Benralizumab in Patients With Inadequate Response to Anti-IL5 Monoclonal Antibody Therapies

In severe prednisone-dependent eosinophilic asthma, Benralizumab would suppress airway eosinophilia that is not suppressed by either Mepolizumab or Reslizumab and this would be associated with greater asthma control

Study Overview

• Status: Completed
• Conditions: Severe Prednisone Dependent Eosinophilic Asthma
• Intervention / Treatment: Biological: Benralizumab; Biological: Placebo

Detailed Description

Benralizumab thus targets 'eosinophil biology', by inhibiting the interleukin (IL-5) receptor signalling, and inducing apoptosis in cells with an IL-5receptor. Hence, for patients who remain 'uncontrolled' on anti-IL-5 therapy (with detectable eosinophil activity and IL5-Rα+ cells in the airways), the investigators believe would benefit from a strategy that not only reduces eosinophil proliferation/recruitment/maturation, but also depletes cells capable of inducing downstream IL-5 signalling.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Firestone Institute for Respiratory Health, Research - St. Joseph's Healthcare

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Informed consent Prior to the beginning of the study, patients must be willing and fully capable to provide written informed consent.
2. Diagnosed prednisone-dependent eosinophilic asthma
3. Previous treatment with 100 mg mepolizumab administered subcutaneously Q4W or reslizumab 3 mg/kg IV Q4W for at least 6 months
4. Sputum eosinophils >3%
5. ACQ ≥1.5
6. Age >18

7. Male or eligible female subjects:

   To be eligible for entry into the study, females of childbearing potential (premenopausal women who are not permanently sterilized by means of hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) must commit to consistent and correct use of a highly effective method of birth control (true sexual abstinence, a vasectomized sexual partner, Implanon, female tubal occlusion, Intrauterine device (IUD), Depo provera injections, oral contraceptive pills or Nuvaring) for the duration of the trial and for 3 months after the last study drug administration. A serum pregnancy test is required of all females at the initial Baseline Visit (Visit 1). In addition, a urine pregnancy test will be performed for all females prior to enrollment, during each scheduled study visit prior to the injection of investigational product, and during the Follow-up Visit.

8. Male subjects who are sexually active must agree to use a double barrier method of contraception (condom with spermicide) from the first dose of study drug and for 3 months after the last dose of study drug.

Exclusion Criteria:

1. Currently receiving another monoclonal antibody
2. Intolerance, hypersensitivity, insensitivity or neutralizing antibody to Mepolizumab and/or Reslizumab
3. Malignancy within the last 5 years
4. Any co-morbidity that the investigator believes is a contraindication. This includes but is not limited to any respiratory, cardiovascular, gastrointestinal, hematological, neurological, immunological, musculoskeletal, renal, infectious, neoplastic or inflammatory condition that may place the safety of the subject at risk during the duration of the study, influence the results of the study or their interpretation, or prevent the patient from completing the entire duration of the study.
5. Current pregnancy or lactation
6. Current smoker or ex-smoker with a smoking history greater than 20 pack years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Benralizumab; Benralizumab 30mg in 1mL subcutaneously	Biological: Benralizumab; 30mg in 1mL pre-filled syringe; Other Names: MEDI-563
Placebo Comparator: Placebo; Matched placebo (1mL) to active Benralizumab subcutaneously	Biological: Placebo; Matched placebo (1mL) in pre-filled syringe

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sputum eosinophil percentage	Change in Percentage of sputum eosinophils (%)	Visit 1 (Week 2) and Visit 10 (Week 38)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood eosinophils	Blood eosinophil level (x10^9/L)	Visit 1 (Week 2) and Visit 10 (Week 38)
Forced Expired Volume in 1 second (FEV1)(pre and post bronchodilator)	FEV1 in litres both pre and post bronchodilator	Visit 1 (Week 2) and Visit 10 (Week 38)
ACQ-5 (Asthma Control Questionnaire)	Asthma Control Questionnaire score (mean answer of 5 questions on a 7-point scale (0=no impairment, 6= maximum impairment).	Visit 1 (Week 2) and Visit 10 (Week 38)
Fraction of exhaled nitric oxide (FeNO)	Exhaled nitric oxide measurement in ppb	Visit 1 (Week 2) and Visit 10 (Week 38)
Number of Exacerbations (defined as: ER visit/hospitalization requiring prednisone burst)	Worsening requiring increase in oral steroids/prednisone (30mg x 5 days)	Visit 1 (Week 2) and Visit 10 (Week 38)
Sputum and blood ILC2 biology	Measurement of ILC2 biological cells in both blood and sputum	Visit 1 (Week 2) and Visit 10 (Week 38)
Sputum autoimmune responses	Measurement of autoimmune markers in sputum: anti-eosinophil peroxidase (EPX) and anti-nuclear antibodies (ANA) - (See last reference PubMed ID: 28751233)	Visit 1 (Week 2) and Visit 10 (Week 38)

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: St. Joseph's Healthcare Hamilton; AstraZeneca
• Investigators: Principal Investigator: Parameswaran Nair, MD, PhD, McMaster University and St. Joseph's Healthcare Hamilton

Publications and helpful links

General Publications

• Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O'Byrne PM, Gauvreau GM, Boulet LP, Lemiere C, Martin J, Nair P, Sehmi R. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016 Jan;137(1):75-86.e8. doi: 10.1016/j.jaci.2015.05.037. Epub 2015 Jul 17.
• Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, Reed JL, Woods R, Dall'acqua WW, Stephens GL, Erjefalt JS, Bjermer L, Humbles AA, Gossage D, Wu H, Kiener PA, Spitalny GL, Mackay CR, Molfino NA, Coyle AJ. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010 Jun;125(6):1344-1353.e2. doi: 10.1016/j.jaci.2010.04.004.
• Mukherjee M, Lim HF, Thomas S, Miller D, Kjarsgaard M, Tan B, Sehmi R, Khalidi N, Nair P. Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy. Allergy Asthma Clin Immunol. 2017 Jan 6;13:2. doi: 10.1186/s13223-016-0174-5. eCollection 2017.
• Mukherjee M, Bulir DC, Radford K, Kjarsgaard M, Huang CM, Jacobsen EA, Ochkur SI, Catuneanu A, Lamothe-Kipnes H, Mahony J, Lee JJ, Lacy P, Nair PK. Sputum autoantibodies in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2018 Apr;141(4):1269-1279. doi: 10.1016/j.jaci.2017.06.033. Epub 2017 Jul 24.
• Sehmi R, Smith SG, Kjarsgaard M, Radford K, Boulet LP, Lemiere C, Prazma CM, Ortega H, Martin JG, Nair P. Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy. 2016 Jun;46(6):793-802. doi: 10.1111/cea.12695.
• Mukherjee M, Aleman Paramo F, Kjarsgaard M, Salter B, Nair G, LaVigne N, Radford K, Sehmi R, Nair P. Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab. Am J Respir Crit Care Med. 2018 Jan 1;197(1):38-46. doi: 10.1164/rccm.201707-1323OC.
• Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M; ZONDA Trial Investigators. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017 Jun 22;376(25):2448-2458. doi: 10.1056/NEJMoa1703501. Epub 2017 May 22.

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2018
• Primary Completion (Actual): June 14, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: March 1, 2018
• First Submitted That Met QC Criteria: March 16, 2018
• First Posted (Actual): March 19, 2018

Study Record Updates

• Last Update Posted (Actual): January 20, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: asthma; inflammation; Eosinophils; prednisone
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Pulmonary Eosinophilia; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: 17-12992

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes