NCT04098718.

Study name	Acute Exacerbations Treated With BenRAlizumab (The ABRA Study) (ABRA)
Methods	Randomised, double‐blinded, randomised, placebo‐controlled, phase 2 study Study location: UK
Participants	Patients with a diagnosis of COPD or asthma (or both COPD and asthma) Estimated enrolment: 158 participants Inclusion criteria: Participant is willing and able to give written informed consent for participation in the trial. Male or female, aged ≥ 18 years or above. Diagnosis made in primary or secondary care of: COPD with current or historic evidence of spirometry confirming airflow obstruction (FEV₁/FVC ratio < 0.7) and a smoking pack‐year history of ≥ 10. Or, asthma with current or historic evidence of spirometry confirming variable airflow limitation (any one of airflow reversibility FEV₁ change > 200 mL; and/or FEV₁% change of 12%; and/or Pc20 ≤ 8; and/or peak flow diurnal variation; and/or variable FEV₁/FVC ratio) and a smoking pack‐year history < 10. Or, COPD and asthma (as defined above). History of at least 1 exacerbation requiring oral/intravenous corticosteroids in the previous 12 months. Prior (within 2 years) evidence of eosinophilic inflammation; including an elevated exhaled nitric oxide (FENO) ≥ 25 ppb; and/or peripheral blood eosinophil count ≥ 250 cells/μL; and/or sputum eosinophils ≥ 3% of the total cell count. Female participants of childbearing potential unless surgically sterile and/or at least 2 years postmenopause must agree to use effective measures of birth control (including sexual abstinence, vasectomised sexual partner, female sterilisation by tubal ligation, any effective intrauterine device, Depo‐Provera injections, oral or transdermal contraceptive) from study recruitment to 16 weeks of the last dose of IMP. Male participants who are sexually active with partner(s) of childbearing potential must use an adequate method of contraception (condom) or be surgically sterile from the first dose of IMP until 16 weeks after this dose. In the Investigator's opinion, is able and willing to comply with all trial requirements Exclusion criteria: Known allergy to IP (benralizumab or prednisolone). Clinically important and significant pulmonary disease other than asthma or COPD (e.g. lung cancer, pulmonary fibrosis, bronchiectasis as primary respiratory problem, active pulmonary tuberculosis, cystic fibrosis, obesity hypoventilation syndrome). Another clinically significant pulmonary or systemic disease associated with an elevated peripheral blood eosinophil count (e.g. allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangitis, hyper‐eosinophilic syndrome, and helminth infection). Unstable ischaemic heart disease, arrhythmia, cardiomyopathy, heart failure, significant renal or hepatic impairment, uncontrolled hypertension, or ECG abnormality as defined by the investigator, which in the judgement of the investigator may put the individual at risk or negatively affect the outcome of the study. Confirmed (radiological) diagnosis of pneumonia 8 weeks prior to Exacerbation Visit, based on the last date of antibiotic treatment or hospitalisation date. An ALT or AST level that is persistently ≥ 1.5 times the upper limit of normal. Regular use of immunosuppressive medication (including but not limited to maintenance daily prednisolone (> 10 mg per day), hydrocortisone, azathioprine, or weekly methotrexate). Established use (greater than 3 months) of long‐term oxygen therapy (i.e. receiving oxygen therapy for > 15 hours per day). The presence of hypercapnic ventilatory failure or the requirement of nocturnal non‐invasive ventilation therapy (or both). Scheduled elective surgery or other procedures requiring general anaesthesia during the trial. Participant with life expectancy of less than 6 months. Any other unstable significant disease or disorder which, in the opinion of the Investigator, could either put the individual at risk because of participation in the trial, or could influence the result of the trial or the individual's ability to participate in the trial. Receipt of any licenced (e.g. omalizumab, mepolizumab, or benralizumab) or other monoclonal antibody or polyclonal antibody therapy (e.g. gamma globulin) within 6 months. History of known immunodeficiency disorder (including HIV‐1 or HIV‐2). Positive hepatitis B surface antigen, or positive hepatitis C virus antibody serology or a known medical history of hepatitis B or C. History of drug or alcohol abuse in the previous 12 months, which in the opinion of the investigator may compromise study data interpretation. Current (or within 5 years) history of solid organ or haematological malignancy. Female participant who is pregnant, lactating, or breastfeeding. Additional exclusion criteria on day of exacerbation (Visit 2): Fever recorded as > 38 °C measured using the tympanic temperature and/or a suspected pulmonary bacterial infection (chest radiograph demonstrating consolidation). Type 2 respiratory failure necessitating non‐invasive or invasive ventilation. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry or urinalysis, which in the opinion of the investigator, could put the individual at risk because of their participation, or could influence the results of the study or the ability of the individual to complete the duration of the study. An alternative cause for the increase in symptoms that are unrelated to an exacerbation such as: suspicion or clinical evidence of pneumonia; high probability and suspicion of pulmonary embolism; suspicion or clinical evidence of a pneumothorax; primary ischaemic event: ST or non‐ST elevation myocardial infarct and left ventricular failure (i.e. not an exacerbation of asthma and/or COPD). Treatment with oral corticosteroids and/or hospitalisation for an exacerbation of asthma and/or COPD in the previous 4 weeks prior to randomisation. More than 12 hours of oral corticosteroid treatment for a current exacerbation. Pregnancy or a positive urinary βHCG. Donation of blood, plasma, or platelets within 90 days prior to Visit 2. Receipt of blood products within 30 days prior to Visit 2. Individuals who have participated in another research trial involving an investigational product in the past 4 weeks or 5 half‐lives prior to Visit 2. Treatment with allergy immunotherapy, actively or within 90 days prior to Visit 2.
Interventions	4‐arm study: standard care prednisolone 30 mg given daily for 5 days to treat an exacerbation versus benralizumab as a single 100 mg SC injection and oral placebo tablet daily for 5 days versus benralizumab as a single 100 mg SC injection and oral prednisolone 30 mg daily for 5 days versus placebo SC injection and oral prednisolone 30 mg daily for 5 days
Outcomes	Primary outcome measures: Change from baseline in respiratory visual analogue scale symptom scores with benralizumab treatment with and without prednisolone. Time Frame: Day 0 to 28 Rate of treatment non‐response with benralizumab treatment with and without prednisolone. Time Frame: Day 7 Rate of treatment non‐response with benralizumab treatment with and without prednisolone. Time Frame: Day 28 Rate of treatment non‐response with benralizumab treatment with and without prednisolone. Time Frame: Day 90 Secondary outcome measures: Evaluate the effect of benralizumab on time to next exacerbation. Time Frame: Day 28, 90, and 360 Evaluate the effect of benralizumab on quality of life questionnaire. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of benralizumab on breathlessness. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of benralizumab on CAT. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of benralizumab on ACQ‐6. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of benralizumab on AQLQ. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of benralizumab on ACT. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of benralizumab on spirometry. Time Frame: Day 0, 7, 14, 28, and 90 Evaluate the effect of prednisolone on respiratory symptoms. Time Frame: Day 0 and 28 Evaluate the effect of prednisolone on rates of treatment non‐response. Time Frame: Day 7 and 28 Evaluate the effect of prednisolone on time to next exacerbation. Time Frame: Day 28 and 90 Evaluate the effect of prednisolone on quality of life questionnaire. Time Frame: Day 0, 7, 14, and 28 Evaluate the effect of prednisolone on breathlessness. Time Frame: Day 0, 7, 14, and 28 Evaluate the effect of prednisolone on CAT. Time Frame: Day 0, 7, 14, and 28 Evaluate the effect of prednisolone on ACQ‐6. Time Frame: Day 0, 7, 14, and 28 Evaluate the effect of prednisolone on AQLQ. Time Frame: Day 0, 7, 14, and 28 Evaluate the effect of prednisolone on ACT. Time Frame: Day 0, 7, 14, and 28 Evaluate the effect of prednisolone on spirometry. Time Frame: Day 0, 7, 14, and 28 Additional predefined outcome measures: Sputum eosinophil count. Time Frame: Day 0, 7, 14, 28, and 90 Sputum neutrophil count. Time Frame: Day 0, 7, 14, 28, and 90
Starting date	October 2019
Contact information	Mona Bafadhel, PhD, MBChB. Nuffield Department of Medicine, University of Oxford, UK
Notes	Sponsor: University of Oxford