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    Summary
    EudraCT Number:2020-002165-34
    Sponsor's Protocol Code Number:RC19_0292
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-09-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-002165-34
    A.3Full title of the trial
    Predictive Signature of Benralizumab Response
    Signature prédictive de la réponse au Benralizumab
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Predictive Signature of Benralizumab Response
    Signature prédictive de la réponse au Benralizumab
    A.3.2Name or abbreviated title of the trial where available
    BENRAPRED
    A.4.1Sponsor's protocol code numberRC19_0292
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCHU of Nantes
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMinistère de la santé - DGOS
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportAstra-Zeneca France
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU of Nantes
    B.5.2Functional name of contact pointDirection Recherche, CHU de Nantes
    B.5.3 Address:
    B.5.3.1Street Address5 allée de l'île Gloriette
    B.5.3.2Town/ cityNANTES
    B.5.3.3Post code44093
    B.5.3.4CountryFrance
    B.5.4Telephone number0033253526231
    B.5.5Fax number0033253482836
    B.5.6E-mailbp-prom-regl@chu-nantes.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fasenra
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBenralizumab
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBENRALIZUMAB
    D.3.9.2Current sponsor codePRD8275546
    D.3.9.4EV Substance CodeSUB181746
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe asthma
    Asthme sévère
    E.1.1.1Medical condition in easily understood language
    Severe asthma
    Asthme sévère
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10068462
    E.1.2Term Eosinophilic asthma
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    The key secondary objectives of this study are:
    SO1: To establish at M0 (baseline) a molecular signature predictive of stabilization in severe asthmatic patients treated by Benralizumab.
    SO2: To evaluate the stability of the signature over time (from early at M0, M3, to late prediction at M6 and M9) considering patient trajectories.
    SO3: To evaluate the association of gene expression patterns with both objective and subjective improvement.
    S04: To evaluate association of gene expression patterns at M0 (baseline) and clinical characteristics of frequent exacerbations.
    SO5: 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.
    SO6: To conduct a scenario-based cost-utility analysis.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients between 18 and 75 years old.
    - Patients diagnosed with severe asthma (Chung and al, Eur Respir J 2014), i.e.:
    o asthma requiring high doses of ICS (>1000 g per day of Beclomethasone or equivalent) associated with LABA and/or systemic corticosteroids to be controlled over one year,
    o and/or uncontrolled asthma despite the later medications,
    o and/or a controlled asthma worsening after decreasing medications,
    - Pre-BD FEV1 <80% of the predicted value at M-1.
    - Documented historical reversibility of FEV1 ≥12% and FEV1 gain ≥ 200mL.
    - ACQ-7 score ≥ 1,5 at M-1 and M0.
    - Superior or equal 3 exacerbations in the 12 months prior to screening visit M-1.
    - Eosinophil blood count ≥ 0,3 G/L at screening visit or in the 12 months prior to the screening 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:
    o FeNO > 25 ppm at screening visit or in the 12 months prior to the screening visit.
    o Sputum eosinophils  3% at screening visit or in the 12 months prior to the screening visit.
    - Patients who provide written informed consent prior to participation in the study
    E.4Principal exclusion criteria
    - Patients diagnosed with difficult-to-treat asthma and/or with asthma differential diagnosis that have not yet been excluded (vocal cord dysfunction, gastroesophageal reflux disease, granulomatous eosinophilic vasculitis, obstructive sleep apnea syndrome, hyperventilation syndrome, allergic broncho-pulmonary aspergillosis, Carrington disease, DIPNEC, asthma/COPD overlap syndrome).
    - Non-adherent patients to inhaled treatment (ICS + LABA).
    - Active smokers or former smokers exceeding 20 packs year.
    - Exacerbation at screening visit M-1.
    - Exacerbation within the past 4 weeks prior to M0, to avoid confounding effects of a short course of systemic corticosteroids that could bias basal molecular signature.
    - 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
    - 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
    E.5 End points
    E.5.1Primary end point(s)
    Evaluation an early blood gene expression signature of Benralizumab response through a clinically relevant reduction of the number of exacerbations at month 12 (M12).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Blood sample for tha analyse of gene expresssion at baseline, 3 months, 6 months, 9 months and 12 months
    E.5.2Secondary end point(s)
    SO1: 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. The methods used for the primary objective (PO) are applied to SO1 using similar input data on a different 3-class prediction target.
    SO2: 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).
    SO3: 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 + Asthma Quality of Life Questionnaire (AQLQ) + peak-flow values and expected decrease of Asthma Control Questionnaire-7 items (ACQ-7), -6 items (ACQ-6) scores.
    SO4: Correlations network between blood gene expression at M0 and clinical characteristics of frequent exacerbations will be assessed thanks to WGCNA.
    SO5: 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.
    SO6: 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 (Methodological details are provided in section 6.2.7).
    E.5.2.1Timepoint(s) of evaluation of this end point
    SO1 : at baseline
    S02 : at baseline, 3 months, 6 months, 9 months
    S03 : at baseline, 3 months, 6 months, 9 months and 12 months
    SO4 : at baseline, 3 months, 6 months, 9 months and 12 months
    SO5 : at baseline, 3 months, 6 months, 9 months and 12 months
    SO6 : at baseline, 3 months, 6 months, 9 months and 12 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned15
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months40
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 165
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state220
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the study or in case of early termination, the patient medical care will be discussed between the investigator and the patient. Whatever is decided, patient follow up will occur between pulmonologist in asthma competence center and patient’s usual pulmonologist. All authorized and emergency treatments during the trial could be used afterward. In case of sustained clinical response to Benralizumab, treatment continuation could be expected.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-03
    P. End of Trial
    P.End of Trial StatusOngoing
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