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

Primary Purpose

Severe Prednisone Dependent Eosinophilic Asthma

Status

Completed

Phase

Phase 3

Locations

Canada

Study Type

Interventional

Intervention

Benralizumab

Placebo

About this trial

This is an interventional treatment trial for Severe Prednisone Dependent Eosinophilic Asthma focused on measuring Eosinophils, asthma, inflammation, prednisone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Currently receiving another monoclonal antibody
Intolerance, hypersensitivity, insensitivity or neutralizing antibody to Mepolizumab and/or Reslizumab
Malignancy within the last 5 years
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.
Current pregnancy or lactation
Current smoker or ex-smoker with a smoking history greater than 20 pack years.

Sites / Locations

Firestone Institute for Respiratory Health, Research - St. Joseph's Healthcare

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Benralizumab

Placebo

Arm Description

Benralizumab 30mg in 1mL subcutaneously

Matched placebo (1mL) to active Benralizumab subcutaneously

Outcomes

Primary Outcome Measures

Sputum eosinophil percentage

Change in Percentage of sputum eosinophils (%)

Secondary Outcome Measures

Blood eosinophils

Blood eosinophil level (x10^9/L)

Forced Expired Volume in 1 second (FEV1)(pre and post bronchodilator)

FEV1 in litres both pre and post bronchodilator

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).

Fraction of exhaled nitric oxide (FeNO)

Exhaled nitric oxide measurement in ppb

Number of Exacerbations (defined as: ER visit/hospitalization requiring prednisone burst)

Worsening requiring increase in oral steroids/prednisone (30mg x 5 days)

Sputum and blood ILC2 biology

Measurement of ILC2 biological cells in both blood and sputum

Sputum autoimmune responses

Measurement of autoimmune markers in sputum: anti-eosinophil peroxidase (EPX) and anti-nuclear antibodies (ANA) - (See last reference PubMed ID: 28751233)

Full Information

NCT ID

NCT03470311

First Posted

March 1, 2018

Last Updated

January 18, 2023

Sponsor

McMaster University

Collaborators

St. Joseph's Healthcare Hamilton, AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT03470311

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

April 26, 2018 (Actual)

Primary Completion Date

June 14, 2022 (Actual)

Study Completion Date

November 30, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

McMaster University

Collaborators

St. Joseph's Healthcare Hamilton, AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Prednisone Dependent Eosinophilic Asthma

Keywords

Eosinophils, asthma, inflammation, prednisone

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Non-Randomized

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Benralizumab

Arm Type

Active Comparator

Arm Description

Benralizumab 30mg in 1mL subcutaneously

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Matched placebo (1mL) to active Benralizumab subcutaneously

Intervention Type

Biological

Intervention Name(s)

Benralizumab

Other Intervention Name(s)

MEDI-563

Intervention Description

30mg in 1mL pre-filled syringe

Intervention Type

Biological

Intervention Name(s)

Placebo

Intervention Description

Matched placebo (1mL) in pre-filled syringe

Primary Outcome Measure Information:

Title

Sputum eosinophil percentage

Description

Change in Percentage of sputum eosinophils (%)

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Secondary Outcome Measure Information:

Title

Blood eosinophils

Description

Blood eosinophil level (x10^9/L)

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Title

Forced Expired Volume in 1 second (FEV1)(pre and post bronchodilator)

Description

FEV1 in litres both pre and post bronchodilator

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Title

ACQ-5 (Asthma Control Questionnaire)

Description

Asthma Control Questionnaire score (mean answer of 5 questions on a 7-point scale (0=no impairment, 6= maximum impairment).

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Title

Fraction of exhaled nitric oxide (FeNO)

Description

Exhaled nitric oxide measurement in ppb

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Title

Number of Exacerbations (defined as: ER visit/hospitalization requiring prednisone burst)

Description

Worsening requiring increase in oral steroids/prednisone (30mg x 5 days)

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Title

Sputum and blood ILC2 biology

Description

Measurement of ILC2 biological cells in both blood and sputum

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

Title

Sputum autoimmune responses

Description

Measurement of autoimmune markers in sputum: anti-eosinophil peroxidase (EPX) and anti-nuclear antibodies (ANA) - (See last reference PubMed ID: 28751233)

Time Frame

Visit 1 (Week 2) and Visit 10 (Week 38)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Informed consent Prior to the beginning of the study, patients must be willing and fully capable to provide written informed consent. Diagnosed prednisone-dependent eosinophilic asthma Previous treatment with 100 mg mepolizumab administered subcutaneously Q4W or reslizumab 3 mg/kg IV Q4W for at least 6 months Sputum eosinophils >3% ACQ ≥1.5 Age >18 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. 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: Currently receiving another monoclonal antibody Intolerance, hypersensitivity, insensitivity or neutralizing antibody to Mepolizumab and/or Reslizumab Malignancy within the last 5 years 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. Current pregnancy or lactation Current smoker or ex-smoker with a smoking history greater than 20 pack years.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Parameswaran Nair, MD, PhD

Organizational Affiliation

McMaster University and St. Joseph's Healthcare Hamilton

Official's Role

Principal Investigator

Facility Information:

Facility Name

Firestone Institute for Respiratory Health, Research - St. Joseph's Healthcare

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8N 4A6

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

28070196

Citation

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.

Results Reference

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PubMed Identifier

26194544

Citation

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.

Results Reference

background

PubMed Identifier

26685004

Citation

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.

Results Reference

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PubMed Identifier

20513525

Citation

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.

Results Reference

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PubMed Identifier

28915080

Citation

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.

Results Reference

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PubMed Identifier

28530840

Citation

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.

Results Reference

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PubMed Identifier

28751233

Citation

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.

Results Reference

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

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