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Acute Exacerbations Treated With BenRAlizumab (The ABRA Study) (ABRA)

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ClinicalTrials.gov Identifier: NCT04098718
Recruitment Status : Not yet recruiting
First Posted : September 23, 2019
Last Update Posted : November 12, 2020
Sponsor:
Information provided by (Responsible Party):
University of Oxford

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.


Condition or disease Intervention/treatment Phase
Asthma COPD Drug: Benralizumab Drug: Prednisolone Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 158 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The Use of Benralizumab, an Interleukin-5 Receptor-α Monoclonal Antibody as Treatment of Acute Exacerbations of Airways Disease
Estimated Study Start Date : November 19, 2020
Estimated Primary Completion Date : February 19, 2024
Estimated Study Completion Date : November 19, 2024


Arm Intervention/treatment
PO open label prednisolone (in low blood eosinophils)
Standard care Prednisolone 30mg given daily for 5 days to treat an exacerbation.
Drug: Prednisolone
30mg tablet daily for 5 days

Experimental: Benralizumab SC + PO placebo
Benralizumab as a single 100mg sub cut injection and oral placebo tablet daily for 5 days
Drug: Benralizumab
100mg sub cut once only
Other Name: Fasenra

Experimental: Benralizumab SC + PO prednisolone
Benralizumab as a single 100mg sub cut injection and oral prednisolone 30mg daily for 5 days
Drug: Benralizumab
100mg sub cut once only
Other Name: Fasenra

Drug: Prednisolone
30mg tablet daily for 5 days

Active Comparator: Placebo SC + PO prednisolone
Placebo sub cut injection and oral prednisolone 30mg daily for 5 days.
Drug: Prednisolone
30mg tablet daily for 5 days




Primary Outcome Measures :
  1. Change from baseline in respiratory visual analogue scale symptom scores with Benralizumab treatment with and without prednisolone [ Time Frame: Day 0 to 28 ]
    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.

  2. Rate of treatment non response with Benralizumab treatment with and without prednisolone [ Time Frame: Day 7 ]
    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.

  3. Rate of treatment non response with Benralizumab treatment with and without prednisolone [ Time Frame: Day 28 ]
    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.

  4. Rate of treatment non response with Benralizumab treatment with and without prednisolone [ Time Frame: Day 90 ]
    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.


Secondary Outcome Measures :
  1. Evaluate the effect of Benralizumab on time to next exacerbation [ Time Frame: Day 28, 90 and 360 ]
    Time to next exacerbation

  2. Evaluate the effect of Benralizumab on quality of life questionnaire [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    European Quality of Life-5 dimension-3 level (EQ 5D 3L) questionnaire. A higher number on each of the 5 dimension reflects worse quality of life

  3. Evaluate the effect of Benralizumab on breathlessness [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    Medical Research Council (MRC) breathlessness score. A higher score reflects worse breathlessness

  4. Evaluate the effect of Benralizumab on COPD Assessment Test (CAT) [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    CAT questionnaire. A higher score (max score of 40) reflects worse COPD symptoms

  5. Evaluate the effect of Benralizumab on asthma control questionnaire (ACQ-6) [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    ACQ-6. Result reported as average of 6 questions. Result range 0-6. Higher result reflects worse asthma control

  6. Evaluate the effect of Benralizumab on asthma quality of life questionnaire (AQLQ) [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    AQLQ. 32 item questionnaire with each item rated 0 to 7 on a Likert Scale. A higher score reflects better asthma related quality of life.

  7. Evaluate the effect of Benralizumab on asthma control test (ACT) questionnaire [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    ACT questionnaire. 5 point questionnaire. Likert scale of 1-5 for each item. Score range 5-25. Higher score reflects better asthma control

  8. Evaluate the effect of Benralizumab on spirometry [ Time Frame: Day 0, 7, 14, 28 and 90 ]
    Forced expiratory volume in 1 second (in litres). Greater volume reflects better lung function.

  9. Evaluate the effect of prednisolone on respiratory symptoms [ Time Frame: Day 0 and 28 ]
    Visual analogue scale (VAS) symptom score. 0-100 mm. Patient marks how well they feel. Result reported in millimetres. A higher score reports fewer symptoms.

  10. Evaluate the effect of prednisolone on rates of treatment non response [ Time Frame: Day 7 and 28 ]
    Rates of treatment non response

  11. Evaluate the effect of prednisolone on time to next exacerbation [ Time Frame: Day 28 and 90 ]
    Time to next exacerbation

  12. Evaluate the effect of prednisolone on on quality of life questionnaire [ Time Frame: Day 0, 7, 14 and 28 ]
    European Quality of Life-5 dimension-3 level (EQ 5D 3L) questionnaire. A higher number on each of the 5 dimension reflects worse quality of life

  13. Evaluate the effect of prednisolone on breathlessness [ Time Frame: Day 0, 7, 14 and 28 ]
    Medical Research Council (MRC) breathlessness score. A higher score reflects worse breathlessness

  14. Evaluate the effect of prednisolone on COPD Assessment Test [ Time Frame: Day 0, 7, 14 and 28 ]
    CAT questionnaire. A higher score (max score of 40) reflects worse COPD symptoms

  15. Evaluate the effect of prednisolone on asthma control questionnaire (ACQ-6) [ Time Frame: Day 0, 7, 14 and 28 ]
    ACQ-6. Result reported as average of 6 questions. Result range 0-6. Higher result reflects worse asthma control

  16. Evaluate the effect of prednisolone on asthma quality of life questionnaire (AQLQ) [ Time Frame: Day 0, 7, 14 and 28 ]
    AQLQ. 32 item questionnaire with each item rated 0 to 7 on a Likert Scale. A higher score reflects better asthma related quality of life.

  17. Evaluate the effect of prednisolone on Asthma control test (ACT) questionnaire [ Time Frame: Day 0, 7, 14 and 28 ]
    ACT questionnaire. 5 point questionnaire. Likert scale of 1-5 for each item. Score range 5-25. Higher score reflects better asthma control

  18. Evaluate the effect of prednisolone on spirometry [ Time Frame: Day 0, 7, 14 and 28 ]
    Forced expiratory volume in 1 second (in litres). Greater volume reflects better lung function


Other Outcome Measures:
  1. Sputum eosinophil count [ Time Frame: Day 0, 7, 14, 28 and 90. ]
    Sputum eosinophil count (data reported as number of eosinophils and proportion of eosinophils as a proportion of 400 non squamous cells seen on microscopy

  2. Sputum neutrophil count [ Time Frame: Day 0, 7, 14, 28 and 90. ]
    Sputum neutrophil count (data reported as number of neutrophils and proportion of neutrophils as a proportion of 400 non squamous cells seen on microscopy



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04098718


Contacts
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Contact: Mona Bafadhel, PhD, MBChB +44 (0) 1865 225205 mona.bafadhel@ndm.ox.ac.uk
Contact: Sanjay Ramakrishnan, MBBS +44 (0) 1865 222905 sanjay.ramakrishnan@ndm.ox.ac.uk

Sponsors and Collaborators
University of Oxford
Investigators
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Principal Investigator: Mona Bafadhel, PhD, MBChB Nuffield Department of Medicine, University of Oxford, UK
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT04098718    
Other Study ID Numbers: 249196
2018-004401-79 ( EudraCT Number )
First Posted: September 23, 2019    Key Record Dates
Last Update Posted: November 12, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Oxford:
Exacerbations
Interleukin 5
Prednisolone
Randomised Clinical Trial
Additional relevant MeSH terms:
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Prednisolone
Benralizumab
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Asthmatic Agents
Respiratory System Agents