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

• 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: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: July 31, 2013
• First Posted Date: August 2, 2013
• Results First Submitted Date: September 8, 2016
• Results First Posted Date: January 25, 2017
• Last Update Posted Date: January 25, 2017
• Study Start Date: August 2013
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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

Current Secondary Outcome Measures (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 (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: Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Asthma

Intervention

• 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

• 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 *

• Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, Jison M, Brooks CL, Papeleu P, Katial R. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. Adv Ther. 2022 May;39(5):2065-2084. doi: 10.1007/s12325-022-02098-1. Epub 2022 Mar 14.
• Lugogo NL, Kreindler JL, Martin UJ, Cook B, Hirsch I, Trudo FJ. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Ann Allergy Asthma Immunol. 2020 Aug;125(2):171-176. doi: 10.1016/j.anai.2020.04.011. Epub 2020 Apr 22.
• Jackson DJ, Humbert M, Hirsch I, Newbold P, Garcia Gil E. Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma. Adv Ther. 2020 Feb;37(2):718-729. doi: 10.1007/s12325-019-01191-2. Epub 2019 Dec 14.
• Chipps BE, Hirsch I, Trudo F, Alacqua M, Zangrilli JG. Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma. Ann Allergy Asthma Immunol. 2020 Jan;124(1):79-86. doi: 10.1016/j.anai.2019.10.006. Epub 2019 Oct 15.
• Chupp G, Lugogo NL, Kline JN, Ferguson GT, Hirsch I, Goldman M, Zangrilli JG, Trudo F. Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2019 May;122(5):478-485. doi: 10.1016/j.anai.2019.02.016. Epub 2019 Feb 23.
• Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, Goldman M, Newbold P, Zangrilli JG. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018 Oct 18;52(4):1800936. doi: 10.1183/13993003.00936-2018. Print 2018 Oct.
• DuBuske L, Newbold P, Wu Y, Trudo F. Seasonal variability of exacerbations of severe, uncontrolled eosinophilic asthma and clinical benefits of benralizumab. Allergy Asthma Proc. 2018 Sep 4;39(5):345-349. doi: 10.2500/aap.2018.39.4162. Epub 2018 Aug 4.
• Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018 May;120(5):504-511.e4. doi: 10.1016/j.anai.2018.01.030. Epub 2018 Feb 1.
• Ohta K, Adachi M, Tohda Y, Kamei T, Kato M, Mark Fitzgerald J, Takanuma M, Kakuno T, Imai N, Wu Y, Aurivillius M, Goldman M. Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma. Allergol Int. 2018 Apr;67(2):266-272. doi: 10.1016/j.alit.2017.10.004. Epub 2017 Nov 8.
• FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, Gilmartin G, Werkstrom V, Aurivillius M, Goldman M; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29;388(10056):2128-2141. doi: 10.1016/S0140-6736(16)31322-8. Epub 2016 Sep 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 11, 2016): 2508
• Original Estimated Enrollment (submitted: July 31, 2013): 1026
• Actual Study Completion Date: March 2016
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 12 Years to 75 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Canada, Chile, Germany, Japan, Philippines, Poland, Romania, Sweden, Ukraine, United States

Administrative Information

• NCT Number: NCT01914757
• Other Study ID Numbers: D3250C00018
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• 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