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

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ClinicalTrials.gov Identifier: NCT02258542
Recruitment Status : Completed
First Posted : October 7, 2014
Results First Posted : February 6, 2019
Last Update Posted : February 6, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE September 1, 2014
First Posted Date  ICMJE October 7, 2014
Results First Submitted Date  ICMJE October 18, 2018
Results First Posted Date  ICMJE February 6, 2019
Last Update Posted Date February 6, 2019
Actual Study Start Date  ICMJE November 19, 2014
Actual Primary Completion Date October 18, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
  • Change From Baseline in Basophils, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in hematologic lab parameter of Basophils.
  • Change From Baseline in Leukocytes, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in hematologic lab parameter of Leukocytes.
  • Change From Baseline in Lymphocytes, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in hematologic lab parameter of Lymphocytes.
  • Change From Baseline in Neutrophils, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in hematologic lab parameter of Neutrophils.
  • Change From Baseline in Eosinophils, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in hematologic lab parameter of Eosinophils.
  • Change From Baseline in ALT, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in chemistry tests ALT.
  • Change From Baseline in AST, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in chemistry tests AST.
  • Change From Baseline in Bilirubin, Full Analysis Set, Excluding MELTEMI Patients [ Time Frame: Week 56 ]
    Change from baseline in chemistry test Bilirubin.
Original Primary Outcome Measures  ICMJE
 (submitted: October 3, 2014)
  • Number of patients with Adverse Events/abnormal lab variables, ECG, Physical Examinations as measures of safety and tolerability of two dosing regimens of benralizumab for adult patients [ Time Frame: From week 0 to week 56 in study treatment period ]
    - Number of Number of Adverse Events/Serious Adverse Events (AEs/SAEs); - Laboratory variables; - Electrocardiogram (ECG); - Physical Examination
  • Number of adolescent patients with Adverse Events/abnormal lab variables, ECG, Physical Examinations as measures of safety and tolerability of two dosing regimens of benralizumab for adolescent patients [ Time Frame: From week 0 to week 108-week in study treatment period ]
    - Number of AEs/SAEs; - Laboratory variables; - ECG; - Physical Examination
Change History Complete list of historical versions of study NCT02258542 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
  • Number of Overall Patients With Asthma Exacerbations During Study Period [ Time Frame: From week 0 to week 56 in study treatment period and through the follow up period (16 weeks from day of last dose) ]
    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
  • Change From Baseline in Pre-brochodilator FEV1 (L) [ Time Frame: Week 56 ]
    Change from baseline to Week 56 in Pre-bronchodilator Forced expiratory volume in 1 second (FEV1).
  • Change From Baseline in Post-brochodilator FEV1 (L) [ Time Frame: Week 56 ]
    Change from baseline to Week 56 in Post-bronchodilator Forced expiratory volume in 1 second (FEV1).
  • Change From Baseline in Asthma Control Questionnaire (ACQ) as a Measure of Asthma Control in Overall Patients [ Time Frame: Week 56 ]
    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.
  • Change From Baseline in Total Score of Asthma Related and General Health-related Quality of Life Questionnaire (AQLQ(S)+12) [ Time Frame: Week 56 ]
    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.
  • Change of Blood Eosinophil Levels' Measurement in Overall Patients [ Time Frame: Week 56 ]
    Change from baseline to Week 56 in Blood eosinophils
  • Change From Baseline in EQ-5D-5L Visual Analog Scale [ Time Frame: Week 56 ]
    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.
  • Work Productivity Loss in Adults, Using Work Productivity and Activity Impairment Questionnaire (WPAI) [ Time Frame: Baseline and Week 68 ]
    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.
  • Classroom Productivity Loss Using Classroom Impairment Questionnaire (CIQ) [ Time Frame: Baseline and Week 56 ]
    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.
  • Activity Impairment (%), Using Work Productivity and Activity Impairment Questionnaire (WPAI) [ Time Frame: Baseline and Week 68 ]
    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.
  • 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 [ Time Frame: From week 0 to week 68 in study treatment period and through the follow up period (16 weeks from day of last dose) ]
    Hospitalizations, ED visits, urgent care visits and all other outpatient visits due to asthma
  • Pre-dose Benralizumab Concentration in Serum During the Treatment Phase of the Safety Study [ Time Frame: Week 0 and Week 56 ]
    Endpoint: Pharmacokinetic (PK) parameters
  • Number of Patients With Anti-drug Antibodies (ADA) Responses During the Study [ Time Frame: 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 ]
    Assessments for the presence of ADA and nAb throughout study
Original Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2014)
  • Number of adult patients with asthma exacerbations during study treatment period [ Time Frame: From week 0 to week 56 in study treatment 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
  • Number of adolescent patients with asthma exacerbations during study treatment period [ Time Frame: From week 0 to week 108-week in study treatment 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
  • Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions (WPAI+CIQ) utilization as a measure of health care utilization and work & productivity loss in adult patients [ Time Frame: From week 0 to week 56 in study treatment period ]
    Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions (WPAI+CIQ); Hospitalizations, Emergency Department (ED) visits, urgent care visits and all other outpatient visits due to asthma
  • Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions (WPAI+CIQ) utilization as a measure of health care utilization and work & productivity loss in adolescent patients [ Time Frame: From week 0 to week 108-week in study treatment period ]
    WPAI+CIQ; Hospitalizations, ED visits, urgent care visits and all other outpatient visits due to asthma
  • Asthma related and general health-related quality of life in adult patients [ Time Frame: From week 0 to week 56 in study treatment period ]
    Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12); European Quality of Life-5 Dimensions (EQ-5D-5L) questionnaire
  • Asthma related and general health-related quality of life in adolescent patients [ Time Frame: From week 0 to week 108-week in study treatment period ]
    AQLQ(S)+12; EQ-5D-5L
  • Asthma Control Questionnaire as a measure of asthma control in adult patients [ Time Frame: From week 0 to week 56 in study treatment period ]
    Asthma Control Questionnaire 6 (ACQ-6)
  • Asthma Control Questionnaire as a measure of asthma control in adolescent patients [ Time Frame: From week 0 to week 108-week in study treatment period ]
    ACQ-6
  • Pre-dose Benralizumab Concentration in Serum During the Treatment Phase of the Safety Study [ Time Frame: From week 0 to week 56 in study treatment period (adults); From week 0 to week 108-week in study treatment period (adolescents) ]
    Endpoint: Pharmacokinetic (PK) parameters
  • Anti-drug antibodies (ADA) as a measure of immunogenicity assessments [ Time Frame: From week 0 to week 56 in study treatment period (adults); From week 0 to week 108-week in study treatment period (adolescents) ]
    Neutralizing antibody responses (nAb responses) measurement as a positive or negative determination on the ADA-positive samples
  • Spirometry tests as a measure of pulmonary function in adult patients [ Time Frame: From week 0 to week 56 in study treatment period ]
    Pre-bronchodilator Forced expiratory volume in 1 second (FEV1) and post-bronchodilator FEV1 at the study centre
  • Spirometry tests as a measure of pulmonary function in adolescent patients [ Time Frame: From week 0 to week 108-week in study treatment period ]
    Pre-bronchodilator FEV1 and post-bronchodilator FEV1 at the study centre
  • Collection of blood samples for eosinophil levels' measurement in adult patients [ Time Frame: From week 0 to week 56 in study treatment period ]
    Blood eosinophils
  • Collection of blood samples for eosinophil levels' measurement in adolescent patients [ Time Frame: From week 0 to week 108-week in study treatment period ]
    Blood eosinophils
  • Daily inhaled steroid dose and number of other daily asthma controller medications collection as a measure of concomitant asthma controller medications [ Time Frame: From week 0 to week 56 in study treatment period for adult patients; from week 0 to week 104 in study treatment period for adolescents ]
    Total daily inhaled steroid dose; Number of other daily asthma controller medications
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus LABA
Official Title  ICMJE 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)
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
Condition  ICMJE Asthma
Intervention  ICMJE Biological: Benralizumab
Benralizumab administered subcutaneously
Study Arms  ICMJE
  • Experimental: Benralizumab Arm A
    Benralizumab administered subcutaneously
    Intervention: Biological: Benralizumab
  • Experimental: Benralizumab Arm B
    Benralizumab administered subcutaneously
    Intervention: Biological: Benralizumab
Publications * Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, Olsson RF, Martin UJ, Goldman M; BORA study investigators. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med. 2019 Jan;7(1):46-59. doi: 10.1016/S2213-2600(18)30406-5. Epub 2018 Nov 8. Erratum in: Lancet Respir Med. 2019 Jan;7(1):e1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 24, 2017)
2133
Original Estimated Enrollment  ICMJE
 (submitted: October 3, 2014)
2550
Actual Study Completion Date  ICMJE July 2, 2018
Actual Primary Completion Date October 18, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  1. 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.
  2. Female and male patients who completed the double-blind treatment period in a predecessor study on benralizumab or matching placebo.
  3. 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).
  4. For WOCBP only: Have a negative urine pregnancy test prior to administration of Investigational Product (IP) at Visit 1.
  5. 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

  1. 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
  2. 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
  3. 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
  4. 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).
  5. 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
  6. Receipt of immunoglobulin or blood products within 30 days prior to Visit 1
  7. Planned major surgical procedures during the conduct of the study
  8. Previous participation in the present study
  9. Concurrent enrolment in another clinical trial
  10. AstraZeneca staff involved in the planning and/or conduct of the study
  11. Employees of the study centre or any other individuals involved with the conduct of the study or immediate family members of such individuals
  12. Patients with major protocol deviations in any of the predecessor studies at the discretion of the Sponsor
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Brazil,   Bulgaria,   Canada,   Chile,   Czechia,   France,   Germany,   Japan,   Korea, Republic of,   Peru,   Philippines,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   Sweden,   Turkey,   Ukraine,   United Kingdom,   United States,   Vietnam
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02258542
Other Study ID Numbers  ICMJE D3250C00021
U1111-1162-2422 ( Other Identifier: WHO )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: William W. Busse, M.D., Professor of Medicine Allergy, Pulmonary, and Critical Care Medicine 600 Highland Avenue; Madison, WI
PRS Account AstraZeneca
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP