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Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist

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ClinicalTrials.gov Identifier: NCT01914757
Recruitment Status : Completed
First Posted : August 2, 2013
Results First Posted : January 25, 2017
Last Update Posted : January 25, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE July 31, 2013
First Posted Date  ICMJE August 2, 2013
Results First Submitted Date  ICMJE September 8, 2016
Results First Posted Date  ICMJE January 25, 2017
Last Update Posted Date January 25, 2017
Study Start Date  ICMJE August 2013
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2016)
Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils >=300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.
Original Primary Outcome Measures  ICMJE
 (submitted: July 31, 2013)
To evaluate the effect of benralizumab on asthma exacerbations in adult patients with uncontrolled asthma. [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
Annual asthma exacerbation rate
Change History Complete list of historical versions of study NCT01914757 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2016)
  • Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils <300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.
  • Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils >=300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
  • Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils <300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
  • Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils >=300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma). Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
  • Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils <300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma). Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
  • Change in Asthma Rescue Medication Use [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Change from Baseline to Week 56 in number of Rescue medication use (puffs/day)
  • Home Lung Function Assessments Based on PEF [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Change from Baseline to Week 56 in Home lung function (morning and evening Peak expiratory flow [PEF])
  • Proportion of Nights With Awakening Due to Asthma [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Change from Baseline to Week 56 on Proportion of Nights with awakening due to asthma
  • Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils >=300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
  • Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils <300/uL [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
  • Number of Patients With >=1 Asthma Exacerbation [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
  • Time to First Asthma Exacerbation [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
  • Annual Rate of Asthma Exacerbation Resulting Emergency Room Visits and Hospitalizations [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization (adjudicated)
  • Pharmacokinetics of Benralizumab [ Time Frame: Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 60 ]
    Mean PK Concentration at each visit
  • Immunogenicity of Benralizumab [ Time Frame: Pre-treatment until end of follow-up ]
    Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post-baseline assessments (with >=16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive.
  • Extent of Exposure [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    Extent of exposure is defined as the duration of treatment in days
  • Mean Change From Baseline to Week 56 in AQLQ(S)+12 [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of >=0.5 are considered clinically meaningful.
  • Change From Baseline to Week 56 in EQ-5D-5L VAS [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    EQ-5D-5L VAS is to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state.
  • Mean Work Productivity Loss Due to Asthma [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Work productivity loss is derived by sum of percentage of missed work due to asthma and product of percentage of actual working hours times degree of asthma affecting work productivity while working. Percentage of missed work due to asthma is calculated by number of hours missed work due to asthma divided by total number of hours missed work plus number of hours actually worked. This is only applicable to patients who were employed.
  • Mean Productivity Loss Due to Asthma in Classroom [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Classroom productivity loss is derived by sum of percentage of missed classes due to asthma and product of percentage of actual hours attending classes times degree of asthma affecting classroom productivity. Percentage of missed classes due to asthma is calculated by number of hours missed classes due to asthma divided by total number of hours missed classes plus number of hours actually attending classes. This is only applicable for patients who took classes.
  • Number of Participants That Utilized Health Care Resources [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
  • Patient and Clinician Assessment of Response to Treatment [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    CGIC (clinician global impression of change), and PGIC (patient global impression of change) are overall evaluation of response to treatment, conducted separately by investigator and patient using a 7-point rating scale, ranging from 1 (Very much Improved), to 7 (Very much Worse). This endpoint was added after the second protocol amendment, thus not all patients had data to be analyzed.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2013)
  • To assess the effect of benralizumab on pulmonary function [ Time Frame: Immediately following the first administration of study drug through Study Week 56 ]
    Endpoints: Pre-dose/pre-bronchodilator FEV1 and post-bronchodilator FEV1 at the study centre
  • To assess the effect of benralizumab on asthma symptoms and other asthma control metrics (as per the ePRO) [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Endpoints: - Asthma symptom score (total,daytime and night time) - Rescue medication use - Home lung function (morning and evening PEF) - Nights with awakening due to asthma - ACQ-6
  • To assess the effect of benralizumab on emergency room visits and hospitalizations due to asthma [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization
  • To evaluate the pharmacokinetics and immunogenicity of benralizumab [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Endpoints: - PK parameters- Anti-drug antibodies (ADA)
  • To assess the safety and tolerability of benralizumab [ Time Frame: Immediately following the first administration of study drug through Study Week 56. ]
    Endpoints: - AE/SAE - Laboratory variables - ECG - Physical Examination
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist
Official Title  ICMJE A Multicentre, Randomized, Double-blind, Parallel Group, Placebocontrolled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Asthmatic Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist (CALIMA)
Brief Summary The purpose of this study is to determine whether Benralizumab reduces the exacerbation rate in patients with a history of asthma exacerbations and uncontrolled asthma receiving ICS-LABA with or without oral corticosteroids and additional asthma controllers.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Biological: Benralizumab
    Benralizumab subcutaneously on study week 0 until study week 52 inclusive.
  • Biological: Placebo
    Placebo subcutaneously on study week 0 until study week 52 inclusive.
Study Arms  ICMJE
  • Experimental: Benralizumab 30 mg q.4 weeks
    Benralizumab administered subcutaneously every 4 weeks
    Intervention: Biological: Benralizumab
  • Experimental: Benralizumab 30 mg q.8 weeks
    Benralizumab administered subcutaneously every 8 weeks
    Intervention: Biological: Benralizumab
  • Placebo Comparator: Placebo
    Placebo administered subcutaneously
    Intervention: Biological: Placebo
Publications *

*   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: April 11, 2016)
2508
Original Estimated Enrollment  ICMJE
 (submitted: July 31, 2013)
1026
Actual Study Completion Date  ICMJE March 2016
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision of informed consent prior to any study specific procedures
  2. Female and male aged 12 to 75 years, inclusively, at the time of Visit 1
  3. History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (>250µg fluticasone dry powder formulation equivalents total daily dose) and a LABA, for at least 12 months prior to Visit 1.
  4. Documented treatment with ICS and LABA for at least 3 months prior to Visit 1 with or without oral corticosteroids and additional asthma controllers. The ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry powder formulation or equivalent daily. For ICS/LABA combination preparations, the mid-strength approved maintenance dose in the local country will meet this ICS criterion.

Exclusion criteria:

  1. Clinically important pulmonary disease other than asthma (e.g. active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, Churg- Strauss syndrome, hypereosinophilic syndrome)
  2. 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
  3. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period
  4. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in period, 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 the patient's ability to complete entire duration of the study
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,   Canada,   Chile,   Germany,   Japan,   Philippines,   Poland,   Romania,   Sweden,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01914757
Other Study ID Numbers  ICMJE D3250C00018
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: Mark Fitzgerald, MD, PhD, Professor of Medicine The Lung Centre, Gordon and Leslie Diamond Health Care Centre, Vancouver Canada
PRS Account AstraZeneca
Verification Date November 2016

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