Acute Exacerbations Treated With BenRAlizumab (The ABRA Study)

• Status: Recruiting
• Trial end date: 2024-11-19
• Target enrollment: 0
• Participant gender: All

Summary

Exacerbations of asthma and COPD are an important cause of hospital admission and the main cause of annual winter bed shortages. Despite current guideline treatment with prednisolone, 40% of patients require further treatment, 15% are readmitted and, of those hospitalised, 10% die within 3 months, all by definition treatment failures. The investigators have shown that there are two dominant patterns of airway inflammation in patients presenting with an acute episode: infection associated neutrophilic airway inflammation; and non-infection related eosinophilic airway inflammation. These patterns cannot be distinguished reliably by clinical categories (i.e. asthma or COPD) or a standard clinical assessment but are identified by the peripheral blood eosinophil count. These findings raise important questions that targeted treatment based on the blood eosinophil count would result in more efficient and effective management. However, even in patients with the right pattern of airway inflammation the beneficial effects of prednisolone have to be offset against a high potential for harm, with an estimated the number needed to harm as 5 for every 10 patients treated.

Benralizumab is an interleukin-5 receptor-α monoclonal antibody, injected subcutaneously, which rapidly reduces peripheral blood eosinophils for 90 days with a satisfactory safety profile. Benralizumab treatment at stable state has been shown to increase post-bronchodilator FEV1 and reduce the rates of severe exacerbations in patients with severe eosinophilic asthma and improve lung function in patients with eosinophilic COPD. Benralizumab is an attractive candidate for the acute treatment of eosinophilic exacerbations, without the side-effects of prednisolone. The investigators propose to test the hypothesis that, for participants who have a raised eosinophil count at exacerbation, a single injection of Benralizumab alone or in combination with prednisolone will improve clinical outcomes compared to prednisolone alone. The investigators will also study the effect of prednisolone on symptoms, lung function and quality of life, in an exacerbation when the eosinophil count is not raised.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Oxford
• Treatments: Benralizumab; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate

Criteria

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.

• A 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 >200mL; 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)

• A 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) ≥25ppb; and/or peripheral blood eosinophil count ≥250 cells/uL; and/or sputum eosinophils ≥3% of the total cell count.

• Female participants of child bearing potential unless surgically sterile and/or at least 2 years post-menopause must agree to use effective measures of birth control (including sexual abstinence, vasectomised sexual partner, female sterilization by tubal ligation, any effective intra-uterine 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 child-bearing 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:

• A known allergy to IMP (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 patient at risk or negatively affect the outcome of the study.

• A confirmed (radiological) diagnosis of pneumonia 8 weeks prior to Exacerbation Visit, based on the last date of antibiotic treatment or hospitalisation date.

• An alanine aminotransferase (ALT) or aspartate aminotransferase (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 (>10mg per day), hydrocortisone, azathioprine, or weekly methotrexate).

• Established use (greater than 3 months) of long-term oxygen therapy (i.e. receiving oxygen therapy for >15hours per day).

• The presence of hypercapnic ventilatory failure and/or the requirement of nocturnal non-invasive ventilation therapy.

• 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, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant'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.

• A 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.

• A history of drug or alcohol abuse in the previous 12 months, which in the opinion of the investigator, may compromise study data interpretation.

• A current (or within 5 years) history of solid organ or haematological malignancy.

• Female participant who is pregnant, lactating or breast-feeding.

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, may put the subject at risk because of their participation, or may influence the results of the study, or the ability to complete the duration of the study.

• An alternative cause for the increase in symptoms that are unrelated to an exacerbation such as i) suspicion or clinical evidence of pneumonia; ii) high probability and suspicion of pulmonary embolism; iii) suspicion or clinical evidence of a pneumothorax; iv) 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.

• Participants 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.