Benralizumab Initiated During Severe Asthma Attack

Study Overview
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Brief Summary
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Approximately 300 million people have asthma worldwide and 400,000 people died from asthma globally in 2015 (GINA Asthma). Singapore's asthma mortality and hospitalisation rates are several times higher than OECD countries. Spot Blood eosinophil count (BEC) during an acute exacerbation of asthma was a predictor of more severe respiratory failure and was associated with future acute health care utilization (HR 1.8, 95% CI 1.1-2.9, p=0.02) in a previous study conducted across 4 ICUs in Singapore. Benralizumab, an anti-IL5 receptor α monoclonal antibody causes rapid depletion of blood eosinophils and reduces asthma exacerbations when given over 12-month duration in patient with Severe Eosinophilic Asthma. However, the efficacy of Benralizumab when given during an acute exacerbation of asthma in reducing future exacerbations or severity of asthma exacerbation is relatively unexplored. A Phase 2A randomized double-blind placebo-controlled trial involving the use of one dose of the intravenous formulation of Benralizumab (0.3 mg/kg or 1.0mg/kg) in patients presenting with acute asthma exacerbation did not demonstrate difference in the proportion of subjects with >/=1 asthma exacerbation at 12 weeks when compared to placebo (33.3% vs. 38.9%; P=0.67). However, compared with placebo, Benralizumab reduced asthma exacerbation rates by 49% (3.59 vs 1.82; P=0.01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P=.02) in the combined groups at 12 weeks (secondary outcomes). Benralizumab, an anti-IL5 receptor α monoclonal antibody causes rapid depletion of blood eosinophils and reduces asthma exacerbations when given over 12-month duration in patient with Severe Eosinophilic Asthma. This study aims to look at whether subcutaneous administration of Benralizumab when initiated during an acute severe asthma exacerbation and then continued over 48 weeks period can increase time to first exacerbation compared to placebo as well as other key secondary outcome such as hospital readmission and health care utilization. We hypothesise that administration of Benralizumab when initiated during an acute severe asthma exacerbation and then continued over 48 weeks period can increase time to first exacerbation compared to placebo as well as other key secondary outcome such as hospital readmission and health care utilization.

Detailed Description
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The efficacy of Benralizumab when given during an acute exacerbation of asthma in reducing future exacerbations or severity of asthma exacerbation is relatively unexplored. A Phase 2A randomized double-blind placebo-controlled trial involving the use of one dose of the intravenous formulation of Benralizumab (0.3 mg/kg or 1.0mg/kg) in patients presenting with acute asthma exacerbation did not demonstrate difference in the proportion of subjects with >/=1 asthma exacerbation at 12 weeks when compared to placebo (33.3% vs. 38.9%; P=0.67). However, compared with placebo, Benralizumab reduced asthma exacerbation rates by 49% (3.59 vs 1.82; P=0.01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P=.02) in the combined groups at 12 weeks (secondary outcomes). The purpose of this study is to look at whether Benralizumab, an anti-IL5 receptor α monoclonal antibody given subcutaneously compared to placebo given subcutaneously, can increase time to first exacerbation, reduce health care utilisation and improve other asthma outcomes in patients presenting with acute severe asthma exacerbation requiring hospitalisation. Randomized double-blind placebo-controlled trial design was chosen to reduce selection bias by randomisation and concealment of allocation, reduce analysis or interobserver ascertainment bias by blinding, and reduce bias introduced by exclusion after randomisation by using Intention- to-treat (ITT) analysis. In addition, biomarker stratified approach using spot BEC < or >/= 300 cells/microL during an acute exacerbation will be used to evaluate its role as a predictive biomarker for response to Benralizumab. The study aims to recruit 128 patients over a 2-year period at Singapore General Hospital and Changi General Hospital.

Official Title
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Randomized Double Blind Placebo Controlled Trial of Benralizumab, an Antiinterleukin 5 Receptor α Monoclonal Antibody, Initiated During Hospitalization for Severe Asthma Attack in Reducing Severe Exacerbations: Phase 2B Study

Conditions
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Asthma Attack, Asthma

