
| Number of Patients Who Had Health Care Encounter (ie, Hospitalization, Emergency Department Visits, Urgent Care Visits, and All Other Outpatient Visits Due to Asthma) During Study Period | Hospitalizations, Emergency department (ED) visits, urgent care visits and all other outpatient visits due to asthma | From week 0 to week 68 in study treatment period and through the follow up period (16 weeks from day of last dose) | 
| Number of Patients Who Had Health Care Encounter (ie, Hospitalization, Emergency Department Visits, Urgent Care Visits, and All Other Outpatient Visits Due to Asthma) During Study Period, Adolescents Only (SIROCCO/CALIMA) | Hospitalizations, ED visits, urgent care visits and all other outpatient visits due to asthma | Baseline and Week 108 | 
| Pre-dose Benralizumab Concentration in Serum During the Treatment Phase of the Safety Study | Endpoint: Pharmacokinetic (PK) parameters | Week 0 and Week 56 | 
| Pre-dose Benralizumab Concentration in Serum During the Treatment Phase of the Safety Study, Adolescents Only (SIROCCO/CALIMA) | Endpoint: Pharmacokinetic (PK) parameters | Baseline and Week 108 | 
| Number of Patients With Anti-drug Antibodies (ADA) Responses During the Study | Assessments for the presence of ADA and neutralizing antibody (nAb) throughout study | From week 0 to week 56 in study treatment period (adults) and plus 16 weeks the follow up period; From week 0 to week 108-week in study treatment period (adolescents) and plus 16 weeks the follow up period | 
| Number of Patients With Anti-drug Antibodies (ADA) Responses During the Study, Adolescents Only (SIROCCO/CALIMA) | Assessments for the presence of ADA and nAb throughout study | From week 0 to week 108 study treatment period (adults) and plus 16 weeks the follow up period; From week 0 to week 108-week in study treatment period (adolescents) and plus 16 weeks the follow up period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases