Clinical trial NCT04617171: Benralizumab Initiated During Severe Asthma Attack
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Asthma Attack
Asthma
Lead sponsor: Singapore General Hospital
Sponsor class: OTHER
First posted: 2020-11-05
Enrollment: 128
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to first exacerbation in patients with a severe asthma exacerbation with raised blood eosinophil count
timeFrame: Change from baseline (Day 1) to 52 weeks
Secondary outcomes:
measure: Time to hospital readmission due to asthma exacerbation (Key Secondary outcome)
timeFrame: Baseline (Day 1) to 52 weeks
measure: Rate of severe exacerbation (i.e. requiring admission to hospital for asthma exacerbation)
timeFrame: Baseline (Day 1) to 52 weeks
measure: Hospital LOS (index admission and subsequent admissions)
timeFrame: Change from baseline (Day 1) to 52 weeks
measure: Need for Intensive Care Unit (ICU) admission with/without mechanical ventilation during the index admission
timeFrame: Baseline (Day 1) to index admission discharge date
measure: Hospital survival post admission (index admission)
timeFrame: Baseline (Day 1) to index admission discharge date
measure: Total OCS burden
timeFrame: Baseline (Day 1) to 52 weeks
measure: Total number of exacerbations requiring emergency healthcare utilization (including ED, polyclinic visits, Specialist outpatient visits)
timeFrame: Baseline (Day 1) to 52 weeks
measure: Pre/post bronchodilator Forced Expiratory Volume 1s (FEV1), FVC, FEV1/FVC at baseline and at 52 weeks
timeFrame: Change from baseline (Day 1) to 52 weeks
measure: Blood eosinophil counts (serial measurement over 52 weeks)
timeFrame: Change from baseline (Day 1) to 52 weeks
measure: GINA assessment of symptom control
timeFrame: Change from baseline (Day 1) to 52 weeks
measure: Asthma Control Questionnaire 7 (ACQ 7)
timeFrame: Change from baseline (Day 1) to 52 weeks
measure: St George's Respiratory Questionnaire (SGRQ)
timeFrame: Change from baseline (Day 1) to 52 weeks
Other outcomes:
measure: Adverse Events
timeFrame: Change from baseline (Day 1) to 52 weeks
Locations:
city: Singapore
country: Singapore
facility: Singapore General Hospital
state: Foreign
Study officials:
affiliation: Singapore General Hospital
name: Mariko Koh
role: PRINCIPAL_INVESTIGATOR
References:
citation: Yii ACA, Tay TR, Puah SH, Lim HF, Li A, Lau P, Tan R, Neo LP, Chung KF, Koh MS. Blood eosinophil count correlates with severity of respiratory failure in life-threatening asthma and predicts risk of subsequent exacerbations. Clin Exp Allergy. 2019 Dec;49(12):1578-1586. doi: 10.1111/cea.13465. Epub 2019 Aug 6.
citation: Nowak RM, Parker JM, Silverman RA, Rowe BH, Smithline H, Khan F, Fiening JP, Kim K, Molfino NA. A randomized trial of benralizumab, an antiinterleukin 5 receptor alpha monoclonal antibody, after acute asthma. Am J Emerg Med. 2015 Jan;33(1):14-20. doi: 10.1016/j.ajem.2014.09.036. Epub 2014 Oct 5.
citation: Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, Sproule S, Gilmartin G, Aurivillius M, Werkstrom V, Goldman M; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29;388(10056):2115-2127. doi: 10.1016/S0140-6736(16)31324-1. Epub 2016 Sep 5.
citation: FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, Gilmartin G, Werkstrom V, Aurivillius M, Goldman M; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29;388(10056):2128-2141. doi: 10.1016/S0140-6736(16)31322-8. Epub 2016 Sep 5.