Acute Exacerbations Treated With BenRAlizumab (The ABRA Study)

NCT04098718 | Unknown Phase 2 DMC

• 2 other identifiers: 2491962018-004401-79
• Study Type: interventional
• Target: 158
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Asthma; COPD

Keywords

Exacerbations; Interleukin 5; Prednisolone; Randomised Clinical Trial

Outcome Measures

Primary Outcomes (4)

• Change from baseline in respiratory visual analogue scale symptom scores with Benralizumab treatment with and without prednisolone

  Visual analogue scale (VAS) symptom score. 0-100 mm. Patient marks how well they feel. Result reported in millimetres. A higher score reflects worse symptoms. 5 subscales of 0-100mm will be used. The 5 subscales will assess breathlessness, cough, wheeze, sputum volume and sputum production. Subscales will be summed and total score for each day will be analysed.

  Day 0 to 28

• Rate of treatment non response with Benralizumab treatment with and without prednisolone

  Rate of treatment non response will be defined as as a composite end-point of i) worsening of symptoms which require further treatment or hospitalisation requiring the need of systemic corticosteroids and ii) death from any cause within 90 days of randomisation.

  Day 7

• Rate of treatment non response with Benralizumab treatment with and without prednisolone

  Rate of treatment non response will be defined as as a composite end-point of i) worsening of symptoms which require further treatment or hospitalisation requiring the need of systemic corticosteroids and ii) death from any cause within 90 days of randomisation.

  Day 28

• Rate of treatment non response with Benralizumab treatment with and without prednisolone

  Rate of treatment non response will be defined as as a composite end-point of i) worsening of symptoms which require further treatment or hospitalisation requiring the need of systemic corticosteroids and ii) death from any cause within 90 days of randomisation.

  Day 90

Secondary Outcomes (18)

• Evaluate the effect of Benralizumab on time to next exacerbation

  Day 28, 90 and 360

• Evaluate the effect of Benralizumab on quality of life questionnaire

  Day 0, 7, 14, 28 and 90

• Evaluate the effect of Benralizumab on breathlessness

  Day 0, 7, 14, 28 and 90

• Evaluate the effect of Benralizumab on COPD Assessment Test (CAT)

  Day 0, 7, 14, 28 and 90

• Evaluate the effect of Benralizumab on asthma control questionnaire (ACQ-6)

  Day 0, 7, 14, 28 and 90

Other Outcomes (2)

• Sputum eosinophil count

  Day 0, 7, 14, 28 and 90.

• Sputum neutrophil count

  Day 0, 7, 14, 28 and 90.

Study Arms (4)

PO open label prednisolone (in low blood eosinophils)

OTHER

Standard care Prednisolone 30mg given daily for 5 days to treat an exacerbation.

Drug: Prednisolone

Benralizumab SC + PO placebo

EXPERIMENTAL

Benralizumab as a single 100mg sub cut injection and oral placebo tablet daily for 5 days

Drug: Benralizumab

Benralizumab SC + PO prednisolone

EXPERIMENTAL

Benralizumab as a single 100mg sub cut injection and oral prednisolone 30mg daily for 5 days

Drug: Benralizumab; Drug: Prednisolone

Placebo SC + PO prednisolone

ACTIVE COMPARATOR

Placebo sub cut injection and oral prednisolone 30mg daily for 5 days.

Drug: Prednisolone

Interventions

Benralizumab DRUG

100mg sub cut once only

Also known as: Fasenra

Benralizumab SC + PO placebo; Benralizumab SC + PO prednisolone

Prednisolone DRUG

30mg tablet daily for 5 days

Benralizumab SC + PO prednisolone; PO open label prednisolone (in low blood eosinophils); Placebo SC + PO prednisolone

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Oxford University Hospitals NHS Foundation Trust

Oxford, Oxfordshire, OX3 9DU, United Kingdom

Location

Related Publications (1)

• Ramakrishnan S, Russell REK, Mahmood HR, Krassowska K, Melhorn J, Mwasuku C, Pavord ID, Bermejo-Sanchez L, Howell I, Mahdi M, Peterson S, Bengtsson T, Bafadhel M. Treating eosinophilic exacerbations of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, active placebo-controlled randomised trial. Lancet Respir Med. 2025 Jan;13(1):59-68. doi: 10.1016/S2213-2600(24)00299-6. Epub 2024 Nov 29.

  PMID: 39615502 DERIVED

MeSH Terms

Conditions

Asthma; Pulmonary Disease, Chronic Obstructive

Interventions

benralizumab; Prednisolone

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Mona Bafadhel, PhD, MBChB

  Nuffield Department of Medicine, University of Oxford, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2019
• First Posted: September 23, 2019
• Study Start: March 29, 2021
• Primary Completion: February 19, 2024
• Study Completion: November 19, 2024
• Last Updated: January 23, 2024

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)