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    Summary
    EudraCT Number:2021-004573-32
    Sponsor's Protocol Code Number:21-05
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-08-18
    Trial results View 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 number2021-004573-32
    A.3Full title of the trial
    Effect of High-Dose Quadrivalent Influenza Vaccine (Efluelda®) versus Standard-Dose (QIV-SD), in subjects 65 years of age and older on innate immunity, including gene expression.
    Effet d’un vaccin antigrippal quadrivalent à haute dose (Efluelda®) versus dose standard (QIV-SD) sur l'immunité innée, notamment l'expression des gènes, chez des sujets âgés de 65 ans et plus.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of High-Dose Quadrivalent Influenza Vaccine (Efluelda®) versus Standard-Dose (QIV-SD), in subjects 65 years of age and older on innate immunity, including gene expression.
    Effet d’un vaccin antigrippal quadrivalent à haute dose (Efluelda®) versus dose standard (QIV-SD) sur l'immunité innée, notamment l'expression des gènes, chez des sujets âgés de 65 ans et plus.
    A.3.2Name or abbreviated title of the trial where available
    INFLUOMICS
    INFLUOMICS
    A.4.1Sponsor's protocol code number21-05
    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 SponsorCentre Hospitalier Annecy Genevois
    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 supportSANOFI PASTEUR
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre Hospitalier Annecy Genevois
    B.5.2Functional name of contact pointDRCI - Marion GHIDI
    B.5.3 Address:
    B.5.3.1Street Address1 avenue de l'Hôpital, BP 90074
    B.5.3.2Town/ cityEPAGNY METZ-TESSY
    B.5.3.3Post code74370
    B.5.3.4CountryFrance
    B.5.4Telephone number033450637031
    B.5.6E-mailmghidi@ch-annecygenevois.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 EFLUELDA
    D.2.1.1.2Name of the Marketing Authorisation holderSANOFI PASTEUR
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Suspension for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    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 No
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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.3.4Pharmaceutical form Suspension for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    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 No
    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
    Healthy volunteers (influenza vaccination)
    Volontaires sains (vaccination anti-grippale)
    E.1.1.1Medical condition in easily understood language
    Healthy volunteers (influenza vaccination)
    Volontaires sains (vaccination anti-grippale)
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of QIV-HD and QIV-SD vaccines in subjects 65 years of age and older on:
    - the early systemic innate immune response through transcriptomic analysis i.e. innate gene signature including interferon signaling pathways,
    - innate cells including antigen presenting and inflammatory cells,
    - gene signature associate with adaptive immune response before and after the influenza vaccination,
    - humoral immunity i.e. HI titers, at different time points.
    Évaluer l'effet des vaccins QIV-HD et QIV-SD chez les sujets âgés de 65 ans et plus sur :
    - La réponse immunitaire innée systémique précoce par analyse transcriptomique, c'est-à-dire la signature des gènes innés, y compris les voies de signalisation de l'interféron,
    - Les cellules innées, y compris les cellules présentatrices d'antigènes et les cellules inflammatoires,
    - La signature génique associée à la réponse immunitaire adaptative avant et après la vaccination contre la grippe,
    - L'immunité humorale, c'est-à-dire les titres d’inhibition de l’hémagglutinine (IHA), à différents moments.
    E.2.2Secondary objectives of the trial
    Not applicable
    Non applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged 65 years or older, the day of inclusion;
    2. Have signed and dated Informed Consent Form;
    3. Able and willing to attend all scheduled visits, and to comply with study procedures;
    4. Covered by French health insurance.
    1. Sujet âgé de 65 ans ou plus, le jour de l'inclusion ;
    2. Sujet ayant daté et signé le formulaire de consentement éclairé ;
    3. Sujet capable et accepter d'assister à toutes les visites prévues, et de se conformer aux procédures de l'étude ;
    4. Sujet affilié à un régime de sécurité social français.
    E.4Principal exclusion criteria
    Non-inclusion:
    1. Any vaccine injection (including COVID-19 vaccine) in the 4 weeks preceding study inclusion;
    2. Plan to receive any vaccine (including COVID-19 vaccine) in the 4 weeks following study inclusion;
    3. Already vaccinated against influenza for 2021-2022 season;
    4. Hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances;
    5. HIV infection;
    6. Active Hepatitis B, or active Hepatitis C;
    7. Previous Guillain Barré syndrome;
    8. Ongoing immunosuppressive treatment or active immunodeficiency;
    9. Receipt of immune globulins, blood or blood-derived products in the past 3 months;
    10. Thrombocytopenia or bleeding disorder, receipt of anticoagulants contraindicating IM vaccination based on investigator’s judgment;
    11. Influenza-like illness symptoms, including COVID-19, within 4 weeks before study inclusion;
    12. Patients subject to legal protection measures.
    Exclusion:
    1. Any subject presenting with influenza-like illness symptoms, including COVID-19 between inclusion (visit 1) and randomization (visit 2);
    2. Subject unable to attempt visit at Day 0 (visit 2) and Day 1 (visit 3);
    3. Blood sample at Day 0 (visit 2) impossible to obtain;
    4. Receipt of vaccine injection or equivalent between inclusion (visit 1) and randomization (visit 2), other than those allowed and planned in the study. This includes non-study dose of 2021–2022 influenza vaccine, blood-derived immune globulins, blood, or blood-derived products.
    5. Any unexpected event relevant to the physician in charge, after discussion with the coordinating investigator and the sponsor
    These subjects will not be randomized and not followed after the second visit. Study team will propose influenza vaccination outside of the study, as per standard of care.
    Non-inclusion:
    1. Sujet ayant reçu une injection de vaccin (y compris le vaccin contre la COVID-19) dans les 4 semaines précédant l'inclusion dans l'étude ;
    2. Sujet prévoyant de recevoir tout vaccin (y compris le vaccin contre la COVID-19) dans les 4 semaines suivant l'inclusion dans l'étude ;
    3. Sujet ayant déjà reçu une vaccination antigrippale pour la saison 2021-2022;
    4. Sujet hypersensible à l'un des composants du vaccin, ou présenter des antécédents de réaction potentiellement mortelle aux vaccins utilisés dans l'étude ou à un vaccin contenant l'une des mêmes substances ;
    5. Sujet infecté par le VIH ;
    6. Sujet porteur d’Hépatite B active, ou hépatite C active ;
    7. Sujet présentant un antécédent de Syndrome de Guillain Barré ;
    8. Sujet sous traitement immunosuppresseur en cours ou présentant une immunodéficience active ;
    9. Sujet ayant reçu des immunoglobulines, du sang ou des produits dérivés du sang au cours des 3 derniers mois ;
    10. Sujet présentant une thrombocytopénie ou un trouble de la coagulation, ou sous anticoagulants contre-indiquant la vaccination IM selon le jugement de l'investigateur ;
    11. Sujet présentant des symptômes de syndrome grippal, y compris COVID-19, dans les 4 semaines précédant l'inclusion dans l'étude ;
    12. Sujet faisant l'objet de mesures de protection juridique.
    Exclusion :
    1. Sujet présentant des symptômes de syndrome grippal, y compris COVID-19 entre l'inclusion (visite 1) et la randomisation (visite 2) ;
    2. Sujet ne pouvant se présenter à la visite de randomisation (visite 2) ou du jour 1 (visite 3) ;
    3. Impossibilité d'obtenir un échantillon de sang au jour 0 (visite 2) ;
    4. Sujet recevant une injection de vaccin ou équivalent entre l'inclusion (visite 1) et la randomisation (visite 2), autre que ceux autorisés dans l'étude. Cela inclut une dose d’un vaccin contre la grippe 2021-2022 ne faisant pas partie de l’étude, des immunoglobulines dérivées du sang, du sang ou des produits dérivés du sang.
    5. Tout événement inattendu pertinent pour le médecin investigateur, après discussion avec l'investigateur coordinateur et le sponsor.
    Ces sujets ne seront pas randomisés et ne seront pas suivis après la deuxième visite. L'équipe de l'étude proposera une vaccination contre la grippe en dehors de l'étude, conformément aux soins standard.