Intervention / Treatment
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* Drug: Benralizumab 30 MG/ML [Fasenra]
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with severe asthma exacerbation requiring hospital admission Subjects aged 21 to 65 years with a physician diagnosis of asthma for greater than or equal to 1 year Subjects with 2 or more exacerbations in the past 12 months On maintenance of medium to high dose ICS/LABA (GINA Step 4 and 5) for at least 6 months Blood Eosinophil count of ≥ 150 cells/microL at time of admission or ≥ 300 cells/microL documented over the past 52 weeks Informed consent obtained Exclusion Criteria: Subjects with asthma exacerbations who are treated and then discharged from ED within 24 hours Subjects with a physician diagnosis of COPD, bronchiectasis Smokers > 20 pack years Anaphylactic/anaphylactoid reaction presenting with bronchospasm Other known causes of eosinophilia besides asthma (e.g. parasitic infection) Subjects who are deemed by investigators to have with life expectancy of < 12 months (any cause) Subjects who are already on investigational drug or has been participating in another clinical study with an investigational product during the last 6 months Female subjects who are pregnant or planning pregnancy. All subjects should refrain from family planning during and 4 months following the last dose. Male subjects should refrain from fathering a child or donating sperm during the study and 4 months following the last dose Subjects with known history of allergy or reaction to any component of the investigational product formation Subjects with history of primary immunodeficiency Subjects who have received Xolair (anti-IgE mAb) within 4 months before randomization Subjects who receive immunoglobulin or blood products within 30 days before randomization

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab<br>Benralizumab 30 mg given in the form of subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks subsequently up till Week 48. | Drug: Benralizumab 30 MG/ML [Fasenra]<br>* Benralizumab/placebo initiated at an acute severe asthma exacerbation, then continued over a period of 48 weeks<br>* Other names: Fasenra;|
| Placebo Comparator: Placebo<br>Normal Saline given subcutaneously every 4 weeks for the first three doses, then every 8 weeks subsequently up till Week 48. | Drug: Placebos<br>* Benralizumab/placebo initiated at an acute severe asthma exacerbation, then continued over a period of 48 weeks<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first exacerbation in patients with a severe asthma exacerbation with raised blood eosinophil count | Time to first exacerbation requiring either oral corticosteroid (OCS) use and/or an unscheduled visit to the Emergency Department or hospitalization | Change from baseline (Day 1) to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to hospital readmission due to asthma exacerbation (Key Secondary outcome) | Time to hospital readmission due to asthma exacerbation | Baseline (Day 1) to 52 weeks | 
| Rate of severe exacerbation (i.e. requiring admission to hospital for asthma exacerbation) | NUmber of severe exacerbation (i.e. requiring admission to hospital for asthma exacerbation) | Baseline (Day 1) to 52 weeks | 
| Hospital LOS (index admission and subsequent admissions) | Total hospital LOS | Change from baseline (Day 1) to 52 weeks | 
| Need for Intensive Care Unit (ICU) admission with/without mechanical ventilation during the index admission | ICU admission during index admission | Baseline (Day 1) to index admission discharge date | 
| Hospital survival post admission (index admission) | Hospital survival for index admission | Baseline (Day 1) to index admission discharge date | 
| Total OCS burden | Cumulative OCS dose | Baseline (Day 1) to 52 weeks | 
| Total number of exacerbations requiring emergency healthcare utilization (including ED, polyclinic visits, Specialist outpatient visits) | Total number of emergency healthcare utilization for exacerbations | Baseline (Day 1) to 52 weeks | 
| Pre/post bronchodilator Forced Expiratory Volume 1s (FEV1), FVC, FEV1/FVC at baseline and at 52 weeks | Change in Pre/post bronchodilator Forced Expiratory Volume 1s (FEV1), FVC, FEV1/FVC | Change from baseline (Day 1) to 52 weeks | 
| Blood eosinophil counts (serial measurement over 52 weeks) | Change in blood eosinophils | Change from baseline (Day 1) to 52 weeks | 
| GINA assessment of symptom control | Change in GINA assessment of symptom control ( Well controlled, Partly controlled or Uncontrolled) | Change from baseline (Day 1) to 52 weeks | 
| Asthma Control Questionnaire 7 (ACQ 7) | Change in Asthma Control Questionnaire 7 (ACQ 7) Scores range from 0-6( higher is worse). A score of 0.0-0.75 is classified as well-controlled asthma; 0.75-1.5 is a grey zone; and >1.5 is poorly controlled asthma. The minimum clinically important difference is 0.5 | Change from baseline (Day 1) to 52 weeks | 
| St George's Respiratory Questionnaire (SGRQ) | Change in St George's Respiratory Questionnaire (SGRQ) The SGRQ total score is made up of 2 parts : Part 1 addresses the frequency of respiratory symptoms and Part 2 addresses the patient's current state. Data is entered into the calculator and scores will be generated ( 0 to 100). The lower the score, the better. | Change from baseline (Day 1) to 52 weeks |