Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients With Mild to Moderate Persistent Asthma

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients With Mild to Moderate Persistent Asthma.

The purpose of this trial is to confirm the safety and clinical benefit of benralizumab administration in asthma patients with mild to moderate persistent asthma in order to gain an understanding of the benefit/risk of benralizumab across the spectrum of asthma disease.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Biological: Benralizumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1G 3Y8
    • Research Site
  • Quebec, Canada, G1V 4G5
    • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Research Site
  • Ontario
    • Ajax, Ontario, Canada, L1Z 0M1
      • Research Site
    • Burlington, Ontario, Canada, L7N 3V2
      • Research Site
    • Hamilton, Ontario, Canada, L9C 2Y6
      • Research Site
    • Ottawa, Ontario, Canada, K2H 8T5
      • Research Site
    • Toronto, Ontario, Canada, M9C 4Z5
      • Research Site
  • Quebec
    • St Charles Borromee, Quebec, Canada, J6E 2B4
      • Research Site
    • Trois Rivieres, Quebec, Canada, G8T 7A1
      • Research Site
• Germany
  • Bamberg, Germany, 96049
    • Research Site
  • Berlin, Germany, 10787
    • Research Site
  • Frankfurt, Germany, 60596
    • Research Site
  • Frankfurt/Main, Germany, 60389
    • Research Site
  • Hannover, Germany, 30173
    • Research Site
  • Neu-Isenburg, Germany, 63263
    • Research Site
• Hungary
  • Balassagyarmat, Hungary, 2660
    • Research Site
  • Komárom, Hungary, 2900
    • Research Site
  • Miskolc, Hungary, 3529
    • Research Site
  • Pécs, Hungary, 7626
    • Research Site
  • Pécs, Hungary, 7635
    • Research Site
  • Százhalombatta, Hungary, 2440
    • Research Site
• Poland
  • Katowice, Poland, 40-954
    • Research Site
  • Mrągowo, Poland, 11-700
    • Research Site
  • Ostrów Wielkopolski, Poland, 63-400
    • Research Site
  • Pabianice, Poland, 95-200
    • Research Site
  • Poznań, Poland, 60-693
    • Research Site
  • Poznań, Poland, 60-823
    • Research Site
  • Tarnów, Poland, 33-100
    • Research Site
  • Wrocław, Poland, 53-301
    • Research Site
  • Wrocław, Poland, 51-162
    • Research Site
• Slovakia
  • Bratislava, Slovakia, 821 06
    • Research Site
  • Bratislava, Slovakia, 851 01
    • Research Site
  • Humenne, Slovakia, 066 01
    • Research Site
  • Kosice, Slovakia, 040 01
    • Research Site
  • Levice, Slovakia, 934 01
    • Research Site
  • Poprad, Slovakia, 058 01
    • Research Site
  • Presov, Slovakia, 081 81
    • Research Site
  • Vrable, Slovakia, 952 01
    • Research Site
  • Zilina, Slovakia, 010 01
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Research Site
    • Rolling Hills Estates, California, United States, 90274
      • Research Site
  • Florida
    • Clearwater, Florida, United States, 33756
      • Research Site
    • Orlando, Florida, United States, 32825
      • Research Site
  • Illinois
    • Blue Island, Illinois, United States, 60406
      • Research Site
  • New Jersey
    • Skillman, New Jersey, United States, 08558
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Research Site
    • Monroe, North Carolina, United States, 28112
      • Research Site
    • Raleigh, North Carolina, United States, 27607
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Research Site
    • Grove City, Ohio, United States, 43123
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Research Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Research Site
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Research Site
  • Texas
    • El Paso, Texas, United States, 79903
      • Research Site
    • San Antonio, Texas, United States, 78229
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.

• Female and male aged 18 to 75 years, inclusively, at the time of Visit 1.
• Weight of ≥40 kg.
• Evidence of asthma as documented by post-bronchodilator (post-BD) reversibility in FEV1 of ≥ 12% demonstrated at Visit 2.
• Documented use of 1 of the following types of asthma therapy at time of informed consent: Low- to medium-dose ICS (ie, 100 to 500 μg fluticasone dry powder formulation equivalents total daily dose) with or without other controller medications, eg, an LTRA and/or theophylline or Low-dose ICS/LABA fixed combination therapy (eg, the lowest regular maintenance dose approved in the local country will meet this criterion)
• Morning pre-bronchodilator (pre-BD) FEV1 of > 50% to ≤ 90% predicted at Visit 2.

Exclusion Criteria:

• Clinically important pulmonary disease other than asthma (eg, 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 (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
• Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 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
• nfluence the findings of the studies or their interpretations,- Impede the patient's ability to complete the entire duration of study.
• Known history of allergy or reaction to the investigational product formulation.
• History of anaphylaxis to any biologic therapy.- History of Guillain-Barré syndrome.
• A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy.- 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.
• Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening 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.
• Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll.
• A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
• History of cancer:
• Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.
• Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Benralizumab administered subcutaneously every 4 weeks	Biological: Benralizumab; Benralizumab administered subcutaneously every 4 weeks
Experimental: Arm B; Placebo administered subcutaneously every 4 weeks	Biological: Placebo; Placebo administered subcutaneously every 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12	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.	Baseline, Week 4, Week 8 and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12	The changes from baseline of weekly average of morning PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline morning PEF (L/min) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12	The changes from baseline of weekly average of evening PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline evening PEF (L/min) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Change From Baseline in Total Asthma Symptom Score at Week 12	Asthma symptoms were recorded by the patient each morning and evening in the asthma daily diary. Symptoms were recorded using a scale of 0-3, where 0 indicates no asthma symptoms. The daily asthma symptom total score was calculated by taking the sum of the daytime score recorded in the evening and the nighttime score recorded the following morning. The weekly total asthma score was averaged from the daily scores over a 7 day period, with score ranging from 0 to 6, where 0 indicates no asthma symptoms. The changes from baseline of weekly total asthma score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline total asthma score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12	The number of rescue medication inhalations and nebulizer treatments taken were recorded by the patient in the asthma daily diary twice daily. The number of inhalations (puffs) per day was calculated as [number of night inhaler puffs] + 2 x [number of night nebulizer times] + number of day inhaler puffs + 2 x [number of day nebulizer times]. The changes from baseline in weekly total asthma rescue medication use (puffs) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline total asthma rescue medication use (puffs) as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12	Nocturnal awakenings due to asthma symptoms and requiring rescue medication use was recorded by the patient in the asthma daily diary each morning. Proportion of nights with nocturnal awakenings was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data for awakening due to asthma. The outcome variable for proportion of nights with nocturnal awakenings was the change from baseline at Week 12 in weekly proportion of nights with nocturnal awakenings. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline proportion of nights with nocturnal awakenings as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Change From Baseline in Mean ACQ-6 Score at Week 12	The asthma control questionnaire, ACQ-6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions. The changes from baseline of ACQ-6 score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) 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 ACQ-6 score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 4, Week 8 and Week 12
Asthma Exacerbations	An asthma exacerbation was defined as a worsening of asthma that led to use of systemic corticosteroids for at least 3 days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids) or an emergency room or 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) or 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. Number of patients experiencing an event included in the definition of asthma exacerbation was presented.	Up to Week 12
Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12	The asthma quality of life questionnaire for 12 years and older, AQLQ(S)+12, consists of 32 questions; all assessed on a 7-point scale from 7 to 1, where 7 represents no impairment and 1 represents severe impairment. The 4 individual domain scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the means of the responses to the questions in each of the domains. The overall score is calculated as the mean response to all questions. The changes from baseline of AQLQ(S)+12 score are compared between benralizumab 30 mg Q4W and placebo by using the analyse of covariance (ANCOVA) with baseline blood eosinophil count (≥300 cells/μL or <300 cells/μL) and region (Europe or North America) as fixed effects and baseline AQLQ(S)+12 score as a covariate. Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline and Week 12
Serum Concentrations (ng/mL)	Blood samples (processed to serum) for pharmacokinetic assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Serum concentrations of benralizumab were determined using a validated electrochemiluminescent (ECL) immunoassay.	Baseline, Week 12 and Week 20
Peripheral Blood Eosinophil Levels	Peripheral blood eosinophil levels assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Changes at Week 12 (respectively at Week 20) were calculated based on patients with both baseline and Week 12 (respectively Week 20).	Baseline, Week 12 and Week 20

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Gary T. Ferguson, M.D.,P.C., Pulmonary Research Institute of Southeast Michigan

Publications and helpful links

General Publications

• Ferguson GT, FitzGerald JM, Bleecker ER, Laviolette M, Bernstein D, LaForce C, Mansfield L, Barker P, Wu Y, Jison M, Goldman M; BISE Study Investigators. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2017 Jul;5(7):568-576. doi: 10.1016/S2213-2600(17)30190-X. Epub 2017 May 22.

Helpful Links

• CSP redacted

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2015
• Primary Completion (Actual): October 7, 2015
• Study Completion (Actual): October 7, 2015

Study Registration Dates

• First Submitted: December 19, 2014
• First Submitted That Met QC Criteria: December 19, 2014
• First Posted (Estimate): December 23, 2014

Study Record Updates

• Last Update Posted (Actual): August 15, 2017
• Last Update Submitted That Met QC Criteria: August 14, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases,
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: D3250C00032; 2014-004427-40 (EudraCT Number)