    E.5 End points
    E.5.1Primary end point(s)
    Outcomes will be measure in each subject. Measures will be reported by allocated arm: QIV-HD arm or QIV-SD arm.

    Transcriptomic
    Transcriptomic profiles of blood cells (microarrays) will be performed to measure early systemic innate immune response. Samples will be collected seven days prior vaccine injection (D-7, first baseline), the day of vaccine injection (D0, second baseline) to assess the stability of biomarkers, and one day after vaccine injection (D+1).

    Innate cellular phenotyping
    Innate cellular phenotyping will be performed using 36 surface markers deciphering lineage cells monocytes, neutrophils, NK, antigen-presenting cells. The technology used is based on Aurora spectral cytometry (Cyteck). These data will be integrated in final innate gene signature analysis.

    Gene signature
    The innate immune response will be assessed at D+1 after vaccination. We will compare gene expression with the basal gene expression status at baseline (D-7 and D0), by studying the transcriptional profile of the blood cells by microarrays.

    Humoral immune responses
    We will measure and report the evolution of:
    • HAI titers obtained on D0, D21, D90 and D210
    • Individual HAI titers ratio D21/D0, D90/D0 and D210/D0
    • Subjects with titers ≥ 40 at D21, D90 and D210
    • Seroconversion: titer < 10 at D0 and post-vaccination titer ≥ 40 at D21, D90 and D210 or titer ≥ 10 at D0 and a ≥ 4-fold increase in titer at D21, D90 and D210)
    Humoral response results will be reported in HAI titers for each of the 4 antigens at D0, D21, D90 and D210 time.
    Les résultats seront mesurés chez chaque sujet. Les mesures seront rapportées par bras attribué : bras QIV-HD ou bras QIV-SD.
    Transcriptomique
    Les profils transcriptomiques des cellules sanguines (puce à ADN) seront réalisés pour mesurer la réponse immunitaire innée systémique précoce. Les échantillons seront collectés sept jours avant l'injection du vaccin (J-7, premier point de référence), le jour de l'injection du vaccin (J0, deuxième point de référence) pour évaluer la stabilité des biomarqueurs, et un jour après l'injection du vaccin (J+1).
    Phénotypage cellulaire inné
    Le phénotypage cellulaire inné sera réalisé à l'aide de 36 marqueurs de surface permettant de décrypter les lignées cellulaires : monocytes, neutrophiles, Natural Killers, cellules présentatrices d'antigènes. La technologie utilisée est basée sur la cytométrie spectrale Aurora (Cyteck). Ces données seront intégrées dans l'analyse finale de la signature génique innée.
    Signature génique
    La réponse immunitaire innée sera évaluée à J+1 après la vaccination. Nous comparerons l'expression des gènes avec le statut basal d'expression des gènes au départ (J-7 et J0), en étudiant le profil transcriptionnel des cellules sanguines à l’aide de puce à ADN (microarray).
    Réponse immunitaire humorale
    Nous mesurerons et rapporterons l'évolution de :
    - Titres d’inhibition de l’hémagglutination (IHA) obtenus à J0, J21, J90 et J210
    - Rapport des titres IHA individuels à J21/D0, J90/D0 et J210/D0
    - Sujets ayant des titres ≥ 40 à J21, J90 et J210
    - Séroconversion : titre < 10 à J0 et titre post-vaccination ≥ 40 à J21, J90 et J210 ou titre ≥ 10 à J0 et augmentation ≥ 4 fois du titre à J21, J90 et J210.
    Les résultats de la réponse humorale seront rapportés en titres IHA pour chacun des 4 antigènes aux temps J0, J21, J90 et J210.
    E.5.1.1Timepoint(s) of evaluation of this end point
    D1, D21, D90 and D210
    J1, J21, J90 et J210
    E.5.2Secondary end point(s)
    Not applicable
    Non applicable
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not applicable
    Non applicable
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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 Yes
    E.8.1.1Randomised Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned2
    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
    LSLV
    LSLV
    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 months10
    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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    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 state60
    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)
    None
    Aucun
    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 Decision2021-10-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-04
    P. End of Trial
    P.End of Trial StatusCompleted
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