BENRALIZUMAB for Severe asthma | Asthma

Inclusion criteria

• {"criterion_text":"- Patients between 18 and 75 years old\n- 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\n- Documented historical reversibility of FEV1 ≥12% and FEV1 gain ≥ 200mL\n- ACQ-7 score ≥ 1,5 at M0\n- At least 3 exacerbations in the 12 months prior to inclusion visit M0\n- 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\tSputum eosinophils at leat 3% at inclusion visit or in the 12 months prior to the inclusion visit\n- Patient who has never received treatment with Benralizumab before prior to participation in the study\n- Patients who provide written informed consent prior to participation in the study"}

Exclusion criteria

• {"criterion_text":"- 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).\n- Non-adherent patients to inhaled treatment (ICS + LABA).\n- Active smokers or former smokers exceeding 20 packs year.\n- Exacerbation at inclusion visit M0\n- Active malignancy or malignancy in remission over less than 5 years.\n- Active parasitic infection or parasitic infection in the past 24 weeks.\n- Hypersensitivity to Benralizumab or to any of the excipients of Fasenra® (histidine, histidine hydrochloride monohydrate, trehalose dihydrate, polysorbate 20)\n- Patients requiring other immunosuppressive and immunomodulator drugs\n- Patients requiring other biotherapy than Benralizumab, with or without French’s marketing authorisation in severe asthma\n- Patients requiring other biotherapy than Benralizumab that affects the immune system\n- SARS-COV2 infection\n- Pregnancy, lactation, or patients with childbearing potential refusing efficient contraceptive method.\n- Patients under psychiatric condition altering their comprehension and their ability to give informed consent.\n- Patients already enrolled in a clinical interventional research.\n- Patients not affiliated to a health insurance plan\n- Patients under guardianship, curatorship or safeguard of justice"}

Primary endpoints

• {"endpoint_text":"- We will evaluate an early blood gene expression signature of Benralizumab response through a clinically relevant reduction of the number of exacerbations at M12 assessed in: -\tThree patient response groups (responders, intermediates responders, non-responders), -\tGene expression signature. A 3 categories Pi-PLS-DA analysis will identify the major molecular discriminants of the responders groups.","definition_or_measurement_approach":"Evaluation of an early blood gene expression signature associated with a clinically relevant reduction in number of exacerbations at month 12 (M12). Assessment in three patient response groups (responders, intermediate responders, non-responders) and identification of molecular discriminants using a 3-category Pi-PLS-DA analysis."}

Secondary endpoints

• {"endpoint_text":"- At M0 a composite blood molecular signature predictive of reduction of the exacerbation rate at M12 in severe asthmatic patients treated by Benralizumab will be assessed as mentioned above. The definition of stable class of patients (low category) is used as a target for the prediction. Methods used for the primary objective (PO) applies to SO1 using similar input data on a different 3-class prediction target.","definition_or_measurement_approach":"Assessment at baseline (M0) of a composite blood molecular signature predictive of reduction in exacerbation rate at M12 using similar methods as primary objective (3-class prediction target with PO methods)."}
• {"endpoint_text":"- The significance of center and the relevance of time dependent modelling will be evaluated using Generalised Mixed Models on independently established molecular response signature. It is expected a robust and reproducible gene expression to assess the inter and intra-individual trajectories of the signature over time and across centers (from early at M0 and M3, to late prediction at M6 and M9).","definition_or_measurement_approach":"Use of Generalised Mixed Models to evaluate center effects and time-dependent modeling on molecular response signatures across timepoints M0, M3, M6, M9."}
• {"endpoint_text":"- Correlations network between blood gene expression of Benralizumab significant response will be assessed thanks to weighted gene correlation network analysis (gene co-expression network analysis (WGCNA)) with an expected increase in FEV1 + AQLQ + peak-flow values and expected decrease of ACQ-7, ACQ-6 scores","definition_or_measurement_approach":"Correlation networks assessed by WGCNA; clinical correlates include expected increases in FEV1, AQLQ, peak-flow and decreases in ACQ-7/ACQ-6 scores."}
• {"endpoint_text":"- Correlations network between blood gene expression at M0 and clinical characteristics of frequent exacerbations will be assessed thanks to WGCNA.","definition_or_measurement_approach":"WGCNA to assess correlations between baseline gene expression and clinical characteristics of frequent exacerbations."}
• {"endpoint_text":"- Correlation network between stratification value of gene expressions in severe asthma and its correlation with clinical subgroups will be assessed thanks to WGCNA. This analysis is based on pairwise correlations between genetic variables and clinical variables underlying the amount of overall variance captured by high dimensional gene expression datasets.","definition_or_measurement_approach":"WGCNA-based pairwise correlation analysis between gene expression variables and clinical subgroup variables to assess stratification value."}
• {"endpoint_text":"- Concerning cost-utility analysis, two strategies of treatment with Benralizumab will be compared: the first one will consider a strategy not using an early blood gene expression signature of Benralizumab response and the second will consider a simulated strategy using an early blood gene expression signature of Benralizumab response","definition_or_measurement_approach":"Scenario-based cost-utility analysis comparing standard strategy vs simulated strategy using early blood gene expression signature."}

France

Earliest CTIS Part Ii Submission Date

13-06-2024

Latest Decision Or Authorization Date

24-06-2024

Processing Time Days

11

Number Of Sites

15

Number Of Participants

220

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Nantes

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France