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

Exclusion Criteria

• •1. 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).
• •2. 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.
• •3. 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.
• •4. 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).
• •5. 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
• •6. Signs and/or symptoms of cor pulmonale and/or right ventricular failure.
• •7. 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.
• •8. 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.
• •9. History of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2.
• •10. 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.
• •11. 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.
• •12. 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.
• •13. History of alcohol or drug abuse within the past year, which may compromise the study data interpretation as judged by investigator.
• •14. Malignancy, current or within the past 5 years, except for adequately treated non-invasive basal cell and squamous cell carcinoma of the skin or cervical carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1. Suspected malignancy or undefined neoplasms.
• •15. Patients who, in the opinion of the investigator or qualified designee, have evidence of active Tuberculosis (TB). Patients with a recent (within 2 years) first-time or newly positive purified protein derivative (PPD) test or Quantiferon test need to complete an appropriate course of treatment before being considered for enrollment. Evaluation will be according to the local standard of care and may consist of history and physical examinations, chest X-ray, and/or TB test as determined by local guidelines.
• •16. Patients participating in, or scheduled for, an intensive (active) COPD rehabilitation program (patients who are in the maintenance phase of a rehabilitation program are eligible to take part).
• •17. Patients with a history of surgical or endoscopic (e.g. valves) lung volume reduction within the 6 months prior to enrollment. Patients with a history of partial or total lung resection (single lobe or segmentectomy is acceptable).
• •18. Scheduled major surgical procedure during the course of the study. Minor elective procedures are allowed.
• •19. History of anaphylaxis to benralizumab or any other biologic therapy. Prior/concomitant therapy
• •20. Receipt of blood products or immunoglobulins within 30 days prior to randomization.
• •21. Receipt of any marketed or investigational biologic product for any reason within 4 months or 5 half-lives prior to randomization, whichever is longer.
• •22. Receipt of live attenuated vaccines 30 days prior to randomization.
• •23. Chronic use of immunosuppressive medication (including but not limited to: methotrexate, troleandomycin, cyclosporine, azathioprine, rectal corticosteroids, and systemic corticosteroids) or expected need for chronic use during the study.
• •24. Chronic use of antibiotics if duration of treatment is \<9 months prior to randomization (Visit 3). Chronic macrolide or other antibiotic therapy is allowed provided the patient has been on a stable dose/regimen for ≥ 9 months prior to randomization and has had ≥ 2 COPD exacerbations in the past year while on stable therapy. If the patient was previously on chronic antibiotic but is no longer taking it, the patient cannot be randomized until 6 weeks after the last dose.
• •Prior/concurrent clinical study experience
• •25. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to enrollment, whichever is longer.
• •26. Receipt of benralizumab within 12 months prior to enrollment.
• •27. Known history of allergy or reaction to any component of the intraperitoneal (IP) formulation.
• •Other exclusions
• •28. Donation of blood, plasma, or platelets within the past 90 days prior to enrollment.
• •29. Pregnant, breastfeeding, or lactating women.
• •30. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• •31. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
• •Lifestyle restrictions Women of childbearing potential must use highly effective contraceptive methods from enrollment throughout the study and for at least 12 weeks (≥ 5 half-lives) after last administration of the IP, as stated in inclusion criterion 11.
• •Patients must abstain from donating blood, plasma, or platelets from the time of informed consent and for 12 weeks (≥ 5 half-lives) after last dose of IP.
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