Immunological Basis for Benralizumab Activity in Chronic Obstructive Pulmonary Disease (COPD)

NCT05273359 | Unknown Phase 2 FDA Drug

• 1 other identifier: ESR-19-20357
• Study Type: interventional
• Target: 45
• Locations: 0 countries
• Sites: N/A

Brief Summary

The current literature suggests that the mode of action of benralizumab is to deplete eosinophils through a mechanism of antibody-dependent cell-mediated cytotoxicity. This direct cellular cytotoxicity may not explain all of the benralizumab effects. The investigators propose a set of studies to systematically examine the spectrum of effects of this drug on the immune system.

Conditions

Chronic Obstructive Pulmonary Disease (COPD)

Outcome Measures

Primary Outcomes (1)

• Change from baseline of peripheral blood eosinophil and B cell levels

  Peripheral blood eosinophil and B cell number counts

  The duration of a subject's participation in the research study is 6 months for those patients with eosinophil counts ≥220 cells/microliter and 1 day for those patients with eosinophil counts <150 cells/microliter.

Secondary Outcomes (10)

• Change from baseline of peripheral blood T cells

  6 months

• Change from baseline of peripheral blood monocytes

  6 months

• Change from baseline of peripheral blood neutrophils

  6 months

• Change from baseline of peripheral blood NK cells

  6 months

• Change from baseline of peripheral blood dendritic cells

  6 months

Study Arms (3)

Benralizumab Intervention

ACTIVE COMPARATOR

15 subjects (≥220 eosinophils/microliter) will receive benralizumab 100 mg subcutaneous injection every 4 weeks for 4 complete doses.

Drug: Benralizumab

Benralizumab Placebo

PLACEBO COMPARATOR

15 subjects (\>220 eosinophils/microliter) will receive a matching benralizumab placebo subcutaneous injection every 4 weeks for 4 complete doses.

Other: Benralizumab placebo

Comparison (control) group; no intervention

OTHER

15 subjects (\<150 eosinophils/microliter) will not receive any intervention.

Other: Comparison (control) group; no intervention

Interventions

Benralizumab DRUG

15 subjects (≥220 eosinophils/microliter) will receive benralizumab 100 mg subcutaneous injection every 4 weeks for 4 complete doses.

Benralizumab Intervention

Benralizumab placebo OTHER

15 subjects (\>220 eosinophils/microliter) will receive a matching benralizumab placebo subcutaneous injection every 4 weeks for 4 complete doses.

Benralizumab Placebo

Comparison (control) group; no intervention OTHER

15 subjects (\<150 eosinophils/microliter) will not receive any intervention.

Comparison (control) group; no intervention

Eligibility Criteria

• Age: 40 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Current smoker or ex-smoker with a tobacco history of ≥10 pack-years (1 pack year = 20 cigarettes smoked per day for 1 year). (Note: electronic cigarette \[e-cigarette\] use does not contribute to the pack-year count for eligibility).
• History of moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) with a post-bronchodilator forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) \<0.70 and a post-bronchodilator FEV1 ≤ 65% of predicted normal value at screening central spirometry assessment.
• Documented history of 2 or more moderate and/or severe COPD exacerbations in the past year that required treatment with systemic corticosteroids (at least 3 days or a single depot formulation injection) and/or hospitalization within 52 weeks prior to enrollment.
• Exacerbations treated with antibiotics alone are not considered as meeting the criterion unless it is accompanied by treatment with systemic corticosteroids and/or hospitalization.
• Hospitalization is defined as an inpatient admission ≥ 24 hours in the hospital, in an observation area, the emergency department, or other equivalent healthcare facility depending on the country and healthcare system.
• Previous exacerbations should be confirmed to have occurred while patient was on stable triple Inhaled Corticosteroid (ICS)/ Long-Acting Beta2-Agonist (LABA)/ Long-Acting Muscarinic Antagonist (LAMA) background therapy for COPD and not as a result of a step down in therapy, i.e. change from triple to dual therapy.
• Documented use of triple (ICS/LABA/LAMA) background therapy for COPD throughout the year (52 weeks) prior to enrollment.
• ICS in a dose approved for COPD or equivalent or greater than 250 mcg of fluticasone propionate daily.
• Patient could have switched therapies during the previous year and/or stepped down for short periods of time, although the total cumulative duration that the patient was not using triple (ICS/LABA/LAMA) background therapy must not exceed 2 months.
• Patient must be on stable therapy/doses for the last 3 months prior to randomization. (Individual component changes or switches between devices are allowed as long as the patient remains on ICS/LABA/LAMA with an acceptable ICS dose).
• For the 30 patients that will be randomized to treatment, blood eosinophil counts must be ≥ 220 cells/μL at screening (Temple Hospital lab), supported by at least 1 documented historical blood eosinophil count of ≥150 cells/microliter within 52 weeks of enrollment. In the absence of historical data, an additional blood eosinophil count must be obtained by repeating the testing during the run-in period (at least 4 weeks apart) with a result of \>=220 cells/microliter. For the 15 patients in the comparison group, blood eosinophil count \<150 cells/microliter at screening central laboratory testing. In the absence of historical data, an additional blood eosinophil count must be obtained by repeating the testing during the run-in period (at least 4 weeks apart) with a result of \<150 cells/microliter.
• COPD assessment test (CAT) total score ≥ 15 at Visit 1. Ability to read and write English.
• Reproduction Negative pregnancy test (serum) for female patients of childbearing potential at Visit 1 (enrollment).
• Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control (confirmed by the investigator) from enrollment throughout the study duration and within 12 weeks after last dose of IP. Highly effective forms of birth control include:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation- oral, intravaginal, or transdermal

