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    Summary
    EudraCT Number:2020-001430-35
    Sponsor's Protocol Code Number:35RC19_8860_FLUDROSEPSIS
    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:2021-02-02
    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 number2020-001430-35
    A.3Full title of the trial
    Evaluation of the hemodynamic effects of fludrocortisone on the pressive response to norepinephrine in patients in septic shock
    Evaluation des effets hémodynamiques de la fludrocortisone sur la réponse pressive à la noradrénaline chez des patients en choc septique
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of the hemodynamic effects of fludrocortisone on the pressive response to norepinephrine in patients in septic shock
    Evaluation des effets hémodynamiques de la fludrocortisone sur la réponse pressive à la noradrénaline chez des patients en choc septique
    A.3.2Name or abbreviated title of the trial where available
    FLUDROSEPSIS
    FLUDROSEPSIS
    A.4.1Sponsor's protocol code number35RC19_8860_FLUDROSEPSIS
    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 Rennes
    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 supportCHU de Rennes
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportHAC Pharma
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportGETINGE
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de Rennes
    B.5.2Functional name of contact pointClaire FOUGEROU
    B.5.3 Address:
    B.5.3.1Street Address2 rue Henri Le Guilloux
    B.5.3.2Town/ cityRENNES
    B.5.3.3Post code35033
    B.5.3.4CountryFrance
    B.5.6E-mailclaire.fougerou@chu-rennes.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 FLUCORTAC 50 microgrammes, comprimé sécable
    D.2.1.1.2Name of the Marketing Authorisation holderAssistance Publique Hôpitaux de Paris
    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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPNasogastric use (Noncurrent)
    Oral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    septic shock
    choc septique
    E.1.1.1Medical condition in easily understood language
    septic shock
    choc septique
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    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
    The main objective of the study is to evaluate the effect of oral administration of fludrocortisone (100 µg every 6 hours) on vascular reactivity to norepinephrine in patients in septic shock.
    L'objectif principal de l'étude est d’évaluer l'effet d’une administration orale de fludrocortisone (100 µg toutes les 6 heures) sur la réactivité vasculaire à la noradrénaline chez des patients en choc septique.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate the clinical, biological effects and pharmacokinetic profile of oral administration of fludrocortisone (100 µg every 6 hours) in patients in septic shock.
    Les objectifs secondaires sont d’évaluer les effets cliniques, biologiques et le profil pharmacocinétique de l’administration orale de fludrocortisone (100 µg toutes les 6 heures) chez des patients en choc septique.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Adult 18 years of age or older
    - Patient presenting with septic shock for less than 24 hours, as defined by The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) by the association of:
    Sepsis defined as an organ dysfunction caused by an inappropriate host response to infection (increase in SOFA score of at least 2 points following infection),
    Persistent hypotension requiring vasopressor drugs to maintain MAP ≥ 65 mmHg,
    Serum lactate level > 2 mmol/l despite adequate vascular filling.
    - Hemodynamic stability for more than 30 min with mean blood pressure ≥ 65 mmHg and noradrenaline dose ≤ 0.5 µg/kg/min,
    - Consent signed by the patient, relative or legal representative or inclusion under emergency procedure.
    - Adulte âgé de 18 ans ou plus
    - Patient présentant un choc septique depuis moins de 24h, défini selon The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) par l’association de:
     Sepsis défini comme une dysfonction d’organe causée par une réponse inappropriée de l’hôte à une infection (augmentation du score SOFA d’au moins 2 points consécutive à l'infection),
     Hypotension persistante nécessitant des drogues vasopressives pour maintenir une PAM ≥ 65 mmHg,
     Taux de lactate sérique > 2 mmol/l malgré un remplissage vasculaire adéquat.
    - Stabilité hémodynamique depuis plus de 30 min avec une pression artérielle moyenne ≥ 65 mmHg et une dose de noradrénaline ≤ 0,5 µg/kg/min,
    - Consentement signé par le patient, le proche ou le représentant légal ou inclusion sous procédure d’urgence.
    E.4Principal exclusion criteria
    Non-inclusion criteria:
    - Ongoing treatment with steroids or other treatment that may act on the hypothalamic-pituitary-adrenal axis,
    - Anaesthetic induction with etomidate in the 6 hours prior to randomization due to its selective inhibitory effect on 11 β-hydroxylase,
    - Known hypersensitivity to fludrocortisone (or one of its excipients), or tetracosactide (Synacthène®),
    - Disorders of gastric emptying (gastric residue > 800 ml),
    - Pregnant or breastfeeding woman,
    - Concomitant participation in another trial that may interfere with study procedures,
    - A person who is not affiliated to social security ,
    - Known situation of deprivation of liberty (safeguarding of justice), guardianship or curatorship,
    - Patient whose life expectancy is less than 24 hours.

    Exclusion criteria:
    - Patients under legal protection will be excluded as soon as the investigator is aware of their status.
    - Hemodynamic worsening with noradrenaline dose > 1.5 µg/kg/min before evaluation of the primary endpoint.
    - Catecholamine withdrawal prior to evaluation of the primary endpoint.
    Critères de non-inclusion:
    - Traitement en cours par stéroïdes ou autre traitement pouvant agir sur l’axe hypothalamo-hypophyso-surrénalien,
    - Induction anesthésique avec de l’étomidate au cours des 6 heures précédant la randomisation compte tenu de son effet inhibiteur sélectif sur la 11 β-hydroxylase,
    - Hypersensibilité connue à la fludrocortisone (ou un de ses excipients), ou au tétracosactide (Synacthène®),
    - Troubles de la vidange gastrique (résidu gastrique > 800 ml),
    - Femme enceinte ou allaitante,
    - Participation concomitante à un autre essai pouvant interférer avec les procédures de l’étude,
    - Personne non affiliée à un régime de la sécurité sociale,
    - Situation connue de privation de liberté (sauvegarde de justice), tutelle ou curatelle,
    - Patient dont l’espérance de vie est inférieure à 24h.

    Critères d'exclusion:
    - Les patients sous sauvegarde de justice seront exclus dès que l’investigateur aura eu connaissance de leur statut.
    - Aggravation hémodynamique avec dose de noradrénaline > 1,5 µg/kg/min avant évaluation du critère de jugement principal.
    - Sevrage en catécholamines avant évaluation du critère de jugement principal.
    E.5 End points
    E.5.1Primary end point(s)
    The main primary endpoint is the vascular reactivity explored by the realization of a pressure dose-response curve judged on the mean blood pressure at increasing doses of norepinephrine.
    Le critère de jugement principal est la réactivité vasculaire explorée par la réalisation d’une courbe de relation dose-réponse pressive jugée sur la pression artérielle moyenne sanglante à des doses croissantes de noradrénaline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is assessed 1.5 hours after the second administration of the treatment or its placebo.
    L'évaluation du critère de jugement principal est réalisée 1,5 h après la deuxième administration du traitement ou de son placebo.
    E.5.2Secondary end point(s)
    Hemodynamics:
    - Heart rate, Systolic, Diastolic and Mean Arterial Pressure measured invasively by an arterial catheter.
    - Cardiac Output, Cardiac Index, Indexed Systemic Vascular Resistances, Evaluation of Cardiac Preload by Indexed Global Telediastolic Volume, "Optimal" Cardiac Preload by ejection volume variability in the ventilated patient and measurement of Indxed Extra Vascular Pulmonary Water with PiCCO® monitor.

    Patient's follow-up:
    - Mortality at D28 and D90,
    - Length of hospitalisation in intensive care, length of hospitalisation in the care unit (excluding rehabilitation)
    - Weaning time for cathecolamines
    - Mechanical ventilation time

    Biological:
    - Adrenal function assessed at inclusion by a Synacthène® test
    - Markers of inflammation: IFNγ, TNF α, IL1β, IL6, IL10
    - Blood and urinary kalemia and natremia

    Pharmacokinetics of fludrocortisone:
    - Area under the plasma concentration-time curve from administration of treatment (t0) to the next dose at 6h (AUC0-6);
    - Area under the plasma concentration-time curve from treatment administration (t0) and extrapolated to infinity (AUC0-∞), according to the formula AUC0-∞ = AUC0-t + Ct/k where Ct is the last measurable plasma concentration and k is the elimination constant of the product;
    - Half-life (t1/2) determined according to the formula t1/2 = Ln2/k ;
    - Apparent total clearance (ClT) and apparent volume of distribution (Vd) calculated according to the formulas ClT = F.Dose/ AUC0-∞ and Vd = ClT/k where F is the absolute bioavailability.
    Hémodynamiques:
    - Fréquence cardiaque, Pressions Artérielles Systolique, Diastolique et Moyenne mesurées de façon invasive par un cathéter artériel.
    - Débit cardiaque, Index cardiaque, Résistances vasculaires systémiques indexées, évaluation de la précharge cardiaque par le volume télédiastolique global indexé, de la précharge cardiaque « optimale » par la variabilité du volume d’éjection chez le patient ventilé et mesure de l’eau pulmonaire extra-vasculaire indéxée grâce au moniteur PiCCO®.

    Devenir des patients
    - Mortalité à J28 et à J90,
    - Durée d’hospitalisation en réanimation, durée d’hospitalisation en service de soins (hors rééducation)
    - Délai de sevrage des cathécolamines
    - Durée de ventilation mécanique

    Biologiques
    - Fonction surrénalienne évaluée à l’inclusion par un test au Synacthène®
    - Marqueurs de l’inflammation : IFNγ, TNF α, IL1β, IL6, IL10
    - Kaliémie et natrémie sanguines et urinaires

    Pharmacocinétique de la fludrocortisone:
    - Aire sous la courbe des concentrations plasmatiques en fonction du temps depuis l’administration du traitement (t0) jusqu’à la prise suivante à 6h (AUC0-6) ;
    - Aire sous la courbe des concentrations plasmatiques en fonction du temps depuis l’administration du traitement (t0) et extrapolée à l’infini (AUC0-∞), selon la formule AUC0-∞ = AUC0-t + Ct/k où Ct est la dernière concentration plasmatique mesurable et k est la constante d’élimination du produit ;
    - Demi-vie (t1/2) déterminée selon la formule t1/2 = Ln2/k ;
    - Clairance totale apparente (ClT) et volume apparent de distribution (Vd) calculés selon les formules ClT = F.Dose/ AUC0-∞ et Vd = ClT/k où F est la biodisponibilité absolue.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Haemodynamic data are collected:
    - before the 1st administration of the experimental drug (fludrocortisone or placebo)
    - at T2 (1.5 hours after the 2nd administration of the experimental drug)
    - when assessing the main judging criterion (at the levels)
    - at T3 (4.5 h after T2)
    - at T4 (6 hours after T3).

    Biological data will be collected:
    - at the inclusion
    - before the 1st administration of fludrocortisone or its placebo
    - 1.5 hours after the 2nd administration of fludrocortisone or its placebo


    Patients will be followed up until D90 maximum.
    Les données hémodynamiques sont recueillies :
    - avant la 1ère administration du médicament expérimental (fludrocortisone ou placebo)
    - à T2 (1,5h après la 2ème administration du médicament expérimental)
    - lors de l’évaluation du critère de jugement principal (aux paliers)
    - à T3 (4.5 h après T2)
    - à T4 (6h après T3).

    Les données biologiques seront recueillies:
    - à l'inclusion
    - avant la 1ère administration de fludrocortisone ou de son placebo
    - 1,5h après la 2ème administration de fludrocortisone ou de son placebo


    Les patients seront suivis jusqu'à J90 maximum.
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    LPLV
    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 months
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 Yes
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients in septic shock might not be able to understand the information and/or give their consent.
    Les patients en choc septiques sont susceptibles de ne pas comprendre l'information et/ou de donner leur consentement.
    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
    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 Decision2021-04-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-15
    P. End of Trial
    P.End of Trial StatusOngoing
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