Evaluation of Benralizumab's Predictive Gene Expression Signature in Reducing Exacerbations in Severe Asthma Patients

Trial ID: 2024-514843-27-00
Protocol: RC19_0292
Sponsor: Centre Hospitalier Universitaire De Nantes

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Diseases & Conditions

Asthma

Objectives

The primary objective of the BENRAPRED Study is to establish the predictive value of an early blood **gene expression** signature for the response to **Benralizumab** in patients with severe asthma. This objective is clinically relevant as it aims to identify biomarkers that can predict a significant reduction in the number of exacerbations, thereby potentially improving patient outcomes and optimizing treatment strategies.

Secondary objectives include:

To establish at baseline a molecular signature predictive of stabilization in severe asthmatic patients treated with Benralizumab.
To evaluate the stability of the signature over time, considering patient trajectories from early to late prediction.
To evaluate the association of gene expression patterns with both objective and subjective improvement.
To evaluate the association of gene expression patterns at baseline with clinical characteristics of frequent exacerbations.
To assess the stratification value of gene expression in severe asthma and its correlation with clinical subgroups and clinically meaningful variables such as the number of exacerbations.
To conduct a scenario-based cost-utility analysis.

Participants

The clinical trial involves participants diagnosed with **severe asthma**, a condition characterized by the need for high doses of inhaled corticosteroids and additional medications to maintain control, or uncontrolled asthma despite such treatments. The study population includes both male and female subjects aged between 18 and 75 years. Participants were selected based on specific criteria, including a documented history of asthma exacerbations and a particular eosinophil blood count. The trial does not involve a vulnerable population. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The sponsor did not provide information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the **predictive value** of early blood gene expression signatures in response to **Benralizumab** treatment in patients with severe asthma. This is a Phase IV, randomized, double-blind, controlled study. The trial is expected to last until November 2026, with recruitment having commenced in October 2021. Participants will be involved in the study for a maximum treatment period of 12 months. The trial will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, asthma severity, and previous treatment history. Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and collect data on gene expression and clinical outcomes. The end-of-study visit will assess the primary and secondary endpoints, including the reduction in asthma exacerbations and the correlation of gene expression with clinical characteristics.

Participants will be randomly assigned to receive either the active treatment or a control, with neither the participants nor the investigators aware of the group assignments, ensuring a double-blind methodology. The primary endpoint will focus on evaluating the early blood gene expression signature of Benralizumab response, categorized into three patient response groups: responders, intermediate responders, and non-responders. Secondary endpoints will include the assessment of a composite blood molecular signature predictive of exacerbation rate reduction and the evaluation of gene expression correlations with clinical characteristics. Participants may be withdrawn from the study if they experience adverse effects, fail to comply with study procedures, or withdraw consent. The study aims to provide insights into the molecular mechanisms underlying Benralizumab response and improve treatment strategies for severe asthma.

Treatment

The clinical trial involves the administration of **Fasenra**, a 30 mg solution for injection in a pre-filled syringe, containing the active substance **benralizumab**. Benralizumab is a monoclonal antibody classified under the ATC code R03DX10, and it is derived from a protein of other origin. The pharmaceutical form of the medication is a solution for injection, specifically designed for subcutaneous use. The maximum daily dose is 30 mg, with a total maximum dose of 240 mg over the course of the treatment period. The treatment is administered once every four weeks for a maximum duration of 12 months. The medication is manufactured by AstraZeneca AB and is not formulated for pediatric use.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the response to benralizumab in severe asthmatic patients. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to establish the predictive value of early blood gene expression signatures in response to benralizumab, with the objective of significantly reducing the number of exacerbations in the treated population.

Efficacy

The efficacy of Benralizumab in the treatment of severe asthma will be assessed through a primary endpoint focused on evaluating an early blood gene expression signature. This signature is associated with a clinically significant reduction in the number of exacerbations at month 12 (M12). Patients will be categorized into three response groups: responders, intermediate responders, and non-responders. A 3-category Pi-PLS-DA analysis will be employed to identify the major molecular discriminants among these groups.

Secondary endpoints will include the assessment of a composite blood molecular signature at baseline (M0) that predicts the reduction of exacerbation rates at M12. The study will utilize Generalised Mixed Models to evaluate the significance of center effects and the relevance of time-dependent modeling, with molecular response signatures being independently established. The study aims to achieve a robust and reproducible gene expression profile to assess inter- and intra-individual trajectories over time and across centers, with timepoints at M0, M3, M6, and M9.

Additionally, correlation networks will be analyzed using weighted gene correlation network analysis (WGCNA) to assess the relationship between blood gene expression and clinical outcomes, such as improvements in FEV1, AQLQ, and peak-flow values, and decreases in ACQ-7 and ACQ-6 scores. The study will also explore the correlation between gene expression stratification in severe asthma and clinical subgroups. A cost-utility analysis will compare two treatment strategies: one without using an early blood gene expression signature and another simulating its use.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients between 18 and 75 years old
Patients diagnosed with severe asthma (Chung and al, Eur Respir J 2014), i.e.: asthma requiring high doses of ICS (>1000 microgram per day of Beclomethasone or equivalent) associated with LABA and/or systemic corticosteroids to be controlled over one year, and/or uncontrolled asthma despite the later medications, and/or a controlled asthma worsening after decreasing medications
Documented historical reversibility of FEV1 ≥12% and FEV1 gain ≥ 200mL
ACQ-7 score ≥ 1,5 at M0
At least 3 exacerbations in the 12 months prior to inclusion visit M0
Eosinophil blood count ≥ 0,3 G/L at inclusion visit or in the 12 months prior to the inclusion visit. If eosinophil blood count is ≥ 0,15 G/L and < 0,3 G/L, an eosinophilic phenotype defined by at least 1 of the following criteria will be required: FeNO > 25 ppm at inclusion visit or in the 12 months prior to the inclusion visit, or/and Sputum eosinophils at leat 3% at inclusion visit or in the 12 months prior to the inclusion visit
Patient who has never received treatment with Benralizumab before prior to participation in the study
Patients who provide written informed consent prior to participation in the study

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Exclusion Criteria

Patients diagnosed with difficult-to-treat asthma and/or with uncontrolled asthma differential diagnosis according to the judgment of the investigator (e.g., vocal cord dysfunction, gastroesophageal reflux disease, granulomatous eosinophilic vasculitis, obstructive sleep apnea syndrome, hyperventilation syndrome, allergic broncho-pulmonary aspergillosis, Carrington disease, DIPNECH, asthma/COPD overlap syndrome).
Non-adherent patients to inhaled treatment (ICS + LABA).
Active smokers or former smokers exceeding 20 packs year.
Exacerbation at inclusion visit M0
Active malignancy or malignancy in remission over less than 5 years.
Active parasitic infection or parasitic infection in the past 24 weeks.
Hypersensitivity to Benralizumab or to any of the excipients of Fasenra® (histidine, histidine hydrochloride monohydrate, trehalose dihydrate, polysorbate 20)
Patients requiring other immunosuppressive and immunomodulator drugs
Patients requiring other biotherapy than Benralizumab, with or without French’s marketing authorisation in severe asthma
Patients requiring other biotherapy than Benralizumab that affects the immune system
SARS-COV2 infection
Pregnancy, lactation, or patients with childbearing potential refusing efficient contraceptive method.
Patients under psychiatric condition altering their comprehension and their ability to give informed consent.
Patients already enrolled in a clinical interventional research.
Patients not affiliated to a health insurance plan
Patients under guardianship, curatorship or safeguard of justice