You may not qualify if:

• Clinically important pulmonary disease other than COPD (e.g. active lung infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia).
• Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) or other accepted guidelines, prior history of asthma, or asthma-COPD overlap according to GINA/Global Initiative for Obstructive Lung Disease (GOLD). Childhood history of asthma is allowed and defined as asthma diagnosed and resolved (i.e. not requiring use of any maintenance or rescue medication) before the age of 18.
• Radiological findings suggestive of a respiratory disease other than COPD that is contributing to the patient's respiratory symptoms. Radiological findings of a solitary pulmonary nodule without appropriate follow up and demonstration of stability as per standard of care or findings suggestive of acute infection.
• Another diagnosed pulmonary or systemic disease that is associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis, 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/or could:
• Affect the safety of the patient throughout the study
• Influence the findings of the study or their interpretation
• Impede the patient's ability to complete the entire duration of the study
• Signs and/or symptoms of cor pulmonale and/or right ventricular failure.
• Patients receiving long-term oxygen treatment \>4.0 liters/minute (L/min). While breathing supplemental oxygen, patients should demonstrate an oxyhemoglobin saturation ≥ 89%. In order to be admitted to the study, patients on long-term oxygen therapy have to be ambulatory and be able to attend clinic visits.
• Use, or need for chronic use, of any non-invasive positive pressure ventilation device (NIPPV). Note: Patients using continuous positive airway pressure (CPAP) for Sleep Apnea Syndrome are allowed in the study.
• History of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2.
• Active liver disease. Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen or hepatitis C antibody), or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease is defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 3 times the upper limit of normal (ULN), confirmed by repeated testing during the run-in period. Transient increase of AST/ALT level that resolves by the time of randomization is acceptable if, in the investigator's opinion, the patient does not have an active liver disease and meets other eligibility criteria.
• 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.

Sponsors & Collaborators

• Temple University: lead
• AstraZeneca: collaborator

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

benralizumab; Population Groups

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Demography; Population Characteristics

Study Officials

• Thomas Rogers, PhD

  Temple University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Thomas Rogers, PhD

CONTACT

215-707-3215; thomas.rogers@temple.edu

Lauren Miller, BS/CRA

CONTACT

215-707-4821; lauren.e.miller@temple.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Placebo group: 15 subjects (\>220 eosinophils/microliter) will receive a matching benralizumab placebo subcutaneous injection every 4 weeks for 4 complete doses.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A pilot double-blind randomized and placebo-controlled trial; participants will be blinded to the drug group; investigational pharmacist will be unblinded.

Study Record Dates

• First Submitted: January 12, 2022
• First Posted: March 10, 2022
• Study Start: April 1, 2023
• Primary Completion: June 1, 2024
• Study Completion: January 1, 2025
• Last Updated: April 7, 2023

Record last verified: 2023-04