Predictive Signature of Benralizumab Response. BENRAPRED Study.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

11 Oct 2021 → ongoing

Decision date (initial)

2024-06-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514843-27-00

EudraCT number

2020-002165-34

ClinicalTrials.gov

NCT04565483

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To establish the predictive value of early blood gene expression signature of Benralizumab response associated with a significant reduction of the number of exacerbations in treated severe asthmatic patients.

Secondary objectives 6

1. To establish at M0 (baseline) a molecular signature predictive of stabilization in severe asthmatic patients treated by Benralizumab.
2. To evaluate the stability of the signature over time (from early at M0, M3, to late prediction at M6 and M9) considering patient trajectories.
3. To evaluate the association of gene expression patterns with both objective and subjective improvement.
4. To evaluate association of gene expression patterns at M0 (baseline) and clinical characteristics of frequent exacerbations.
5. To assess the stratification value of gene expression in severe asthma and its correlation with clinical subgroups and clinically meaningful variables such as number of exacerbations.
6. To conduct a scenario-based cost-utility analysis.

Conditions and MedDRA coding

Severe asthma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Patients between 18 and 75 years old
2. 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
3. Documented historical reversibility of FEV1 ≥12% and FEV1 gain ≥ 200mL
4. ACQ-7 score ≥ 1,5 at M0
5. At least 3 exacerbations in the 12 months prior to inclusion visit M0
6. 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
7. Patient who has never received treatment with Benralizumab before prior to participation in the study
8. Patients who provide written informed consent prior to participation in the study

Exclusion criteria 16

1. 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).
2. Non-adherent patients to inhaled treatment (ICS + LABA).
3. Active smokers or former smokers exceeding 20 packs year.
4. Exacerbation at inclusion visit M0
5. Active malignancy or malignancy in remission over less than 5 years.
6. Active parasitic infection or parasitic infection in the past 24 weeks.
7. Hypersensitivity to Benralizumab or to any of the excipients of Fasenra® (histidine, histidine hydrochloride monohydrate, trehalose dihydrate, polysorbate 20)
8. Patients requiring other immunosuppressive and immunomodulator drugs
9. Patients requiring other biotherapy than Benralizumab, with or without French’s marketing authorisation in severe asthma
10. Patients requiring other biotherapy than Benralizumab that affects the immune system
11. SARS-COV2 infection
12. Pregnancy, lactation, or patients with childbearing potential refusing efficient contraceptive method.
13. Patients under psychiatric condition altering their comprehension and their ability to give informed consent.
14. Patients already enrolled in a clinical interventional research.
15. Patients not affiliated to a health insurance plan
16. Patients under guardianship, curatorship or safeguard of justice

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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: - Three patient response groups (responders, intermediates responders, non-responders), - Gene expression signature. A 3 categories Pi-PLS-DA analysis will identify the major molecular discriminants of the responders groups.

Secondary endpoints 6

1. 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.
2. 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).
3. 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
4. Correlations network between blood gene expression at M0 and clinical characteristics of frequent exacerbations will be assessed thanks to WGCNA.
5. 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.
6. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette, Cs 69301 Cs 69301

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

François-Xavier BLANC

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

François-Xavier BLANC

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications